WO2010148040A1 - Modulation of systemic exposure to rifaximin - Google Patents

Modulation of systemic exposure to rifaximin Download PDF

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Publication number
WO2010148040A1
WO2010148040A1 PCT/US2010/038742 US2010038742W WO2010148040A1 WO 2010148040 A1 WO2010148040 A1 WO 2010148040A1 US 2010038742 W US2010038742 W US 2010038742W WO 2010148040 A1 WO2010148040 A1 WO 2010148040A1
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subject
rifaximin
hepatic insufficiency
subjects
hepatic
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PCT/US2010/038742
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French (fr)
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William Forbes
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Salix Pharmaceuticals, Ltd.
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Priority to RU2012101310/15A priority Critical patent/RU2571268C2/en
Priority to CA2765577A priority patent/CA2765577A1/en
Priority to AU2010260089A priority patent/AU2010260089B2/en
Priority to NZ597080A priority patent/NZ597080A/en
Priority to MX2011013427A priority patent/MX2011013427A/en
Priority to CN2010800370901A priority patent/CN102625701A/en
Priority to EP10790086A priority patent/EP2442803A4/en
Publication of WO2010148040A1 publication Critical patent/WO2010148040A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • Rifaximin (INN; see The Merck Index, XIJI Ed., 8304) is an antibiotic belonging to the rifamycin class of antibiotics, e.g., a pyrido-imidazo rifamycin. It has been reported that rifaximin is characterized by a negligible systemic absorption, due to its chemical and physical characteristics (Descombe J.J. et al. Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res, 14_ (2), 51-56, (1994)).
  • EP 0161534 discloses a process for rifaximin production using rifamycin O as the starting material (The Merck Index, XIII Ed., 8301).
  • rifaximin exhibits differential pharmacokinetics in subjects with hepatic insufficiency as compared to subjects with normal hepatic systems. Accordingly, in one aspect, provided herein are methods of increasing rifaximin systemic exposure (AUCtau) in a subject after oral administration by selecting a subject having hepatic insufficiency, and orally administering rifaximin to the subject, wherein systemic exposure to rifaximin is increased in the subject with hepatic insufficiency as compared to a subject without hepatic insufficiency.
  • AUCtau rifaximin systemic exposure
  • the subject having hepatic insufficiency has a model end stage liver disease (MELD) score of less than 11 for the subject. In another related embodiment, the subject having hepatic insufficiency has a model end stage liver disease (MELD) score of 11 to 18 for the subject.
  • MELD model end stage liver disease
  • the subject having hepatic insufficiency has a Child-Pugh A score. In another embodiment, the subject having hepatic insufficiency has a Child-Pugh B score.
  • the rifaximin systemic exposure in the subject suffering from hepatic insufficiency comprises exposure at least 5-fold higher than in the subject not having hepatic insufficiency. In another embodiment, the rifaximin systemic exposure in the subject suffering from hepatic insufficiency comprises exposure at least 9.6-fold higher than in the subject not having hepatic insufficiency. In another embodiment, the rifaximin systemic exposure in the subject suffering from hepatic insufficiency comprises exposure at least 13.1- fold higher than in the subject not having hepatic insufficiency. In another embodiment, the rifaximin systemic exposure in the subject suffering from hepatic insufficiency comprises exposure between about 5 fold and about 13.1 -fold higher than in the subject not having hepatic insufficiency.
  • the subject having hepatic insufficiency has hepatic encephalopathy.
  • the methods provided herein further comprise administering rifaximin with food.
  • food delays the time to reach maximum plasma concentration.
  • the methods provided herein further comprise selecting a subject susceptible to or suffering from Travelers' diarrhea.
  • the methods provided herein further comprise informing the subject that the elimination rate of rifaximin is decreased in a population of
  • BOS2 775861 1 subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency.
  • rifaximin plasma concentrations C max
  • methods of increasing rifaximin plasma concentrations (C max ) in a subject after oral administration by selecting a subject comprising hepatic insufficiency, and orally administering rifaximin to the subject having hepatic insufficiency, wherein plasma concentrations of rifaximin are increased in the subject with hepatic insufficiency as compared to a subject without hepatic insufficiency.
  • the subject having hepatic insufficiency has an elevated alanine aminotransferase (ALT).
  • ALT alanine aminotransferase
  • the rifaximin plasma concentration in the subject suffering from hepatic insufficiency comprises exposure at least 2-fold higher than in the subject not comprising hepatic insufficiency.
  • the methods provided herein further comprise administering rifaximin with food, thereby delaying the time to reach maximum plasma concentration.
  • the methods further comprise selecting a subject susceptible to or suffering from Travelers' diarrhea.
  • the methods provided herein further comprise informing the subject that the elimination rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency.
  • rifaximin elimination rate in a subject after oral administration by selecting a subject comprising hepatic insufficiency, and orally administering rifaximin to the subject having hepatic insufficiency, wherein elimination rate of rifaximin is decreased in the subject with hepatic insufficiency as compared to a subject without hepatic insufficiency.
  • the rifaximin elimination rate is decreased by at least 25% in the subject with hepatic insufficiency as compared to the subject without hepatic insufficiency.
  • the subject having hepatic insufficiency has a Child-Pugh A score. In another embodiment, the subject having hepatic insufficiency has a Child-Pugh B score.
  • decreasing the elimination rate further comprises increasing the bioavailability of rifaximin in the subject with hepatic insufficiency.
  • the subject having hepatic insufficiency is a subject having at least one sign, symptom or episode of hepatic encephalopathy, or at least one portal systemic shunt.
  • the subject is susceptible to, or suffering from, Traveler's diarrhea.
  • the methods provided herein further comprise informing the subject that the elimination rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency.
  • provided herein are methods of determining a therapeutically effective dose of rifaximin for a subject by selecting a subject comprising hepatic encephalopathy, and determining a therapeutically effective dose in consideration of the subject having hepatic encephalopathy.
  • the subject has or is susceptible to Traveler's diarrhea.
  • the subject is given a dosage that is increased compared to the dose administered to subject that does not have or is not susceptible to hepatic encephalopathy.
  • the subject is given a dosage that is decreased compared to the dose administered to subject that does not have or is not susceptible to hepatic encephalopathy.
  • the methods further comprise informing the subject of one or more of the following: that the elimination rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency; that systemic exposure to rifaximin is increased in a population of subjects with hepatic insufficiency compared to population of subjects without hepatic insufficiency, that the plasma concentration of rifaximin is increased in a population of subjects with hepatic insufficiency compared to population of subjects without hepatic insufficiency, and/or that the clearance rate of rifaximin is decreased in a population of subjects with hepatic insufficiency compared to population of subjects without hepatic insufficiency.
  • kits for determining a therapeutically effective dose of rifaximin for a subject comprising
  • determining a therapeutically effective dose in consideration of one or more of increased systemic exposure to rifaximin, increased plasma concentration of rifaximin, or decreased clearance rate of rifaximin in the subject associated with hepatic insufficiency.
  • the subject having hepatic insufficiency has a Child-Pugh A score. In another embodiment, the subject having hepatic insufficiency has a Child-Pugh B score.
  • the subject has a model end stage liver disease (MELD) score of less than 11.
  • the subject having or susceptible to hepatic insufficiency has a model end stage liver disease (MELD) score of 11 to 18.
  • the subject has an elevated ALT level.
  • the subject has at least one portal systemic shunt. In another embodiment, the subject has had at least one hepatic encephalopathy episode. In another embodiment, the subject has had at least one hepatic encephalopathy episode in the previous six months. In another embodiment, the subject has had at least two hepatic encephalopathy episodes in the previous six months.
  • the methods further comprise selecting a subject susceptible to or suffering from Traveler' s diarrhea.
  • kits for determining a therapeutically effective dose of rifaximin for a subject comprising:
  • determining a therapeutically effective dose in consideration of at least one of increased systemic exposure to rifaximin, increased plasma concentration of rifaximin, or decreased clearance rate of rifaximin in the subject associated with hepatic insufficiency.
  • TD Travelers' Diarrhea
  • methods of treating Travelers' Diarrhea by selecting a subject suffering from or susceptible to TD, instructing the subject to orally administer rifaximin, and informing the subject of one or more of the elimination rate of rifaximin is decreased in a population of subjects with hepatic insufficiency compared to population of subjects without hepatic insufficiency; the systemic exposure to rifaximin is increased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency; plasma concentrations of rifaximin are increased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency; and/or the clearance rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency.
  • the subject having hepatic insufficiency has a Child-Pugh A score. In another embodiment, the subject having hepatic insufficiency has a Child-Pugh B score.
  • the subject has a model end stage liver disease (MELD) score of less than 11.
  • the subject having hepatic insufficiency has a model end stage liver disease (MELD) score of 11 to 18.
  • hepatic insufficiency comprises hepatic encephalopathy.
  • the methods further comprise identifying subjects having hepatic insufficiency. In a related embodiment, the methods further comprise testing subjects for hepatic insufficiency.
  • the methods further comprise altering the amount of rifaximin administered based on the subject having hepatic insufficiency as compared to a subject without hepatic insufficiency.
  • the methods further comprise altering the dosing regime of rifaximin based on the subject having hepatic insufficiency as compared to a subject without hepatic insufficiency.
  • the methods further comprise informing the subject that systemic exposure to rifaximin and/or plasma concentrations of rifaximin are altered with food.
  • kits comprising rifaximin, or a pharmaceutical composition thereof, and instruction for administering to a subject with hepatic insufficiceny.
  • the kit comprises instructions for administering rifaximin to a subject having hepatic encephalopathy.
  • BOS2 775861 1 is a graph showing the mean + SD of the plasma concentration-time profiles of rifaximin on a linear scale.
  • Figure 2 depicts the time to first breakthrough overt HE episode by subgroup.
  • FIG. 3 depicts CLDQ Overall and Individual Domain Twa Results by Treatment Group (ITT Population).
  • Figure 4 depicts CLDQ Overall and Individual Domain T wa Results by Breakthrough Overt HE Status.
  • Figure 5 depicts a comparison of Kaplan-Meier Estimates of Time to First Breakthrough Overt HE Episode.
  • the Placebo Experience vs.
  • the Rifaximin Experience in Placebo Crossover Subjects up to 6 Months of Treatment is shown.
  • Figure 6 depicts the mean PSE values at baseline and at end-of-treatment in clinical studies.
  • Embodiments provided herein relate to the discovery of the difference in systemic exposure, plasma concentration, and terminal elimination rate constant of rifaximin in a subject suffering from hepatic insufficiency as compared to a subject having normal liver function. Further, the invention relates to the discovery of the effect of food on the time to reach maximum plasma concentrations of rifaximin in a subject.
  • HE The main pathogenesis of HE is related to nitrogenous substances derived from the gut adversely affecting brain function.
  • the most influential of these compounds is thought to be ammonia, a byproduct of protein digestion that is normally detoxified by the liver.
  • gut-derived toxins have also been proposed as being responsible for HE.
  • BOS2 775861 1 In patients with chronic liver disease, the occurrence of hepatic encephalopathy is associated with a low quality of life compared to age-matched patients without HE. Overt HE episodes are debilitating, can present without warning, render the patient incapable of self- care, and frequently result in hospitalization. Patients with HE experience symptoms including fatigue, daytime sleepiness, and lack of awareness (Conn score 1); and confusion and disorientation (Conn score 2) that significantly interfere with day-to-day function and decreased ability for self care. Often, this lack of self care leads to improper nutrition and non-adherence to therapy and further escalates into more severe symptoms such as increased somnolence, gross disorientation and stupor (Conn score 3) or coma (Conn score 4).
  • a history of overt HE episodes and the severity of HE episodes were also found to be predictive of decreased survival in patients with chronic liver disease.
  • survival probability was 42% at 1 year and 23% at 3 years after experiencing an HE episode.
  • the occurrence of an HE episode of Conn score 2 in patients with cirrhosis was associated with a 4-fold increase in the risk of death.
  • HE hepatic function
  • GABA gamma- aminobutyric acid
  • Precipitating factors include azotemia (29%), sedatives, tranquilizers, analgesics (24%), gastrointestinal bleeding (18%), excess dietary protein (9%), metabolic alkalosis (11%), infection (3%), constipation (3%).
  • Surgery particularly transjugular intrahepatic portal- systemic shunt (TIPS) procedures, also may precipitate HE.
  • HE due to unknown causes accounts for only 2% of cases.
  • BOS2 775861 1 HE is manifested as a continuum of psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities, poor concentration and in severe forms, as coma. Changes may be observed in personality, consciousness, behavior and neuromuscular function. Neurologic signs may include hyperreflexia, rigidity, myoclonus and asterixis (coarse "flapping" muscle tremor). Cognitive tasks such as connecting numbers with lines can be abnormal. Fetor hepaticus (sweet breath odor) may be present. Electroencephalogram (EEG) tracings show nonspecific slow, triphasic wave activity mainly over the frontal areas. Prothrombin time may be prolonged and not correctable with Vitamin K. A computed tomography scan of the head may be normal or show general atrophy. Finally, signs of liver disease such as jaundice and ascites may be noted.
  • EEG Electroencephalogram
  • Diagnosis of HE is made on the basis of medical history, and physical and mental status examinations with the required clinical elements being knowledge of existent liver disease, precipitating factor(s), and/or prior history of HE.
  • An EEG may show slow-wave activity, even in mild cases.
  • An elevated serum ammonia level is characteristic but not essential, and correlates poorly with the level of encephalopathy
  • Management of patients with chronic HE includes 1) provision of supportive care, 2) identification and removal of precipitating factors, 3) reduction of nitrogenous load from the gut, and 4) assessment of the need for long term therapy.
  • the nitrogenous load from the gut is typically reduced using non-absorbable disaccharide (lactulose) and/or antibiotics.
  • Lactulose is considered a first-line treatment in the United States, but is not currently approved in the U.S. for either the treatment or prevention of HE.
  • Lactulose is metabolized by the intestinal bacteria of the colon, which leads to reduced fecal pH, then to a laxative effect, and finally to fecal elimination.
  • the reduced fecal pH ionizes ammonia (NH 3 ) to the ammonium ion (NH 4 + ) which is used by the bacteria for amino acid and protein synthesis. This lowers the serum ammonia levels and improves mental function.
  • Lactulose is typically used in doses of 30-60 g daily. However, the dose can be titrated up to 20-40 g TID-QID to affect 2-3 semi-formed bowel movements per day. If lactulose cannot be administered orally or per nasogastric tube, for example to patients with stage 3 and 4 HE, it may be given as a 300 cc (200 g) retention enema.
  • BOS2 775861 1 For acute encephalopathy, lactulose can be administered either orally, by mouth or through a nasogastric tube, or via retention enemas.
  • the usual oral dose is 30 g followed by dosing every 1 to 2 hours until evacuation occurs. At that point, dosing is adjusted to attain two or three soft bowel movements daily.
  • Lactulose for is readily available over-the-counter.
  • a convenient and relatively tasteless formulation, often referred to in the trade as "lactulose powder for oral solution” can be obtained, for example, from Bertek Pharmaceuticals, Sugarland, Tex. as Kristalose R TM in 10 and 20 gm packets.
  • the lactulose syrups commonly sold as laxatives include Cephulac R TM, Chronulac R TM, Cholac R TM, and Enulose R TM. These syrups can be substituted for lactulose powder by using sufficient syrup to provide the desired dosage of lactulose; typically, the named syrups contain about 10 gm lactulose in 15 ml of syrup.
  • GI-active antibiotics including neomycin, metronidazole, vancomycin and paromomycin have been used with or without lactulose.
  • Current guidelines recommend neomycin at 1 to 2 g/day by mouth with periodic renal and annual auditory monitoring or metronidazole at 250.
  • Lactulose can induce diarrhea leading to dehydration, a precipitating factor of HE. Additionally, compliance with lactulose is limited by patient dislike of its overly sweet taste.
  • a dosing schedule that is linked to bowel habits and side effects of flatulence, bloating, diarrhea (which leads to dehydration), and acidosis make lactulose difficult to use long-term.
  • Antibiotic use in treatment of HE is hampered by toxicity associated with long-term use. Specifically, systemic absorption of neomycin, metronidazole and ampicillin has led to rare cases of nephrotoxicity, ototoxicity, S. enterocolitis, and/or development of resistant bacterial strains. Additionally, neomycin inhibits only aerobic bacteria. Metronidazole is metabolized slowly in patients with hepatic dysfunction, has a potential for alcohol interactions (disulfiram-like effect), and high blood levels may result in seizures.
  • Rifaximin is a nonaminoglycoside, semisynthetic antibiotic derived from rifamycin O. It is a non-systemic, non-absorbed, broad- spectrum, oral antibiotic specific for enteric pathogens of the GI tract. Rifaximin was found to be advantageous in treatment of HE relative to previously used antibiotics; e.g., negligible systemic absorption ( ⁇ 0.4%) regardless of food intake or presence
  • BOS2 775861 1 of GI disease exhibits no plasma accumulation with high or repeat doses.
  • the lack of systemic absorption makes rifaximin safe and well tolerated, thus improving patient compliance and reducing side effects associated with currently known treatments.
  • Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an antibiotic belonging to the rifamycin class of antibiotics, e.g., a pyrido-imidazo rifamycin.
  • Rifaximin exerts its broad antibacterial activity, for example, in the gastrointestinal tract against localized gastrointestinal bacteria that cause infectious diarrhea, irritable bowel syndrome, small intestinal bacterial overgrowth, Crohn's disease, and/or pancreatic insufficiency. It has been reported that rifaximin is characterized by a negligible systemic absorption, due to its chemical and physical characteristics (Descombe JJ. et al. Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res, 14 (2), 51- 56, (1994)).
  • EP patent 0161534 discloses a process for rifaximin production using rifamycin O as the starting material (The Merck Index, XIJI Ed., 8301).
  • US 7,045,620 Bl discloses polymorphic forms of rifaximin. The applications and patents referred to here are incorporated herein by reference in their entirety for all purposes
  • Embodiments provided herein also relate to administration of medicinal preparations to a subject in need of treatment with compositions, such as rifaximin.
  • Rifaximin is a compound of the rifamycin class of antibiotics.
  • Rifaximin is a compound having the structure of Formula I:
  • rifaximin is a poorly absorbed molecule in certain subjects. This is shown in clinical pharmacokinetic studies in normal subjects following single and multiple oral doses demonstrate that rifaximin is poorly absorbed from the gastrointestinal tract (e.g.,
  • Ragonal includes solvates and polymorphous forms of the molecule, including, for example, ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ and amorphous forms of rifaximin. These forms are described in more detail, for example, in USSN 11/873,841; USSN 11/658,702; EP 05 004 635.2, filed 03 May 2005; USPN 7,045,620; US 61/031,329; and G. C. Viscomi, et al., CrystEngComm, 2008, 10, 1074-1081 (April 2008). Each of these references is hereby incorporated by reference in entirety.
  • Polymorphism refers to the occurrence of different crystalline forms of a single compound in distinct hydrate status, e.g., a property of some compounds and
  • polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as solubility profiles, melting point temperatures, hygroscopicity, particle shape, density, flowability, compactibility and/or x-ray diffraction peaks.
  • solubility of each polymorph may vary, thus, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predictable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.
  • Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry.
  • X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry.
  • polymorphs and the pharmaceutical applications of polymorphs see G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J Pharm. ScL, 58, 911 (1969); and J. K. Haleblian, J. Pharm. ScL, 64, 1269 (1975), all of which are incorporated herein by reference.
  • systemic exposure is intended to mean the exposure of a subject to rifaximin by the administration and subsequent plasma exposure to rifaximin in the subject followed by the distribution throughout the subject's body.
  • Increased systemic exposure can be measured by determining the plasma concentration of rifaximin in a subject.
  • increased systemic exposure can be due to a decrease in the clearance of rifaximin.
  • Hepatic encephalopathy episodes result from central nervous system accumulation of nitrogenous substances derived from the gut (primarily ammonia) due to porto-systemic shunts and portal hypoperfusion associated with hepatic cirrhosis.
  • Subjects having mild and moderate impairment of liver function and a documented history of hepatic encephalopathy episodes were enrolled in the study.
  • Hepatic encephalopathy is a complication of cirrhosis resulting from portal hypertension, cerebral vasodilatation, and hepatic insufficiency.
  • BOS2 775861 1 showed high prevalence of spontaneous portal-systemic shunts in persistent hepatic encephalopathy.
  • subject includes organisms which are capable of suffering from a bowel disorder or other disorder treatable by rifaximin or who could otherwise benefit from the administration of a rifaximin product as described herein, such as human and non-human animals.
  • non-human animals includes all vertebrates, e.g., mammals, e.g., rodents, e.g., mice, and non-mammals, such as non-human primates, e.g., sheep, dog, cow, chickens, amphibians, reptiles, etc.
  • “Susceptible to a bowel disorder,” as used herein, includes subjects at risk of developing a bowel disorder, e.g., subjects suffering from HE, immune suppression, subjects that have been exposed to other subjects with a bacterial infection, subjects with a family history of a bowel disorder, subjects with a gene profile indicating disease or risk of bowel disorder, subjects with known susceptibility to bowel disorder, physicians, nurses, subjects traveling to remote areas known to harbor bacteria that causes travelers' diarrhea, etc.
  • a subject "suffering from hepatic insufficiency" as used herein includes subjects diagnosed with a clinical decrease in liver function, for example, due to hepatic encephalopathy, hepatitis, or cirrhosis. Hepatic insufficiency can be quantified using any of a
  • MELD model end stage liver disease
  • a MELD score uses the patient's values for serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time (INR) to provide a weighted numeric value to correlate with predicted survival.
  • a score of 10-19 correlates with a 27% mortality rate within three months, and a score of ⁇ 10 correlates with a 4% mortality within three months.
  • Methods for determination and analysis of MELD scores are well known in the art.
  • a Child-Pugh score (sometimes the Child- Turcotte-Pugh score) used to assess the prognosis of chronic liver disease, mainly cirrhosis, is an aggregate score of five clinical measures, billirubin, serum albumin, INR, ascites, and hepatic encephalopathy. Each marker is assigned a value from 1-3, and the total value is used to provide a score categorized as A (5-6 points), B (7-9 points), or C (10-15 points), which can be correlated with one and two year survival rates. Methods for determination and analysis of Child-Pugh scores are well known in the art. Measurements of change in mental status may be done, for example, by the Conn score (also known as the West Haven score).
  • the Conn score has been widely used as a measure of mental state in HE studies and is based on the criteria of Parsons- Smith as modified by Conn. Asterixis will not be considered when assessing the subject's status using the Conn scoring criteria listed below.
  • the scale used in the Conn scoring system is provided below.
  • Grade 0 No personality or behavioral abnormality detected
  • Grade 1 Rare flapping motions
  • Grade 2 Occasional, irregular flaps
  • Grade 3 Frequent flaps
  • Grade 4 Almost continuous flapping motions.
  • Efficacy in regard to asterixis grade can be measured as time to any increase from baseline in asterixis grade. Time to an increase in asterixis grade was computed as the number of days from the first dose of rifaximin to the initial occurrence of an increase from baseline in asterixis grade.
  • a prophylactically effective amount of a compound refers to an amount of a compound provided herein of formula (I) or otherwise described herein which is effective upon single or multiple dose administration to the subject in preventing or treating a bacterial infection or HE.
  • therapeutically effective amount refers to an amount of an agent which is effective, upon single or multiple dose administration to the subject to provide a therapeutic benefit to the subject.
  • therapeutic benefit is inhibiting a bacterial infection or prolonging the survival of a subject with such a bacterial infection beyond that expected in the absence of such treatment.
  • Rifaximin exerts a broad antibacterial activity in the gastrointestinal tract against localized gastrointestinal bacteria that cause infectious diarrhea, including anaerobic strains. It has been reported that rifaximin is characterized by a negligible systemic absorption, due to its chemical and physical characteristics (Descombe JJ. et al. Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res, 14_ (2), 51-56, (1994)).
  • BOS2 775861 1 professional e.g., physician, physician's assistant, nurse practitioner, pharmacist
  • a dose of rifaximin for treatment of a bowel disorder such as Travelers' diarrhea or IBS.
  • Hepatic insufficiency leads to a clinically statistically significant increase in rifaximin adsorbed by subjects undergoing treatment.
  • One embodiment, disclosed herein are methods of modulating the therapeutic action of rifaximin by selecting a subject suffering from hepatic insufficiency and further providing prophylaxis or treatment for the hepatic insufficiency.
  • one embodiment is a method of treating Travelers' Diarrhea (TD) in a subject.
  • rifaximin is administered to a subject suffering from a disease that is treatable by rifaximin.
  • the subject is informed that systemic plasma exposure to rifaximin is increased in subjects suffering from hepatic insufficiency in comparison to subjects not suffering from hepatic insufficiency.
  • This information increases the level of safety of administering the rifaximin to the subject.
  • diseases treatable by rifaximin include Travelers' Diarrhea and Hepatic Encephalopathy.
  • "informing" or “advising” means referring to or providing, published or oral material.
  • providing an active agent with published material to a user or presenting information orally, for example, by presentation at a seminar, conference, or other educational presentation, by conversation between a pharmaceutical sales representative and a medical care worker, or by conversation between a medical care worker and a patient; or demonstrating the intended information to a user for the purpose of comprehension.
  • medical care workers include physicians, nurses and nurse practitioners.
  • One aspect of this invention includes providing information to prescribing physicians and patients receiving rifaximin treatment useful in minimizing safety concerns of rifaximin.
  • the information describes that systemic plasma exposure to rifaximin is increased in subjects suffering from hepatic insufficiency in comparison to subjects not suffering from hepatic insufficiency.
  • the information is provided on a label.
  • the information is provided on an information sheet that is given to the patient when a prescription for rifaximin is filled.
  • the method may also include the step or steps of distributing prescribable doses of rifaximin to pharmacies and distributing educational materials to the pharmacies
  • BOS2 775861 1 including pharmacists with the educational material including information as to what the patient needs to know and what the patients must do in order to both avoid any adverse effects of rifaximin while taking the doses.
  • the method may include the step or steps of providing guidelines to the pharmacists for counseling patients with regard to what the patient needs to know and what the patient must do in order to safely take their rifaximin dosages.
  • the method may further include the step of requiring acknowledgment of receipt of the educational materials and guidelines from the pharmacists and further acknowledgement of receipt of the educational materials by the patient from the pharmacists.
  • Another embodiment is a method of using rifaximin for treating a patient's condition.
  • the embodiment includes providing a patient with rifaximin and informing the patient or a medical care worker that systemic plasma exposure to rifaximin is increased in patients suffering from hepatic insufficiency, and that administration of rifaximin to a patient with hepatic insufficiency can affect plasma concentration, safety, or efficacy of rifaximin.
  • Yet another embodiment includes a method of treating a subject suffering from an indication treatable by rifaximin. This method includes administering rifaximin to the subject and advising the subject that systemic plasma exposure to rifaximin is increased in subjects suffering from hepatic insufficiency in comparison to subjects not suffering from hepatic insufficiency.
  • Bowel related disorders include one or more of hepatic insufficiency, cirrhosis, polycystic liver disease, irritable bowel syndrome, diarrhea, microbe associated diarrhea, Clostridium difficile associated diarrhea, travelers' diarrhea, small intestinal bacterial overgrowth, Crohn's disease, chronic pancreatitis, pancreatic insufficiency, enteritis, colitis, hepatic encephalopathy (or other disease which leads to increases ammonia levels), or pouchitis.
  • hepatic insufficiency includes diseases and disorders in which a subject has defective functional activity of the liver. Clinically, subjects having
  • BOS2 775861 1 hepatic insufficiency have decreased, e.g., statistically significantly decreased, liver function. Hepatic insufficiency often leads to liver failure.
  • One exemplary disease which manifests hepatic insufficiency is hepatic encephalopathy.
  • hepatic encephalopathy refers to a reversible neuropsychiatric abnormality in the setting of chronic or acute liver failure.
  • toxic substances that are normally removed by the liver accumulate in the blood, thereby impairing the function of the brain. These toxic substances are often nitrogenous substances, most notably ammonia.
  • the compounds produce alterations of neurotransmission that affect consciousness and behavior.
  • There are 4 progressive stages of impairment associated with HE that are defined by using the West Haven criteria (or Conn score) which range from Stage 0 (lack of detectable changes in personality) to Stage 4 (coma, decerebrate posturing, dilated pupils).
  • Typical symptoms of hepatic encephalopathy can include impaired cognition, a flapping tremor (asterixis), and a decreased level of consciousness including coma (e.g., hepatic coma), cerebral edema, and, possibly, death.
  • Hepatic encephalopathy is commonly called hepatic coma or portal-systemic encephalopathy in the literature.
  • the term "Travelers' diarrhea” refers to gastrointestinal illness common amongst travelers. The majority of cases are caused by bacterial, viral or protozoan infection. The primary source of infection is ingestion of fecally contaminated food or water. The length of treatment for a particular bowel disorder will depend in part on the disorder. For example, HE may be treated every day for the remainder of a subject's life, travelers' diarrhea may only require treatment duration of 12 to about 72 hours, while Crohn's disease may require treatment durations from about 2 days to 3 months. Dosages of rifaximin will also vary depending on the diseases state. The identification of those subjects who are in need of prophylactic treatment for bowel disorder is well within the ability and knowledge of one skilled in the art.
  • BOS2 775861 1 identify such candidate subjects, by the use of, for example, clinical tests, physical examination and medical/family/travel history.
  • a method of assessing the amount of hepatic insufficiency in a subject can include the use of any of the scoring systems provided above, such as a MELD score, a Child-Pugh score, of a Conn score.
  • a method of treating a subject suffering from or susceptible to a bowel disorder comprises administering to a subject in need thereof a therapeutically effective amount of a rifaximin to thereby treat the subject.
  • rifaximin is administered.
  • Rifaximin may be administered, for example, after diagnosis, after an HE event, during an HE event, after diagnosis of minimal HE, or when the critical flicker frequency reaches a level indicative of an HE event, etc.
  • a physician may choose to alter the dosage of rifaximin administered to a subject for the treatment of a bowel disorder if the subject also has hepatic insufficiency.
  • Efficacy of a treatment may be measured, for example, as reduction of bacterial overgrowth. Efficacy may also be measured in terms of a reduction of symptoms associated with the bowel disorder, a stabilization of symptoms, or a cessation of symptoms associated with a bowel disorder, for example, a reduction in one or more of nausea, bloating, diarrhea, the severity of the next HE event, and the like, or an increase in one or more of time to next HE event, cognitive ability and the like.
  • One embodiment is a method of treating or preventing hepatic encephalopathy (HE) by administering a therapeutically effective amount of a rifaximin to a subject.
  • HE hepatic encephalopathy
  • Embodiments of the invention relate to the discovery of the efficacy rifaximin for the treatment and prevention of Hepatic Encephalopathy.
  • Embodiments relate to the use of rifaximin to prevent the onset of HE symptoms and also to lengthen the time to a first breakthrough HE episode.
  • the time to a first breakthrough HE episode was measured by an increase of the Conn score to Grade > 2 (e.g., 0 or 1 to > 2) or a Conn and asterixis score increase of one grade each for those subjects that have a baseline Conn Score of 0.
  • the time to breakthrough HE episode was measured by the time to any increase from baseline in either the Conn score (mental state grade) or
  • BOS2 775861 1 asterixis grade with Kaplan-Meier estimates of cumulative proportions of subjects with any increase at Days 28, 56, 84, 112, 140, and 168.
  • Another embodiment was a mean change from baseline in blood ammonia concentration over time or a mean change from baseline in critical flicker frequency values over time.
  • An additional embodiment was indicated by a mean daily lactulose consumption over time, shifts from baseline in Conn scores over time; or shifts from baseline in asterixis grades over time. Unless otherwise specified, a shift of a value is the change of that value from a baseline value.
  • CLDQ Chronic Liver Disease Questionnaire
  • Epworth Sleepiness Scale measures of efficacy of the treatments described herein included mean change from baseline in Chronic Liver Disease Questionnaire (CLDQ) scores over time; mean change from baseline in Epworth Sleepiness Scale scores over time; and proportion of subjects who have an Epworth Sleepiness Scale score >10.
  • CLDQ Chronic Liver Disease Questionnaire
  • Epworth Sleepiness Scale measures of efficacy of the treatments described herein included mean change from baseline in Chronic Liver Disease Questionnaire (CLDQ) scores over time; mean change from baseline in Epworth Sleepiness Scale scores over time; and proportion of subjects who have an Epworth Sleepiness Scale score >10.
  • the evaluation of severity of persistent hepatic encephalopathy may also be based, for example, on Conn scores.
  • a subject suffering from, susceptible to or in remission from hepatic encephalopathy can be administered rifaximin for between about 24 weeks and 24 months.
  • rifaximin may be administered to the subject for 12 months and longer, for example for a subject's entire life span.
  • rifaximin is administered daily until the death of the subject.
  • the invention relates to a method of decreasing a subject's risk of having a breakthrough event by administering to the subject a rifaximin.
  • the risk of failure occurrence was reduced by 58%.
  • the risk of failure occurrence was reduced by between about 30 - 70%.
  • the risk was reduced by about 40% to 70%.
  • the risk of failure occurrence was decreased by between about 60%.
  • the risk of failure occurrence was decreased by between about 2% - 80%.
  • BOS2 775861 1 by about a 56%.
  • the risk of a breakthrough HE episode was decreased by between about a 20% - 70%.
  • the risk of a breakthrough HE episode was reduced by about 63%. In another embodiment, the risk was reduced by about 30% - 80%.
  • terminal elimination rate constant refers to the first order rate constant describing rifaximin elimination from the body of a subject. This is an overall elimination rate constant describing removal of rifaximin by all elimination processes including excretion and metabolism.
  • plasma concentration refers to concentaration of rifaximin in the plasma of a subject. Plasma concentrations of rifaximin can be determined, for example, using a reversed-phase high performance liquid chromatographic method with tandem quadrupole mass spectrometric detection (LC/MS/MS) as set forth in the Examples. The maximum plasma concentration at steady-state is referend to herein as Cmax and the minimum plasma conceration is referred to as Cmin.
  • the term "clearance rate” refers to the volume of biological fluid completely cleared of drug metabolites as measured in unit time. Elimination occurs as a result of metabolic processes in the kidney, liver, saliva, sweat, intestine, heart, brain, and other locations.
  • alanine aminotransferase also referred to as ALT, refers to a test preformed in order to identify liver damage or liver failure. The level of the enzyme, ALT, is measured to determine if liver damage or disease is present in an individual. Low levels of ALT are normally found in the blood. But when the liver is damaged or diseased, ALT is released into the bloodstream. ALT levels can be measured by methods known to those of skill in the art.
  • Embodiments also provide pharmaceutical compositions, comprising an effective amount of a rifaximin described herein and a pharmaceutically acceptable carrier.
  • the effective amount is effective to treat a bacterial infection, e.g., small intestinal bacterial overgrowth, Crohn's disease, hepatic encephalopathy, antibiotic
  • BOS2 775861 1 associated colitis, and/or diverticular disease in a subject further suffering from hepatic insufficiency.
  • Embodiments also provide pharmaceutical compositions comprising rifaximin and a pharmaceutically acceptable carrier.
  • Doses may be selected, for example on the basis of desired amounts of systemic absorption, elimination rate, plasma concentration and the like.
  • Embodiments of the pharmaceutical composition further comprise excipients, for example, one or more of a diluting agent, binding agent, lubricating agent, disintegrating agent, coloring agent, flavoring agent or sweetening agent.
  • excipients for example, one or more of a diluting agent, binding agent, lubricating agent, disintegrating agent, coloring agent, flavoring agent or sweetening agent.
  • One composition may be formulated for selected coated and uncoated tablets, hard and soft gelatin capsules, sugar-coated pills, lozenges, wafer sheets, pellets and powders in sealed packet.
  • compositions may be formulated for topical use, for example, ointments, pomades, creams, gels and lotions.
  • rifaximin is administered to the subject using a pharmaceutically- acceptable formulation, e.g., a pharmaceutically-acceptable formulation that provides sustained delivery of the rifaximin to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically- acceptable formulation is administered to the subject.
  • these pharmaceutical compositions are suitable for topical or oral administration to a subject.
  • compositions provided herein may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous,
  • BOS2 775861 1 intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • phrases "pharmaceutically acceptable” refers to rifaximin compositions containing rifaximin and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier includes pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier is preferably “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • the active ingredient is typically mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate,
  • BOS2 775861 1 and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions described herein may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents
  • BOS2 775861 1 agents may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of rifaximin include pharmaceutically- acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to rifaximin may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • compositions for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing rifaximin with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
  • compositions which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of rifaximin includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • Rifaximin may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • Ointments, pastes, creams and gels may contain, in addition to rifaximin, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to rifaximin, excipients such as lactose, talc, silicic acid, aluminium hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Rifaximin can be alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers are preferred because they minimize exposing the agent to shear, which can result in degradation of the compound.
  • a non-aqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers are preferred because they minimize exposing the agent to shear, which can result in degradation of the compound.
  • Injectable depot forms are made by forming microencapsule matrices of rifaximin in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly( anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the rifaximin When the rifaximin is administered as a pharmaceutical, to humans and animals, it can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically- acceptable carrier.
  • BOS2 775861 1 Regardless of the route of administration selected rifaximin which may be used in a pharmaceutical compositions provided herein, is formulated into pharmaceutically-acceptable dosage forms by methods known to those of skill in the art.
  • Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject.
  • An exemplary dose range is from 25 to 3000 mg per day.
  • rifaximin is the maximum that a subject can tolerate without developing serious side effects.
  • rifaximin is administered at a concentration of about 1 mg to about 200 mg per kilogram of body weight, about 10 - about 100 mg/kg or about 40 mg - about 80 mg/kg of body weight. Ranges intermediate to the above-recited values are also intended to be part of the invention.
  • subjects are administered rifaximin 1, 2, 3, or 4 times a day.
  • Exemplary dosages include oral dosages of 100, 200, 300, 400, 500, 550, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900 or 2000 mg of rifaximin. Ranges intermediate to the above-recited values are also intended to be part of the invention.
  • subjects are administered 600mg or rifaximin per day.
  • subjects are administered three 200 mg tablets per day.
  • rifaximin and the other drug agent(s) are administered to mammals (e.g., humans, male or female) by conventional methods.
  • the agents may be administered in a single dosage form or in separate dosage forms.
  • Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective-amount range.
  • the effective amount of the rifaximin is less than its effective amount in case the other therapeutic agent is not administered.
  • the effective amount of the conventional agent is less than its effective amount in case the rifaximin is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized.
  • Other potential advantages including without limitation
  • the therapies are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part.
  • two or more therapies are administered within the same subject's visit.
  • one or more therapies are administered within the same subject's visit.
  • one or more therapies are administered within the
  • Cycling therapy involves the administration of a first therapy (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by the administration of a second therapy (e.g., a second prophylactic or therapeutic agent) for a period of time, optionally, followed by the administration of a third therapy (e.g., prophylactic or therapeutic agent) for a period of time and so forth, and repeating this sequential administration, e.g., the cycle in order to reduce the development of resistance to one of the therapies, to avoid or reduce the side effects of one of the therapies, and/or to improve the efficacy of the therapies.
  • a first therapy e.g., a first prophylactic or therapeutic agent
  • a second therapy e.g., a second prophylactic or therapeutic agent
  • a third therapy e.g., prophylactic or therapeutic agent
  • the administration of the same compounds may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or at least 6 months.
  • the administration of the same therapy (e.g., prophylactic or therapeutic agent) other than rifaximin may be repeated and the administration may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or at least 6 months.
  • BOS2 775861 1 Certain indications may require longer treatment times. For example, travelers' diarrhea treatment may only last from between about 12 hours to about 72 hours, while a treatment for Crohn's disease may be from between about 1 day to about 3 months.
  • a treatment for hepatic encephalopathy may be, for example, for the remainder of the subject's life span.
  • a treatment for IBS may be intermittent for weeks or months at a time or for the remainder of the subject's life.
  • Another embodiment includes articles of manufacture that comprise, for example, a container holding a pharmaceutical composition suitable for oral or topical administration of rifaximin in combination with printed labeling instructions providing a discussion of when a particular dosage form should be administered with food and when it should be taken on an empty stomach.
  • the dosage can be modified for administration to a subject suffering from hepatic insufficiency, or include labeling for administration to a subject suffering from hepatic insufficiency. Exemplary dosage forms and administration protocols are described infra.
  • the composition will be contained in any suitable container capable of holding and dispensing the dosage form and which will not significantly interact with the composition and will further be in physical relation with the appropriate labeling.
  • the labeling instructions will be consistent with the methods of treatment as described hereinbefore.
  • the labeling may be associated with the container by any means that maintain a physical proximity of the two, by way of non-limiting example, they may both be contained in a packaging material such as a box or plastic shrink wrap or may be associated with the instructions being bonded to the container such as with glue that does not obscure the labeling instructions or other bonding or holding means.
  • Another aspect is an article of manufacture that comprises a container containing a pharmaceutical composition comprising rifaximin wherein the container holds preferably rifaximin composition in unit dosage form and is associated with printed labeling instructions advising of the differing absorption when the pharmaceutical composition is taken with and without food.
  • a article of manufacture or a kit comprising rifaximin, or a pharmaceutical composition thereof, packaged with instructions for
  • the instructions will inform the prescribing physician, a pharmacist, or a subject that subjects having hepatic encephalopathy absorb a larger amount of rifaximin systemically than subject with normal, e.g., fully functional, hepatic systems.
  • the instructions will advise the prescribing physician that they should determine if the subject has hepatic insufficiency before prescribing rifaximin to a subject to treat a bowel disease.
  • the instructions will advise the prescribing physician that they should consider altering the dosage or dosing regimen when prescribing rifaximin to a subject having hepatic encephalopathy.
  • the instructions may provide prescribing information for subjects with hepatic insufficiency.
  • the instructions will inform the subject and/or the healthcare provider that there is a difference in the plasma exposure to rifaximin between HE subjects and subjects with normal liver function.
  • compositions are also provided, and may comprise a therapeutically effective amount of rifaximin.
  • Rifaximin and a pharmaceutically acceptable carrier or diluent, wherein the composition is formulated for treating a subject suffering from or susceptible to a bowel disorder, and packaged with instructions to treat a subject suffering from or susceptible to a bowel disorder.
  • Kits are also provided herein, for example, kits for treating a bowel disorder in a subject.
  • the kits may contain, for example, rifaximin and instructions for use when treating a subject for a bowel disorder who is also suffering from hepatic insufficiency.
  • the instructions for use may contain prescribing information, dosage information, storage information, and the like.
  • compositions are also provided, and may comprise a therapeutically effective amount of rifaximin and a pharmaceutically acceptable carrier or diluent, wherein the composition is formulated for treating a subject suffering from or susceptible to a bowel disorder, and packaged with instructions to treat a subject suffering from or susceptible to a bowel disorder.
  • Embodiments of the invention are based, in part, on the demonstration that rifaximin is differentially absorbed in subjects having other clinical conditions, e.g., hepatic encephalopathy. It should be appreciated that the invention should not be construed to be limited to the examples that are now described; rather, the invention should be construed to include any and all applications provided herein and all equivalent variations within the skill of the ordinary artisan.
  • HE hepatic encephalopathy
  • lactulose nonabsorbable disaccharide
  • lactulose is considered a first-line treatment in the United States, it is not currently approved for either the treatment or prevention of HE.
  • Rifaximin is an attractive therapy for the treatment of patients with HE because of its demonstrated effectiveness and because of disadvantages of systemic antibiotics and nonabsorbable disaccharides.
  • Disadvantages of chronic systemic antibiotic therapy include nephrotoxicity and ototoxicity, and disadvantages of lactulose therapy include dehydration due to diarrhea (a precipitating factor of HE), overly sweet taste, and GI side effects.
  • rifaximin was dosed in an outpatient setting at 550 mg BID (for a total daily dose of 1100 mg rifaximin). Subjects were dosed with 550 mg of rifaximin BID for at least 7 consecutive days prior to the day of pharmacokinetic sampling.
  • Blood samples for pharmacokinetic analyses were collected on a single day at after at least 7 consecutive days of 100% compliance with the rifaximin 550 mg BID dosing regimen.
  • Pharmacokinetic parameters of rifaximin in plasma were calculated using noncompartmental methods (e.g., standard model-independent approach).
  • Pharmacokinetic sample collection occurred on a single day following at least 7 consecutive days of 100% compliance with the rifaximin 550 mg BID dosing regimen.
  • a total of 8 blood samples were collected over 12 hours (e.g., predose and at 1, 2, 4, 6, 8, 10, and 12 hours after dosing) to permit characterization of the individual plasma rifaximin concentration-time profile over the 12-hour dosing interval.
  • Plasma concentrations of rifaximin were determined using a reversed-phase high performance liquid chromatographic method with tandem quadrupole mass spectrometric detection (LC/MS/MS) using a validated analytical procedure.
  • LC/MS/MS tandem quadrupole mass spectrometric detection
  • Pharmacokinetic parameters were calculated using noncompartmental methods (e.g., standard model-independent approach). The following steady-state pharmacokinetic
  • BOS2 775861 1 parameters for rifaximin in plasma were calculated using actual concentration-time profiles for each subject:
  • Demographics and other baseline characteristics were summarized for subjects by hepatic impairment severity using Child-Pugh scores (A and B) and Model End-Stage Liver Disease (MELD) score with descriptive statistics.
  • Baseline characteristics included albumin, alkaline phosphate, alanine aminotransferase (ALT), aspartate aminotransferase (AST), international normalized ratio (INR), serum creatinine, and serum total bilirubin, where baseline was defined as last available assessment prior to the first dose of rifaximin.
  • Rifaximin pharmacokinetic parameters AUC ⁇ and C max in subjects with Child-Pugh scores A and B were compared using an analysis of variance (ANOVA) model.
  • BOS2 775861 1 A total of 25 subjects were included in the pharmacokinetic evaluable population and evaluated for safety.
  • Table 1 summarizes demographics for all enrolled subjects. A total of 25 subjects were enrolled in the study; 17 subjects (68.0%) were male and 8 subjects (32.0%) were female. The mean age among participating subjects was 58 years (range 45 to 68 years).
  • MELD model end-stage liver disease. Overall, demographic characteristics were comparable for Child-Pugh A and Child-
  • the 2 nd rifaximin dose was administered without regard to the evening meal, either before food (13 subjects) or after food (12 subjects).
  • the morning rifaximin dose was administered following at least 10 hours of overnight fasting. All subjects had a light meal served 1 hour postdose, subsequent to the 1 hour pharmacokinetic plasma sampling time point. The next rifaximin dose was taken immediately after the 12-hour pharmacokinetic plasma sampling time point, with 1 exception.
  • Table 2 summarizes pharmacokinetic parameters of rifaximin following at least 7 days of treatments in subjects with impaired liver function by Child-Pugh scores and for the overall pharmacokinetic population. A column including the values determined for the healthy subjects in a separate study is provided to facilitate comparison.
  • BOS2 775861 1 an ANOVA model. For cases where the AUC ⁇ could not be calculated the corresponding AUCo-t values were used for inferential statistics.
  • Child- 81
  • rifaximin systemic exposure values were approximately 9.6- and 13.1-fold higher, respectively, than those observed in healthy subjects at steady-state.
  • BOS2 775861.1 Systemic exposure was compared using a different method to assess liver function, MELD score.
  • Rifaximin was rapidly absorbed, with peak plasma concentration observed at 1 hour post-dose in the vast majority of subjects.
  • BOS2 775861.1 observed in healthy subjects following twice daily oral doses of 550 mg (12.3 ng*h/mL), respectively. Except for ty 2> intersubject variabilites in the pharmacokinetics of healthy subjects were generally similar to those measured in subjects with hepatic impairment.
  • a multivariate linear regression model was developed to evaluate the effect of various covariates on the rifaximin AUC ⁇ , C max, and CL/F.
  • the following covariates were tested in the model: Child-Pugh score and laboratory test results (albumin, alkaline phosphatase, ALT, AST, creatinine clearance, serum creatinine, INR, and total bilirubin).
  • the covariates chosen for the analysis are known indicators of hepatic and renal function.
  • a visual diagnostic was performed to detect potential trends between covariates of interest and AUC ⁇ , C max , and CL/F.
  • biochemical markers of impaired hepatic function e.g., elevated albumin, total bilirubin, and INR values correlated with elevated rifaximin systemic exposure (AUC ⁇ and C max ) and decreased oral clearance (CL/F) in this study.
  • the final model for AUC ⁇ is presented in Table 7.
  • the parsimonious model would include 4 parameters: albumin, total bilirubin, INR, and ALT.
  • a pharmacokinetic investigation was performed in subjects with HE in a dose-finding study.
  • a total of 54 subjects 32 male, 22 female, age 32 through 82 years) were included in the study and received 200, 400, or 800 mg rifaximin TID (200 mg tablets) corresponding to daily doses of 600, 1200, and 2400 mg, respectively, for 7 consecutive days.
  • the urine recovery of rifaximin is provided in Table 10.
  • Mean maximum rifaximin plasma concentrations of 2.7, 10.5, and 13.5 ng/mL were measured 3 h after the first single dose of 200, 400, and 800 mg rifaximin, respectively.
  • BOS2 775861 1 Rifaximin was rapidly absorbed, with peak plasma concentration observed at 1 h post- dose in the vast majority of subjects.
  • a total of 3 subjects in the Child-Pugh A group had delayed rifaximin absorption, with peak plasma concentration observed between 6 and 10 h post-dose.
  • results of the multiple linear regression models showed that biochemical markers of hepatic function, e.g., elevated albumin, total bilirubin, and International Normalized Ratio, correlated with increased rifaximin systemic exposure (AUC tau and C max ) and decreased oral clearance (CL/F). A positive correlation between baseline alanine aminotransferase and C max was also observed.
  • biochemical markers of hepatic function e.g., elevated albumin, total bilirubin, and International Normalized Ratio
  • This population included 18 subjects (72%) with mild hepatic impairment (Child-Pugh A) and 7 subjects with moderate hepatic impairment (Child-Pugh B).
  • the healthy subject study included 28 subjects.
  • Rifaximin exposure values (AUC tau ) in subjects with Child-Pugh score A and B were approximately 9.6- and 13.1-fold higher, respectively, than those observed in healthy subjects following twice daily oral doses of 550 mg (12.3 ng»h/mL). Except for t /2 intersubject variability in the pharmacokinetics of healthy subjects were generally similar to those measured in subjects with hepatic impairment.
  • a phase 3 randomized, double-blind, placebo-controlled multicenter study (Study A) to evaluate the efficacy and safety of rifaximin in patients currently in remission from previously demonstrated HE was conducted.
  • the study consisted of a screening period (4 days), observation period (3 days), baseline visit, and treatment period (6 months). After determining eligibility, patients underwent a baseline assessment period prior to randomization. This period was 7 days in duration and was used to determine the patient's eligibility, provide adequate instructions to caregivers and establish baseline mental status
  • BOS2 775861 1 and neuromuscular function before entering the double-blind period were randomized to received rifaximin 550-mg tablet BID or matching placebo tablet BID for 6 months. Subjects had the option to use lactulose as a concomitant medication, and 91% of subjects in both groups were taking lactulose during the course of the study. Subjects underwent extensive evaluations of mental status (Conn score) and neuromuscular functioning (asterixis grade) for determination of the occurrence of a breakthrough overt HE episode by the investigators and site personnel at each in-person study visit, telephone interviews, caregiver reports, and from subject diaries. Subjects were discontinued from the study at the time of breakthrough overt HE episode. After participation in the study subjects had the option to enroll in the open-label, treatment-extension study (Study B).
  • the dosage regimen used (550 mg BID) in Study A was based on past clinical experience with rifaximin in patients with HE and other subject populations. In several previous studies, rifaximin was safe and effective in subjects with HE at a dose of 1200 mg per day (2 x 200 mg tablets TID) with or without concomitant lactulose. In a 6-month study of rifaximin versus neomycin, rifaximin 1200 mg/day and neomycin (3 g/day) had comparable efficacy in patients with HE. In the 3-month studies of rifaximin versus lactitol, subjects who received rifaximin 1200 mg daily (2 x 200 mg tablets TID) showed significant improvements in HE endpoints.
  • PSE portal systemic encephalopathy
  • EEG electroencephalogram
  • a PSE index was calculated as follows: [Mental State (Conn score) X 3 + asterixis grade X l + NCT grade X l + ammom grade X 1 + EEG grade X 1 (if available) / 24 (or 28 if EEG is available)]. (24 [or 28 if EEG results are included] is the highe possible score and higher scores are indicative of worse symptoms of HE.)
  • Study Population For Study A male or female subjects aged 18 years and older were eligible for the study if they met the following inclusion criteria: o Conn score 0 or 1 o History within 6 months of > 2 episodes of overt HE associated with chronic liver disease (eg, cirrhosis or portal hypertension) with a documented severity equivalent to Conn score > 2 prior to screening (ie, subjects had documented recurrent, overt HE). At least 1 prior episode was verified from medical records.
  • chronic liver disease eg, cirrhosis or portal hypertension
  • Hepatic encephalopathy episodes primarily attributed to GI hemorrhage, medications (eg, narcotics, tranquilizers, sedatives), renal failures requiring dialysis, or CNS insult such as a subdural hematoma were not counted as prior, qualifying episodes of HE.
  • BOS2 775861 1 o Consume alcohol within 14 days of screening, sedatives within 7 days or evidence of drug dependence o HF/ as determined by medical history o History of TB infection or treatment for a TB infection o Active SBP or daily prophylactic antibiotic therapy o GI bleeding requiring hospitalization and blood transfusion ⁇ months of screening o Presence of intestinal obstruction or had inflammatory bowel disease o Renal insufficiency (serum Cr > 2.0 mg/dL) o Anemia (HgB ⁇ 8 gm/dL) o Hypovolemia or electrolyte abnormality (Na+ ⁇ 125 mEq/L, Ca++ > 10 mg/dL, K+ ⁇ 2.5 mEq/L o Required prohibited concurrent medications
  • a breakthrough overt HE episode was defined as an increase of Conn score to Grade > 2 (ie, 0 or 1 to > 2) or an increase in Conn and asterixis score of 1 grade each for those subjects who entered the study with a Conn score of 0.
  • Time to breakthrough overt HE episode was the duration from first dose of study drug to the first breakthrough overt HE episode. Key secondary endpoints are listed below:
  • Hepatic encephalopathy baseline characteristics in the ITT population such as HE severity for recent episodes of overt HE (Conn scores and asterixis grades) and time since last HE episode are summarized in
  • liver disease characteristics and other characteristics of subjects at baseline in the ITT population such as disease severity (MELD score), time since first diagnosis of advanced liver disease and etiology of liver disease are summarized in Tables 15, 16 and 17. Baseline characteristics were generally comparable across the treatment groups.
  • MELD Model end-stage liver disease
  • MELD Model end-stage liver disease
  • NAFLD/NASH 17 (11) 13 (9) Hepatitis B 13* (8) 11 (8) Cryptogenic 11 (7) 9 (6) Autoimmune Hepatitis 1 (1) 9 (6) Primary Biliary cirrhosis 5 (3) 4 (3) Drug/chemical induced 1 (1) 2 (1) Genetic 2 (1) 0
  • Gastrointestinal 145 (91) 122 (87) 324 (93)
  • Study B is an ongoing phase 3, multicenter, open-label, treatment-extension study evaluating the long-term safety of rifaximin 550 mg BID in subjects with a history of recurrent, episodic, overt HE. All eligible subjects had a history of overt HE episodes with a documented severity of Conn score > 2 within 12 months prior to screening, a Conn score of ⁇ 2 at enrollment, and either had participated in Study A or were new subjects. Treatment with rifaximin 550 mg tablet BID is planned for at least 24 months or until regulatory approval. Concomitant therapy with lactulose is optional.
  • Study B was primarily designed to evaluate the long-term safety of rifaximin 550 mg, additional efficacy assessments of Conn score and asterixis grade were collected during the study.
  • breakthrough overt HE was defined as an increase of Conn score to Grade > 2, an increase in Conn and asterixis score of 1 grade each for those subjects who entered the study with a Conn score of 0, and an increase in Conn score to > 3 for subjects who had a Conn score of 2 at study entry.
  • Study C was a double-blind, dose-ranging study in subjects with Grade 1-3 HE enrolled at 5 centers in the United Kingdom. Subjects were randomized to rifaximin at daily doses of 600 mg (200 mg TID), 1200 mg (400 mg TID), or 2400 mg (800 mg TID) for 7 days. Planned enrollment was 54 subjects (18 per group).
  • Study D was a double-blind, double-dummy, comparative, phase 3 study of rifaximin 1200 mg/day and lactitol 60 g/day for up to 10 days of treatment in hyperammonemic, cirrhotic subjects with Grade 1-3 HE enrolled at 16 centers in Spain. Planned enrollment was 120 subjects (60 per group).
  • Study E was a phase 3, international, multicenter, randomized, double-blind, placebo- controlled, parallel-group study comparing 14 days of rifaximin 400 mg TID to placebo in cirrhotic subjects with mild to moderate hepatic encephalopathy who were intolerant to the GI side effects of lactulose or lactitol. The study was conducted in the United States, Poland, Hungary, and the United Kingdom. Planned enrollment was 112 subjects (56 per group)
  • Venous ammonia levels, NCT scores, and EEG results were graded according to increasing severity.
  • Study C The primary efficacy endpoint for study C was the PSE index at the end of study.
  • the PSE index was a component score that included scores for mental state (Conn score), asterixis, venous ammonia levels, NCT, and EEG.
  • the primary efficacy endpoint was the overall response rate, defined as the proportions of subjects who showed improvement in mental state (Conn score) by at least 1 level (eg, change from Conn score 2 to Conn score 1 or 0) after completing treatment when compared to baseline.
  • study C mean ages were 55.2 years, 52.3 years, and 55.3 years in the 600 mg, 1200 mg, and 2400 mg groups, respectively.
  • study D mean ages were 61.6 years and 62.9 years in the rifaximin and lactitol groups, respectively.
  • study E mean ages were 53.6 years and 53.3 years in the rifaximin and placebo groups, respectively.
  • Table 8 presents a summary of baseline characteristics for studies C, D, and E.
  • Subjects in study D had more severe HE symptoms, as measured by mental status/Conn scores, asterixis grades, and PSE index, than subjects in study E.
  • disease severity was greater in D compared with C.
  • the proportions of subjects with mental status/Conn scores of >2 at baseline were 70% (rifaximin) and 60.3% (lactitol) in D, 14.6% (rifaximin) and 4.4% in E, and 16.7%, 31.6%, and 23.5% in the 600 mg, 1200 mg, and 2400 mg groups in C.
  • Time since diagnosis of the HE condition ie, duration of HE was substantially longer in the Study D than in Study E and Study C (see Table 8).
  • Baseline characteristics were generally similar between subjects in Study A and subjects in Study B. Demographics are presented in and baseline characteristics are presented in for new rifaximin subjects in Study B.
  • Hazard ratios for the risk of experiencing breakthrough overt HE in the rifaximin group relative to the placebo group are presented in Figure 2.
  • Hazard ratios of less than 1 indicate that the outcome favors rifaximin and greater than 1 favors placebo.
  • Hepatic encephalopathy-related hospitalizations were reported for 19 of 140 subjects and 36 of 159 subjects in the rifaximin and placebo groups, respectively. After normalization to exposure, the HE-related hospitalization rate was 51% lower (0.38 event/PEY, rifaximin versus 0.78 event/PEY, placebo) in the rifaximin group.
  • HE-caused hospitalizations were reported for 15 of 140 subjects and 33 of 159 subjects in the rifaximin and placebo groups, respectively.
  • the HE-caused hospitalization rate was 0.30 events/PEY in the rifaximin group versus 0.72 event/PEY in the placebo group.
  • CLDQ Chronic Liver Disease Questionnaire
  • CLDQ analyses are performed by comparing the changes from baseline to the last assessment in CLDQ overall and domain scores between the 2 treatment groups.
  • the questionnaire measures the subject's quality of life status over the 2 weeks prior to completing the questionnaire.
  • results in the 2 weeks prior to last assessment to the 2 weeks prior to baseline change from baseline analysis
  • changes over the entire course of the study are not captured in the analysis.
  • most subjects in the study also had comorbidities associated with hepatic cirrhosis that can potentially skew results, depending on the timing of complication, and if it occured at or near the first or last assessment.
  • subjects who experienced an overt HE breakthrough episode were
  • the CLDQ results were shown to be predictive of breakthrough overt HE episodes as defined by the primary endpoint ( Figure 4). There were significant differences in frequency distributions of T wa (AUC normalized by exposure time) for all domains of the CLDQ between subjects who had breakthrough overt HE and subjects without breakthrough overt HE. The mean T wa for each domain and overall correlated with presence or absence of breakthrough overt HE episode.
  • BOS2 775861 1 similar proportions of subjects had breakthrough overt HE episodes in the rifaximin group of Study A (22%, 31 of 140 [rifaximin group]) and in the new rifaximin group of Study B (20.5%, 43 of 210). Adjusted for exposure, rates of breakthrough overt HE episodes were 0.62 events/PEY in the rifaximin group from Study A compared to 0.5 events/PEY for new rifaximin subjects in Study B.
  • the comparison of Kaplan Meier estimates of time to first breakthrough overt HE episode between the placebo experience in Study A and during the first 6 months of rifaximin treatment in Study B is shown in Figure 5.
  • the ratio of the incidence of breakthrough overt HE episode for rifaximin treatment relative to placeo treatment was 0.2112 (95% CI: 0.1006 to 0.4432, p ⁇ 0.0001 for between group difference in relative risk). This result represents 79% reduction in risk of experiencing breakthrough overt HE during rifaximin treatment in Study B when compared with their prior placebo experience in Study A.
  • Breakthrough overt HE was experienced by 14 of 82 during 6 months of rifaximin treatment in Study B versus 39 of 82 during placebo treatment in Study A. Rates of breakthrough HE episodes were 1.5 events/PEY during placebo experience in Study A and 0.4 events/PEY during rifaximin experience in Study B.
  • Figure 6 illustrates PSE index results at baseline and at end of studies C, D, and E.
  • Study E the lack of a rifaximin effect on improvements in Conn score may have been due to short duration of therapy in this study (15 days) and the mild HE symptoms at baseline.
  • Subjects in study Study E had mild HE symptoms, as measured by mental status/Conn scores, asterixis grades, and PSE index, when compared with subjects in study Study D or Study C.
  • NCT scores were generally similar across groups in each of the 3 studies.
  • the overall global response to treatment was evaluated in Study D.
  • the percentages of subjects who were considered cured (venous ammonia normalized and mental state/Conn score of 0) by end of study were higher in the rifaximin group when compared with the lactitol group (53.1% versus 39.2%).
  • Study D there were significant between-group differences in the changes in PSE index and venous ammonia levels (both of which were primary endpoints) in favor of the rifaximin group when compared with lactitol; and higher proportion of rifaximin subjects were considered cured at end of treatment (venous ammonia normalized and mental state/Conn score of 0).
  • Study E a significant larger proportion of rifaximin subjects had improvements in asterixis grade when compared with placebo subjects; however, results for the primary endpoint, the proportion of subjects who had improvements in Conn score, were not significantly different between groups.
  • Subjects in study E had mild HE symptoms when compared with subjects in Study D.

Abstract

The present invention relates to the effect of hepatic insufficiency on the pharmacokinetics of rifaximin. Also provided are methods of determining an appropriate dose of rifaximin for a subject suffering from hepatic insufficiency. In addition, methods of treatment are provided subjects having or susceptible to hepatic insufficiency to be treated with rifaximin.

Description

MODULATION OF SYSTEMIC EXPOSURE TO RIFAXIMIN
RELATED APPLICATIONS
This application claims the benefit of US Provisional Application 61/187,251, filed June 15, 2009, and US Provisional Application 61/297,696, filed January 22, 2010. The entire contents of each of which are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
Rifaximin (INN; see The Merck Index, XIJI Ed., 8304) is an antibiotic belonging to the rifamycin class of antibiotics, e.g., a pyrido-imidazo rifamycin. It has been reported that rifaximin is characterized by a negligible systemic absorption, due to its chemical and physical characteristics (Descombe J.J. et al. Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res, 14_ (2), 51-56, (1994)).
Rifaximin is described in Italian Patent IT 1154655 and EP 0161534, both of which are incorporated herein by reference in their entirety for all purposes. EP 0161534 discloses a process for rifaximin production using rifamycin O as the starting material (The Merck Index, XIII Ed., 8301).
SUMMARY OF THE INVENTION
Provided herein is the discovery that rifaximin exhibits differential pharmacokinetics in subjects with hepatic insufficiency as compared to subjects with normal hepatic systems. Accordingly, in one aspect, provided herein are methods of increasing rifaximin systemic exposure (AUCtau) in a subject after oral administration by selecting a subject having hepatic insufficiency, and orally administering rifaximin to the subject, wherein systemic exposure to rifaximin is increased in the subject with hepatic insufficiency as compared to a subject without hepatic insufficiency.
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BOS2 775861 1 In a related embodiment, the subject having hepatic insufficiency has a model end stage liver disease (MELD) score of less than 11 for the subject. In another related embodiment, the subject having hepatic insufficiency has a model end stage liver disease (MELD) score of 11 to 18 for the subject.
In another embodiment, the subject having hepatic insufficiency has a Child-Pugh A score. In another embodiment, the subject having hepatic insufficiency has a Child-Pugh B score.
In another embodiment, the rifaximin systemic exposure in the subject suffering from hepatic insufficiency comprises exposure at least 5-fold higher than in the subject not having hepatic insufficiency. In another embodiment, the rifaximin systemic exposure in the subject suffering from hepatic insufficiency comprises exposure at least 9.6-fold higher than in the subject not having hepatic insufficiency. In another embodiment, the rifaximin systemic exposure in the subject suffering from hepatic insufficiency comprises exposure at least 13.1- fold higher than in the subject not having hepatic insufficiency. In another embodiment, the rifaximin systemic exposure in the subject suffering from hepatic insufficiency comprises exposure between about 5 fold and about 13.1 -fold higher than in the subject not having hepatic insufficiency.
In one specific embodiment, the subject having hepatic insufficiency has hepatic encephalopathy.
In another embodiment, the methods provided herein further comprise administering rifaximin with food.
In one embodiment, food delays the time to reach maximum plasma concentration.
In another embodiment, the methods provided herein further comprise selecting a subject susceptible to or suffering from Travelers' diarrhea.
In another related embodiment, the methods provided herein further comprise informing the subject that the elimination rate of rifaximin is decreased in a population of
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BOS2 775861 1 subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency.
In another aspect, provided herein are methods of increasing rifaximin plasma concentrations (Cmax) in a subject after oral administration by selecting a subject comprising hepatic insufficiency, and orally administering rifaximin to the subject having hepatic insufficiency, wherein plasma concentrations of rifaximin are increased in the subject with hepatic insufficiency as compared to a subject without hepatic insufficiency.
In one embodiment, the subject having hepatic insufficiency has an elevated alanine aminotransferase (ALT).
In one embodiment, the rifaximin plasma concentration in the subject suffering from hepatic insufficiency comprises exposure at least 2-fold higher than in the subject not comprising hepatic insufficiency.
In another embodiment, the methods provided herein further comprise administering rifaximin with food, thereby delaying the time to reach maximum plasma concentration.
In another embodiment, the methods further comprise selecting a subject susceptible to or suffering from Travelers' diarrhea.
In another related embodiment, the methods provided herein further comprise informing the subject that the elimination rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency.
In another aspect, provided herein are methods of decreasing rifaximin elimination rate in a subject after oral administration by selecting a subject comprising hepatic insufficiency, and orally administering rifaximin to the subject having hepatic insufficiency, wherein elimination rate of rifaximin is decreased in the subject with hepatic insufficiency as compared to a subject without hepatic insufficiency.
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BOS2 775861 1 In one embodiment, the rifaximin elimination rate is decreased by at least 25% in the subject with hepatic insufficiency as compared to the subject without hepatic insufficiency.
In another embodiment, the subject having hepatic insufficiency has a Child-Pugh A score. In another embodiment, the subject having hepatic insufficiency has a Child-Pugh B score.
In another embodiment, decreasing the elimination rate further comprises increasing the bioavailability of rifaximin in the subject with hepatic insufficiency.
In another embodiment, the subject having hepatic insufficiency is a subject having at least one sign, symptom or episode of hepatic encephalopathy, or at least one portal systemic shunt. In another embodiment, the subject is susceptible to, or suffering from, Traveler's diarrhea.
In another related embodiment, the methods provided herein further comprise informing the subject that the elimination rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency.
In another aspect, provided herein are methods of determining a therapeutically effective dose of rifaximin for a subject by selecting a subject comprising hepatic encephalopathy, and determining a therapeutically effective dose in consideration of the subject having hepatic encephalopathy.
In one embodiment, the subject has or is susceptible to Traveler's diarrhea.
In another embodiment, the subject is given a dosage that is increased compared to the dose administered to subject that does not have or is not susceptible to hepatic encephalopathy.
In another embodiment, the subject is given a dosage that is decreased compared to the dose administered to subject that does not have or is not susceptible to hepatic encephalopathy.
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BOS2 775861 1 In another embodiment, the methods further comprise informing the subject of one or more of the following: that the elimination rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency; that systemic exposure to rifaximin is increased in a population of subjects with hepatic insufficiency compared to population of subjects without hepatic insufficiency, that the plasma concentration of rifaximin is increased in a population of subjects with hepatic insufficiency compared to population of subjects without hepatic insufficiency, and/or that the clearance rate of rifaximin is decreased in a population of subjects with hepatic insufficiency compared to population of subjects without hepatic insufficiency.
In another aspect, provided herein are methods of determining a therapeutically effective dose of rifaximin for a subject by selecting a subject having or susceptible to hepatic insufficiency, comprising
correlating hepatic insufficiency with at least one of increased systemic exposure to rifaximin, an increased plasma concentration of rifaximin, or a decreased clearance rate of rifaximin, and
determining a therapeutically effective dose in consideration of one or more of increased systemic exposure to rifaximin, increased plasma concentration of rifaximin, or decreased clearance rate of rifaximin in the subject associated with hepatic insufficiency.
In another embodiment, the subject having hepatic insufficiency has a Child-Pugh A score. In another embodiment, the subject having hepatic insufficiency has a Child-Pugh B score.
In a related embodiment, the subject has a model end stage liver disease (MELD) score of less than 11. In another related embodiment, the subject having or susceptible to hepatic insufficiency has a model end stage liver disease (MELD) score of 11 to 18.
In another aspect, the subject has an elevated ALT level.
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BOS2 775861 1 In another aspect, the subject has at least one portal systemic shunt. In another embodiment, the subject has had at least one hepatic encephalopathy episode. In another embodiment, the subject has had at least one hepatic encephalopathy episode in the previous six months. In another embodiment, the subject has had at least two hepatic encephalopathy episodes in the previous six months.
In another embodiment, the methods further comprise selecting a subject susceptible to or suffering from Traveler' s diarrhea.
In another aspect, provided herein are methods of determining a therapeutically effective dose of rifaximin for a subject comprising:
selecting a subject having or susceptible to hepatic insufficiency,
correlating hepatic insufficiency with at least one of increased systemic exposure to rifaximin, increased plasma concentration of rifaximin, or decreased clearance rate of rifaximin, and
determining a therapeutically effective dose in consideration of at least one of increased systemic exposure to rifaximin, increased plasma concentration of rifaximin, or decreased clearance rate of rifaximin in the subject associated with hepatic insufficiency.
In another aspect, provided herein are methods of treating Travelers' Diarrhea (TD) by selecting a subject suffering from or susceptible to TD, instructing the subject to orally administer rifaximin, and informing the subject of one or more of the elimination rate of rifaximin is decreased in a population of subjects with hepatic insufficiency compared to population of subjects without hepatic insufficiency; the systemic exposure to rifaximin is increased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency; plasma concentrations of rifaximin are increased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency; and/or the clearance rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency.
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BOS2 775861 1 In another embodiment, the subject having hepatic insufficiency has a Child-Pugh A score. In another embodiment, the subject having hepatic insufficiency has a Child-Pugh B score.
In a related embodiment, the subject has a model end stage liver disease (MELD) score of less than 11. In another related embodiment, the subject having hepatic insufficiency has a model end stage liver disease (MELD) score of 11 to 18.
In a related embodiment, hepatic insufficiency comprises hepatic encephalopathy.
In another embodiment, the methods further comprise identifying subjects having hepatic insufficiency. In a related embodiment, the methods further comprise testing subjects for hepatic insufficiency.
In another embodiment, the methods further comprise altering the amount of rifaximin administered based on the subject having hepatic insufficiency as compared to a subject without hepatic insufficiency.
In another embodiment, the methods further comprise altering the dosing regime of rifaximin based on the subject having hepatic insufficiency as compared to a subject without hepatic insufficiency.
In another embodiment, the methods further comprise informing the subject that systemic exposure to rifaximin and/or plasma concentrations of rifaximin are altered with food.
In another aspect, provided herein are kits comprising rifaximin, or a pharmaceutical composition thereof, and instruction for administering to a subject with hepatic insufficiceny. In one embodiment, the kit comprises instructions for administering rifaximin to a subject having hepatic encephalopathy.
Other embodiment and aspects are disclosed infra.
BRIEF DESCRIPTION OF THE DRAWINGS
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BOS2 775861 1 Figure 1 is a graph showing the mean + SD of the plasma concentration-time profiles of rifaximin on a linear scale.
Figure 2 depicts the time to first breakthrough overt HE episode by subgroup.
Figure 3 depicts CLDQ Overall and Individual Domain Twa Results by Treatment Group (ITT Population).
Figure 4 depicts CLDQ Overall and Individual Domain Twa Results by Breakthrough Overt HE Status.
Figure 5 depicts a comparison of Kaplan-Meier Estimates of Time to First Breakthrough Overt HE Episode. The Placebo Experience vs. The Rifaximin Experience in Placebo Crossover Subjects up to 6 Months of Treatment is shown.
Figure 6 depicts the mean PSE values at baseline and at end-of-treatment in clinical studies.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Embodiments provided herein relate to the discovery of the difference in systemic exposure, plasma concentration, and terminal elimination rate constant of rifaximin in a subject suffering from hepatic insufficiency as compared to a subject having normal liver function. Further, the invention relates to the discovery of the effect of food on the time to reach maximum plasma concentrations of rifaximin in a subject.
The main pathogenesis of HE is related to nitrogenous substances derived from the gut adversely affecting brain function. The most influential of these compounds is thought to be ammonia, a byproduct of protein digestion that is normally detoxified by the liver.
Correlation of blood levels with mental state in cirrhosis, however, is inaccurate, in part, because the blood-brain barrier permeability to ammonia is increased in patients with HE.
Other gut-derived toxins have also been proposed as being responsible for HE.
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BOS2 775861 1 In patients with chronic liver disease, the occurrence of hepatic encephalopathy is associated with a low quality of life compared to age-matched patients without HE. Overt HE episodes are debilitating, can present without warning, render the patient incapable of self- care, and frequently result in hospitalization. Patients with HE experience symptoms including fatigue, daytime sleepiness, and lack of awareness (Conn score 1); and confusion and disorientation (Conn score 2) that significantly interfere with day-to-day function and decreased ability for self care. Often, this lack of self care leads to improper nutrition and non-adherence to therapy and further escalates into more severe symptoms such as increased somnolence, gross disorientation and stupor (Conn score 3) or coma (Conn score 4). A history of overt HE episodes and the severity of HE episodes were also found to be predictive of decreased survival in patients with chronic liver disease. In patients with liver cirrhosis and a history of overt HE episodes, survival probability was 42% at 1 year and 23% at 3 years after experiencing an HE episode. In another analysis, the occurrence of an HE episode of Conn score 2 in patients with cirrhosis was associated with a 4-fold increase in the risk of death.
These toxic compounds gain access to the systemic circulation as a result of decreased hepatic function or portal- systemic shunts. Once in brain tissue, the compounds produce alterations of neurotransmission that affect consciousness and behavior. HE is attributed to global central nervous system depression from nitrogenous compounds that result in excitation of gamma- aminobutyric acid (GABA) and decreased neurotransmission of glutamate.
Precipitating factors include azotemia (29%), sedatives, tranquilizers, analgesics (24%), gastrointestinal bleeding (18%), excess dietary protein (9%), metabolic alkalosis (11%), infection (3%), constipation (3%). Surgery, particularly transjugular intrahepatic portal- systemic shunt (TIPS) procedures, also may precipitate HE. HE due to unknown causes accounts for only 2% of cases.
Initial manifestations are subclinical and require psychometric testing for diagnosis. There are 4 progressive stages of impairment known as the West Haven criteria (or Conn score) which range from Stage 0 (Lack of detectable changes in personality) to Stage 4 (Coma, decerebrate posturing, dilated pupils) as discussed in more detail below.
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BOS2 775861 1 HE is manifested as a continuum of psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities, poor concentration and in severe forms, as coma. Changes may be observed in personality, consciousness, behavior and neuromuscular function. Neurologic signs may include hyperreflexia, rigidity, myoclonus and asterixis (coarse "flapping" muscle tremor). Cognitive tasks such as connecting numbers with lines can be abnormal. Fetor hepaticus (sweet breath odor) may be present. Electroencephalogram (EEG) tracings show nonspecific slow, triphasic wave activity mainly over the frontal areas. Prothrombin time may be prolonged and not correctable with Vitamin K. A computed tomography scan of the head may be normal or show general atrophy. Finally, signs of liver disease such as jaundice and ascites may be noted.
Diagnosis of HE is made on the basis of medical history, and physical and mental status examinations with the required clinical elements being knowledge of existent liver disease, precipitating factor(s), and/or prior history of HE. An EEG may show slow-wave activity, even in mild cases. An elevated serum ammonia level is characteristic but not essential, and correlates poorly with the level of encephalopathy
Management of patients with chronic HE includes 1) provision of supportive care, 2) identification and removal of precipitating factors, 3) reduction of nitrogenous load from the gut, and 4) assessment of the need for long term therapy. The nitrogenous load from the gut is typically reduced using non-absorbable disaccharide (lactulose) and/or antibiotics. Lactulose is considered a first-line treatment in the United States, but is not currently approved in the U.S. for either the treatment or prevention of HE. Lactulose is metabolized by the intestinal bacteria of the colon, which leads to reduced fecal pH, then to a laxative effect, and finally to fecal elimination. The reduced fecal pH ionizes ammonia (NH3) to the ammonium ion (NH4 +) which is used by the bacteria for amino acid and protein synthesis. This lowers the serum ammonia levels and improves mental function.
Conventional therapy aims to lower the production and absorption of ammonia. Lactulose is typically used in doses of 30-60 g daily. However, the dose can be titrated up to 20-40 g TID-QID to affect 2-3 semi-formed bowel movements per day. If lactulose cannot be administered orally or per nasogastric tube, for example to patients with stage 3 and 4 HE, it may be given as a 300 cc (200 g) retention enema.
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BOS2 775861 1 For acute encephalopathy, lactulose can be administered either orally, by mouth or through a nasogastric tube, or via retention enemas. The usual oral dose is 30 g followed by dosing every 1 to 2 hours until evacuation occurs. At that point, dosing is adjusted to attain two or three soft bowel movements daily. Lactulose for is readily available over-the-counter. A convenient and relatively tasteless formulation, often referred to in the trade as "lactulose powder for oral solution" can be obtained, for example, from Bertek Pharmaceuticals, Sugarland, Tex. as KristaloseR™ in 10 and 20 gm packets. The lactulose syrups commonly sold as laxatives include CephulacR™, ChronulacR™, CholacR™, and EnuloseR™. These syrups can be substituted for lactulose powder by using sufficient syrup to provide the desired dosage of lactulose; typically, the named syrups contain about 10 gm lactulose in 15 ml of syrup.
Broad-spectrum, GI-active antibiotics including neomycin, metronidazole, vancomycin and paromomycin have been used with or without lactulose. Current guidelines recommend neomycin at 1 to 2 g/day by mouth with periodic renal and annual auditory monitoring or metronidazole at 250. Lactulose can induce diarrhea leading to dehydration, a precipitating factor of HE. Additionally, compliance with lactulose is limited by patient dislike of its overly sweet taste. In addition, a dosing schedule that is linked to bowel habits and side effects of flatulence, bloating, diarrhea (which leads to dehydration), and acidosis make lactulose difficult to use long-term. Antibiotic use in treatment of HE is hampered by toxicity associated with long-term use. Specifically, systemic absorption of neomycin, metronidazole and ampicillin has led to rare cases of nephrotoxicity, ototoxicity, S. enterocolitis, and/or development of resistant bacterial strains. Additionally, neomycin inhibits only aerobic bacteria. Metronidazole is metabolized slowly in patients with hepatic dysfunction, has a potential for alcohol interactions (disulfiram-like effect), and high blood levels may result in seizures.
One gastrointestinal specific antibiotic is rifaximin. Rifaximin is a nonaminoglycoside, semisynthetic antibiotic derived from rifamycin O. It is a non-systemic, non-absorbed, broad- spectrum, oral antibiotic specific for enteric pathogens of the GI tract. Rifaximin was found to be advantageous in treatment of HE relative to previously used antibiotics; e.g., negligible systemic absorption (<0.4%) regardless of food intake or presence
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BOS2 775861 1 of GI disease and exhibits no plasma accumulation with high or repeat doses. The lack of systemic absorption makes rifaximin safe and well tolerated, thus improving patient compliance and reducing side effects associated with currently known treatments.
Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an antibiotic belonging to the rifamycin class of antibiotics, e.g., a pyrido-imidazo rifamycin. Rifaximin exerts its broad antibacterial activity, for example, in the gastrointestinal tract against localized gastrointestinal bacteria that cause infectious diarrhea, irritable bowel syndrome, small intestinal bacterial overgrowth, Crohn's disease, and/or pancreatic insufficiency. It has been reported that rifaximin is characterized by a negligible systemic absorption, due to its chemical and physical characteristics (Descombe JJ. et al. Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res, 14 (2), 51- 56, (1994)).
Rifaximin is described in Italian Patent IT 1154655 and EP 0161534. EP patent 0161534 discloses a process for rifaximin production using rifamycin O as the starting material (The Merck Index, XIJI Ed., 8301). US 7,045,620 Bl discloses polymorphic forms of rifaximin. The applications and patents referred to here are incorporated herein by reference in their entirety for all purposes
Embodiments provided herein also relate to administration of medicinal preparations to a subject in need of treatment with compositions, such as rifaximin. Rifaximin is a compound of the rifamycin class of antibiotics. Rifaximin is a compound having the structure of Formula I:
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BOS2 775861 1
Figure imgf000014_0001
In one embodiment, rifaximin is a poorly absorbed molecule in certain subjects. This is shown in clinical pharmacokinetic studies in normal subjects following single and multiple oral doses demonstrate that rifaximin is poorly absorbed from the gastrointestinal tract (e.g.,
<1% of the drug is absorbed after oral administration). While only trace amounts of the parent drug and metabolites were detected in urine, there was high fecal recovery of rifaximin primarily as unchanged drug. Upon repeated administration, there was little or no systemic drug accumulation and the time to reach steady state was short. Unexpectedly, administration of a 1.5 fold higher daily dose in the TID regimen did not result in a commensurate increase in total daily systemic exposure to rifaximin; the AUCiotai was only approximately 13% higher after TID dosing than after BID dosing.
"Rifaximin", as used herein, includes solvates and polymorphous forms of the molecule, including, for example, α, β, γ, δ, ε, η, ζ and amorphous forms of rifaximin. These forms are described in more detail, for example, in USSN 11/873,841; USSN 11/658,702; EP 05 004 635.2, filed 03 May 2005; USPN 7,045,620; US 61/031,329; and G. C. Viscomi, et al., CrystEngComm, 2008, 10, 1074-1081 (April 2008). Each of these references is hereby incorporated by reference in entirety.
"Polymorphism", as used herein, refers to the occurrence of different crystalline forms of a single compound in distinct hydrate status, e.g., a property of some compounds and
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BOS2 775861 1 complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as solubility profiles, melting point temperatures, hygroscopicity, particle shape, density, flowability, compactibility and/or x-ray diffraction peaks. The solubility of each polymorph may vary, thus, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predictable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. For a general review of polymorphs and the pharmaceutical applications of polymorphs see G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J Pharm. ScL, 58, 911 (1969); and J. K. Haleblian, J. Pharm. ScL, 64, 1269 (1975), all of which are incorporated herein by reference.
As used herein, the term "systemic exposure" is intended to mean the exposure of a subject to rifaximin by the administration and subsequent plasma exposure to rifaximin in the subject followed by the distribution throughout the subject's body. Increased systemic exposure can be measured by determining the plasma concentration of rifaximin in a subject. In exemplary embodiments, increased systemic exposure can be due to a decrease in the clearance of rifaximin.
A combination of physiopathological factors may explain the increase in rifaximin exposure in subjects with a history of HE as compared to healthy subjects. Hepatic encephalopathy episodes result from central nervous system accumulation of nitrogenous substances derived from the gut (primarily ammonia) due to porto-systemic shunts and portal hypoperfusion associated with hepatic cirrhosis. Subjects having mild and moderate impairment of liver function and a documented history of hepatic encephalopathy episodes were enrolled in the study. Hepatic encephalopathy is a complication of cirrhosis resulting from portal hypertension, cerebral vasodilatation, and hepatic insufficiency. Recent studies
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BOS2 775861 1 showed high prevalence of spontaneous portal-systemic shunts in persistent hepatic encephalopathy.
In chronic liver disease, a substantial part of the portal circulation does not perfuse functional liver cells due the presence of intrahepatic functional shunts or extrahepatic anatomic shunts. As a result, first pass clearance of orally administered agents is reduced and systemic bioavailability is increased. The higher exposure values of rifaximin were likely, in part due to a reduction of presystemic metabolism in the presence of porto-systemic shunts and/or portal hypoperfusion. This possibility is supported by the fact that although the plasma exposure to rifaximin from the gastrointestinal tract is limited (-0.32% of the dose), it is a hypothesis that this small absorbed fraction undergoes first-pass metabolism in healthy subjects (~ 90.6%), since only a small proportion of unchanged rifaximin is excreted in urine (0.03% of the dose). Additionally, since the rifaximin terminal t/2 was clinically statistically significantly longer (about 2-fold) in HE subjects relative to healthy subjects, higher exposure found in HE may be due to a reduction in the systemic clearance of the drug. As used herein, "subject" includes organisms which are capable of suffering from a bowel disorder or other disorder treatable by rifaximin or who could otherwise benefit from the administration of a rifaximin product as described herein, such as human and non-human animals. The term "non-human animals" provided herein includes all vertebrates, e.g., mammals, e.g., rodents, e.g., mice, and non-mammals, such as non-human primates, e.g., sheep, dog, cow, chickens, amphibians, reptiles, etc.
"Susceptible to a bowel disorder," as used herein, includes subjects at risk of developing a bowel disorder, e.g., subjects suffering from HE, immune suppression, subjects that have been exposed to other subjects with a bacterial infection, subjects with a family history of a bowel disorder, subjects with a gene profile indicating disease or risk of bowel disorder, subjects with known susceptibility to bowel disorder, physicians, nurses, subjects traveling to remote areas known to harbor bacteria that causes travelers' diarrhea, etc.
A subject "suffering from hepatic insufficiency" as used herein includes subjects diagnosed with a clinical decrease in liver function, for example, due to hepatic encephalopathy, hepatitis, or cirrhosis. Hepatic insufficiency can be quantified using any of a
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BOS2 775861 1 number of scales including a model end stage liver disease (MELD) score, a Child-Pugh score, or a Conn score.
A MELD score uses the patient's values for serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time (INR) to provide a weighted numeric value to correlate with predicted survival. A score of 10-19 correlates with a 27% mortality rate within three months, and a score of <10 correlates with a 4% mortality within three months. Methods for determination and analysis of MELD scores are well known in the art.
A Child-Pugh score (sometimes the Child- Turcotte-Pugh score) used to assess the prognosis of chronic liver disease, mainly cirrhosis, is an aggregate score of five clinical measures, billirubin, serum albumin, INR, ascites, and hepatic encephalopathy. Each marker is assigned a value from 1-3, and the total value is used to provide a score categorized as A (5-6 points), B (7-9 points), or C (10-15 points), which can be correlated with one and two year survival rates. Methods for determination and analysis of Child-Pugh scores are well known in the art. Measurements of change in mental status may be done, for example, by the Conn score (also known as the West Haven score). The Conn score has been widely used as a measure of mental state in HE studies and is based on the criteria of Parsons- Smith as modified by Conn. Asterixis will not be considered when assessing the subject's status using the Conn scoring criteria listed below. The scale used in the Conn scoring system is provided below.
Grade 0 = No personality or behavioral abnormality detected
Grade 1 = Trivial lack of awareness, euphoria or anxiety; shortened attention span; impairment of addition or subtraction Grade 2 = Lethargy; disorientation for time; obvious personality change; inappropriate behavior Grade 3 = Somnolence to semi-stupor, responsive to stimuli; confused; gross disorientation; bizarre behavior Grade 4 = Coma; unable to test mental state
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BOS2 775861 1 Asterixis grade (flapping tremor) can be determined with the subject holding both arms and forearms extended with wrists dorsiflexed and fingers open for > 30 seconds. Asterixis was measured on a continuum of 5 grades, e.g., grades 0 and 4 = no abnormal movement vs. almost continuous flapping motions, respectively as shown below: Grade 0 = No tremors;
Grade 1 = Rare flapping motions; Grade 2 = Occasional, irregular flaps; Grade 3 = Frequent flaps; and Grade 4 = Almost continuous flapping motions. Efficacy in regard to asterixis grade can be measured as time to any increase from baseline in asterixis grade. Time to an increase in asterixis grade was computed as the number of days from the first dose of rifaximin to the initial occurrence of an increase from baseline in asterixis grade.
The language "a prophylactically effective amount" of a compound refers to an amount of a compound provided herein of formula (I) or otherwise described herein which is effective upon single or multiple dose administration to the subject in preventing or treating a bacterial infection or HE.
The language "therapeutically effective amount" refers to an amount of an agent which is effective, upon single or multiple dose administration to the subject to provide a therapeutic benefit to the subject. In another embodiment, the therapeutic benefit is inhibiting a bacterial infection or prolonging the survival of a subject with such a bacterial infection beyond that expected in the absence of such treatment.
Rifaximin exerts a broad antibacterial activity in the gastrointestinal tract against localized gastrointestinal bacteria that cause infectious diarrhea, including anaerobic strains. It has been reported that rifaximin is characterized by a negligible systemic absorption, due to its chemical and physical characteristics (Descombe JJ. et al. Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res, 14_ (2), 51-56, (1994)).
The presence of hepatic insufficiency has been found to have an effect on in vivo plasma exposure of rifaximin. Thus, making it a criteria for consideration by a healthcare
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BOS2 775861 1 professional (e.g., physician, physician's assistant, nurse practitioner, pharmacist) when prescribing a dose of rifaximin for treatment of a bowel disorder, such as Travelers' diarrhea or IBS. Hepatic insufficiency leads to a clinically statistically significant increase in rifaximin adsorbed by subjects undergoing treatment. One embodiment, disclosed herein are methods of modulating the therapeutic action of rifaximin by selecting a subject suffering from hepatic insufficiency and further providing prophylaxis or treatment for the hepatic insufficiency.
Accordingly, one embodiment is a method of treating Travelers' Diarrhea (TD) in a subject. In this method rifaximin is administered to a subject suffering from a disease that is treatable by rifaximin. The subject is informed that systemic plasma exposure to rifaximin is increased in subjects suffering from hepatic insufficiency in comparison to subjects not suffering from hepatic insufficiency. This information increases the level of safety of administering the rifaximin to the subject. Examples of diseases treatable by rifaximin include Travelers' Diarrhea and Hepatic Encephalopathy. As used herein, "informing" or "advising" means referring to or providing, published or oral material. For example, providing an active agent with published material to a user; or presenting information orally, for example, by presentation at a seminar, conference, or other educational presentation, by conversation between a pharmaceutical sales representative and a medical care worker, or by conversation between a medical care worker and a patient; or demonstrating the intended information to a user for the purpose of comprehension. Examples of medical care workers include physicians, nurses and nurse practitioners.
One aspect of this invention includes providing information to prescribing physicians and patients receiving rifaximin treatment useful in minimizing safety concerns of rifaximin. In this embodiment, the information describes that systemic plasma exposure to rifaximin is increased in subjects suffering from hepatic insufficiency in comparison to subjects not suffering from hepatic insufficiency. In one embodiment, the information is provided on a label. In another embodiment, the information is provided on an information sheet that is given to the patient when a prescription for rifaximin is filled.
Further, the method may also include the step or steps of distributing prescribable doses of rifaximin to pharmacies and distributing educational materials to the pharmacies
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BOS2 775861 1 including pharmacists with the educational material including information as to what the patient needs to know and what the patients must do in order to both avoid any adverse effects of rifaximin while taking the doses.
In addition, the method may include the step or steps of providing guidelines to the pharmacists for counseling patients with regard to what the patient needs to know and what the patient must do in order to safely take their rifaximin dosages.. The method may further include the step of requiring acknowledgment of receipt of the educational materials and guidelines from the pharmacists and further acknowledgement of receipt of the educational materials by the patient from the pharmacists. Another embodiment is a method of using rifaximin for treating a patient's condition.
The embodiment includes providing a patient with rifaximin and informing the patient or a medical care worker that systemic plasma exposure to rifaximin is increased in patients suffering from hepatic insufficiency, and that administration of rifaximin to a patient with hepatic insufficiency can affect plasma concentration, safety, or efficacy of rifaximin. Yet another embodiment includes a method of treating a subject suffering from an indication treatable by rifaximin. This method includes administering rifaximin to the subject and advising the subject that systemic plasma exposure to rifaximin is increased in subjects suffering from hepatic insufficiency in comparison to subjects not suffering from hepatic insufficiency.
Methods of Treatment
Provided herein are methods of determining a dose of rifaximin for treating, preventing, or alleviating bowel related disorders, particularly Travelers' diarrhea, in a subject further suffering from hepatic insufficiency, e.g. due to hepatic encephalopathy. Bowel related disorders include one or more of hepatic insufficiency, cirrhosis, polycystic liver disease, irritable bowel syndrome, diarrhea, microbe associated diarrhea, Clostridium difficile associated diarrhea, travelers' diarrhea, small intestinal bacterial overgrowth, Crohn's disease, chronic pancreatitis, pancreatic insufficiency, enteritis, colitis, hepatic encephalopathy (or other disease which leads to increases ammonia levels), or pouchitis.
As used herein, the term "hepatic insufficiency" includes diseases and disorders in which a subject has defective functional activity of the liver. Clinically, subjects having
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BOS2 775861 1 hepatic insufficiency have decreased, e.g., statistically significantly decreased, liver function. Hepatic insufficiency often leads to liver failure. One exemplary disease which manifests hepatic insufficiency is hepatic encephalopathy.
As used herein, the term "hepatic encephalopathy" refers to a reversible neuropsychiatric abnormality in the setting of chronic or acute liver failure. When a subject has liver impairment, toxic substances that are normally removed by the liver accumulate in the blood, thereby impairing the function of the brain. These toxic substances are often nitrogenous substances, most notably ammonia. Once in brain tissue, the compounds produce alterations of neurotransmission that affect consciousness and behavior. There are 4 progressive stages of impairment associated with HE that are defined by using the West Haven criteria (or Conn score) which range from Stage 0 (lack of detectable changes in personality) to Stage 4 (coma, decerebrate posturing, dilated pupils). Typical symptoms of hepatic encephalopathy can include impaired cognition, a flapping tremor (asterixis), and a decreased level of consciousness including coma (e.g., hepatic coma), cerebral edema, and, possibly, death. Hepatic encephalopathy is commonly called hepatic coma or portal-systemic encephalopathy in the literature.
As used herein, the term "Travelers' diarrhea" refers to gastrointestinal illness common amongst travelers. The majority of cases are caused by bacterial, viral or protozoan infection. The primary source of infection is ingestion of fecally contaminated food or water.The length of treatment for a particular bowel disorder will depend in part on the disorder. For example, HE may be treated every day for the remainder of a subject's life, travelers' diarrhea may only require treatment duration of 12 to about 72 hours, while Crohn's disease may require treatment durations from about 2 days to 3 months. Dosages of rifaximin will also vary depending on the diseases state. The identification of those subjects who are in need of prophylactic treatment for bowel disorder is well within the ability and knowledge of one skilled in the art. Certain of the methods for identification of subjects which are at risk of developing a bowel disorder which can be treated by the subject method are appreciated in the medical arts, such as family history, travel history and expected travel plans, the presence of risk factors associated with the development of that disease state in the subject. A clinician skilled in the art can readily
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BOS2 775861 1 identify such candidate subjects, by the use of, for example, clinical tests, physical examination and medical/family/travel history.
A method of assessing the amount of hepatic insufficiency in a subject can include the use of any of the scoring systems provided above, such as a MELD score, a Child-Pugh score, of a Conn score.
In yet another aspect, a method of treating a subject suffering from or susceptible to a bowel disorder comprises administering to a subject in need thereof a therapeutically effective amount of a rifaximin to thereby treat the subject. Upon identification of a subject suffering from or susceptible to a bowel disorder, rifaximin is administered. Rifaximin may be administered, for example, after diagnosis, after an HE event, during an HE event, after diagnosis of minimal HE, or when the critical flicker frequency reaches a level indicative of an HE event, etc. As discussed herein, a physician may choose to alter the dosage of rifaximin administered to a subject for the treatment of a bowel disorder if the subject also has hepatic insufficiency. Efficacy of a treatment may be measured, for example, as reduction of bacterial overgrowth. Efficacy may also be measured in terms of a reduction of symptoms associated with the bowel disorder, a stabilization of symptoms, or a cessation of symptoms associated with a bowel disorder, for example, a reduction in one or more of nausea, bloating, diarrhea, the severity of the next HE event, and the like, or an increase in one or more of time to next HE event, cognitive ability and the like. One embodiment is a method of treating or preventing hepatic encephalopathy (HE) by administering a therapeutically effective amount of a rifaximin to a subject.
Embodiments of the invention relate to the discovery of the efficacy rifaximin for the treatment and prevention of Hepatic Encephalopathy. Embodiments relate to the use of rifaximin to prevent the onset of HE symptoms and also to lengthen the time to a first breakthrough HE episode. In one embodiment, the time to a first breakthrough HE episode was measured by an increase of the Conn score to Grade > 2 (e.g., 0 or 1 to > 2) or a Conn and asterixis score increase of one grade each for those subjects that have a baseline Conn Score of 0. In another embodiment, the time to breakthrough HE episode was measured by the time to any increase from baseline in either the Conn score (mental state grade) or
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BOS2 775861 1 asterixis grade, with Kaplan-Meier estimates of cumulative proportions of subjects with any increase at Days 28, 56, 84, 112, 140, and 168.
Another embodiment was a mean change from baseline in blood ammonia concentration over time or a mean change from baseline in critical flicker frequency values over time. An additional embodiment was indicated by a mean daily lactulose consumption over time, shifts from baseline in Conn scores over time; or shifts from baseline in asterixis grades over time. Unless otherwise specified, a shift of a value is the change of that value from a baseline value.
Other measures of efficacy of the treatments described herein included mean change from baseline in Chronic Liver Disease Questionnaire (CLDQ) scores over time; mean change from baseline in Epworth Sleepiness Scale scores over time; and proportion of subjects who have an Epworth Sleepiness Scale score >10. The evaluation of severity of persistent hepatic encephalopathy may also be based, for example, on Conn scores.
In another embodiment, a subject suffering from, susceptible to or in remission from hepatic encephalopathy (HE) can be administered rifaximin for between about 24 weeks and 24 months. In treating HE, rifaximin may be administered to the subject for 12 months and longer, for example for a subject's entire life span. In one embodiment, rifaximin is administered daily until the death of the subject.
In one embodiment, the invention relates to a method of decreasing a subject's risk of having a breakthrough event by administering to the subject a rifaximin. In one embodiment, the for subjects having a last HE episode equal to or greater than 90 days prior to starting on treatment, the risk of failure occurrence was reduced by 58%. In another embodiment, the risk of failure occurrence was reduced by between about 30 - 70%. In another embodiment, the risk was reduced by about 40% to 70%. In one embodiment, for subjects having a last HE episode more than 90 days prior to administration of a rifaximin, the risk of failure occurrence was decreased by between about 60%. In another embodiment, the risk of failure occurrence was decreased by between about 2% - 80%.
In another embodiment, for subjects having two or fewer HE episodes in the six months prior to starting on treatment, the risk of a breakthrough HE episode was decreased
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BOS2 775861 1 by about a 56%. In one embodiment, the risk of a breakthrough HE episode was decreased by between about a 20% - 70%.
In another embodiment, for subjects having greater than two HE episodes in the six months prior to starting on treatment, the risk of a breakthrough HE episode was reduced by about 63%. In another embodiment, the risk was reduced by about 30% - 80%.
As used herein, the term "terminal elimination rate constant" refers to the first order rate constant describing rifaximin elimination from the body of a subject. This is an overall elimination rate constant describing removal of rifaximin by all elimination processes including excretion and metabolism. As used herein, the term "plasma concentration" refers to concentaration of rifaximin in the plasma of a subject. Plasma concentrations of rifaximin can be determined, for example, using a reversed-phase high performance liquid chromatographic method with tandem quadrupole mass spectrometric detection (LC/MS/MS) as set forth in the Examples. The maximum plasma concentration at steady-state is referend to herein as Cmax and the minimum plasma conceration is referred to as Cmin.
As used herein, the term "clearance rate" refers to the volume of biological fluid completely cleared of drug metabolites as measured in unit time. Elimination occurs as a result of metabolic processes in the kidney, liver, saliva, sweat, intestine, heart, brain, and other locations. As used herein, alanine aminotransferase also referred to as ALT, refers to a test preformed in order to identify liver damage or liver failure. The level of the enzyme, ALT, is measured to determine if liver damage or disease is present in an individual. Low levels of ALT are normally found in the blood. But when the liver is damaged or diseased, ALT is released into the bloodstream. ALT levels can be measured by methods known to those of skill in the art.
Pharmaceutical Preparations
Embodiments also provide pharmaceutical compositions, comprising an effective amount of a rifaximin described herein and a pharmaceutically acceptable carrier. In a further embodiment, the effective amount is effective to treat a bacterial infection, e.g., small intestinal bacterial overgrowth, Crohn's disease, hepatic encephalopathy, antibiotic
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BOS2 775861 1 associated colitis, and/or diverticular disease in a subject further suffering from hepatic insufficiency.
For examples of the use of rifaximin to treat Travelers' diarrhea, see Infante RM, Ericsson CD, Zhi-Dong J, Ke S, Steffen R, Riopel L, Sack DA, DuPont, HL. Enteroaggregative Escherichia coli Diarrhea in Travelers: Response to Rifaximin Therapy. Clinical Gastroenterology and Hepatology. 2004;2:135-138; and Steffen R, M.D., Sack DA, M.D., Riopel L, Ph.D., Zhi-Dong J, Ph.D., Sturchler M, M.D., Ericsson CD, M.D., Lowe B, M.Phil., Waiyaki P, Ph.D., White M, Ph.D., DuPont HL, M.D. Therapy of Travelers' Diarrhea With Rifaximin on Various Continents. The American Journal of Gastroenterology. May 2003, Volume 98, Number 5, all of which are incorporated herein by reference in their entirety. Embodiments also provide pharmaceutical compositions comprising rifaximin and a pharmaceutically acceptable carrier. Doses may be selected, for example on the basis of desired amounts of systemic absorption, elimination rate, plasma concentration and the like. Embodiments of the pharmaceutical composition further comprise excipients, for example, one or more of a diluting agent, binding agent, lubricating agent, disintegrating agent, coloring agent, flavoring agent or sweetening agent. One composition may be formulated for selected coated and uncoated tablets, hard and soft gelatin capsules, sugar-coated pills, lozenges, wafer sheets, pellets and powders in sealed packet. For example, compositions may be formulated for topical use, for example, ointments, pomades, creams, gels and lotions. In an embodiment, rifaximin is administered to the subject using a pharmaceutically- acceptable formulation, e.g., a pharmaceutically-acceptable formulation that provides sustained delivery of the rifaximin to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically- acceptable formulation is administered to the subject. In certain embodiments, these pharmaceutical compositions are suitable for topical or oral administration to a subject. In other embodiments, as described in detail below, the pharmaceutical compositions provided herein may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous,
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BOS2 775861 1 intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles containing the compound.
The phrase "pharmaceutically acceptable" refers to rifaximin compositions containing rifaximin and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The phrase "pharmaceutically-acceptable carrier" includes pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body. Each carrier is preferably "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
In solid dosage forms of rifaximin for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is typically mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate,
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BOS2 775861 1 and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) colouring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions described herein, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying
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BOS2 775861 1 agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
Liquid dosage forms for oral administration of rifaximin include pharmaceutically- acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
In addition to inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
Suspensions, in addition to rifaximin may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Pharmaceutical compositions for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing rifaximin with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
Compositions which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
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BOS2 775861 1 Dosage forms for the topical or transdermal administration of rifaximin includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. Rifaximin may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required. Ointments, pastes, creams and gels may contain, in addition to rifaximin, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to rifaximin, excipients such as lactose, talc, silicic acid, aluminium hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
Rifaximin can be alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers are preferred because they minimize exposing the agent to shear, which can result in degradation of the compound.
Injectable depot forms are made by forming microencapsule matrices of rifaximin in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly( anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue. When the rifaximin is administered as a pharmaceutical, to humans and animals, it can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically- acceptable carrier.
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BOS2 775861 1 Regardless of the route of administration selected rifaximin which may be used in a pharmaceutical compositions provided herein, is formulated into pharmaceutically-acceptable dosage forms by methods known to those of skill in the art.
Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject. An exemplary dose range is from 25 to 3000 mg per day.
A preferred dose of rifaximin is the maximum that a subject can tolerate without developing serious side effects. Preferably, rifaximin is administered at a concentration of about 1 mg to about 200 mg per kilogram of body weight, about 10 - about 100 mg/kg or about 40 mg - about 80 mg/kg of body weight. Ranges intermediate to the above-recited values are also intended to be part of the invention.
In exemplary embodiments, subjects are administered rifaximin 1, 2, 3, or 4 times a day. Exemplary dosages include oral dosages of 100, 200, 300, 400, 500, 550, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900 or 2000 mg of rifaximin. Ranges intermediate to the above-recited values are also intended to be part of the invention. In a specific exemplary embodiment, subjects are administered 600mg or rifaximin per day. In a further specific embodiment, subjects are administered three 200 mg tablets per day. In combination therapy treatment, rifaximin and the other drug agent(s) are administered to mammals (e.g., humans, male or female) by conventional methods. The agents may be administered in a single dosage form or in separate dosage forms. Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective-amount range. In one embodiment in which another therapeutic agent is administered to an animal, the effective amount of the rifaximin is less than its effective amount in case the other therapeutic agent is not administered. In another embodiment, the effective amount of the conventional agent is less than its effective amount in case the rifaximin is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation
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BOS2 775861 1 improved dosing regimens and/or reduced drug cost) will be apparent to those skilled in the art.
In various embodiments, the therapies (e.g., prophylactic or therapeutic agents) are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part. In preferred embodiments, two or more therapies are administered within the same subject's visit. In certain embodiments, one or more compounds and one or more other therapies
(e.g., prophylactic or therapeutic agents) are cyclically administered. Cycling therapy involves the administration of a first therapy (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by the administration of a second therapy (e.g., a second prophylactic or therapeutic agent) for a period of time, optionally, followed by the administration of a third therapy (e.g., prophylactic or therapeutic agent) for a period of time and so forth, and repeating this sequential administration, e.g., the cycle in order to reduce the development of resistance to one of the therapies, to avoid or reduce the side effects of one of the therapies, and/or to improve the efficacy of the therapies.
In certain embodiments, the administration of the same compounds may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or at least 6 months. In other embodiments, the administration of the same therapy (e.g., prophylactic or therapeutic agent) other than rifaximin may be repeated and the administration may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or at least 6 months.
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BOS2 775861 1 Certain indications may require longer treatment times. For example, travelers' diarrhea treatment may only last from between about 12 hours to about 72 hours, while a treatment for Crohn's disease may be from between about 1 day to about 3 months. A treatment for hepatic encephalopathy may be, for example, for the remainder of the subject's life span. A treatment for IBS may be intermittent for weeks or months at a time or for the remainder of the subject's life. Article of Manufacture
Another embodiment includes articles of manufacture that comprise, for example, a container holding a pharmaceutical composition suitable for oral or topical administration of rifaximin in combination with printed labeling instructions providing a discussion of when a particular dosage form should be administered with food and when it should be taken on an empty stomach. The dosage can be modified for administration to a subject suffering from hepatic insufficiency, or include labeling for administration to a subject suffering from hepatic insufficiency. Exemplary dosage forms and administration protocols are described infra. The composition will be contained in any suitable container capable of holding and dispensing the dosage form and which will not significantly interact with the composition and will further be in physical relation with the appropriate labeling. The labeling instructions will be consistent with the methods of treatment as described hereinbefore. The labeling may be associated with the container by any means that maintain a physical proximity of the two, by way of non-limiting example, they may both be contained in a packaging material such as a box or plastic shrink wrap or may be associated with the instructions being bonded to the container such as with glue that does not obscure the labeling instructions or other bonding or holding means.
Another aspect is an article of manufacture that comprises a container containing a pharmaceutical composition comprising rifaximin wherein the container holds preferably rifaximin composition in unit dosage form and is associated with printed labeling instructions advising of the differing absorption when the pharmaceutical composition is taken with and without food.
In another aspect, provided herein are a article of manufacture or a kit comprising rifaximin, or a pharmaceutical composition thereof, packaged with instructions for
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BOS2 775861 1 administering to subjects having hepatic insufficiency. In one embodiment, the instructions will inform the prescribing physician, a pharmacist, or a subject that subjects having hepatic encephalopathy absorb a larger amount of rifaximin systemically than subject with normal, e.g., fully functional, hepatic systems. In one embodiment, the instructions will advise the prescribing physician that they should determine if the subject has hepatic insufficiency before prescribing rifaximin to a subject to treat a bowel disease. In one embodiment, the instructions will advise the prescribing physician that they should consider altering the dosage or dosing regimen when prescribing rifaximin to a subject having hepatic encephalopathy. Additionally, the instructions may provide prescribing information for subjects with hepatic insufficiency. In another embodiment, the instructions will inform the subject and/or the healthcare provider that there is a difference in the plasma exposure to rifaximin between HE subjects and subjects with normal liver function.
Packaged compositions are also provided, and may comprise a therapeutically effective amount of rifaximin. Rifaximin and a pharmaceutically acceptable carrier or diluent, wherein the composition is formulated for treating a subject suffering from or susceptible to a bowel disorder, and packaged with instructions to treat a subject suffering from or susceptible to a bowel disorder.
Kits are also provided herein, for example, kits for treating a bowel disorder in a subject. The kits may contain, for example, rifaximin and instructions for use when treating a subject for a bowel disorder who is also suffering from hepatic insufficiency. The instructions for use may contain prescribing information, dosage information, storage information, and the like.
Packaged compositions are also provided, and may comprise a therapeutically effective amount of rifaximin and a pharmaceutically acceptable carrier or diluent, wherein the composition is formulated for treating a subject suffering from or susceptible to a bowel disorder, and packaged with instructions to treat a subject suffering from or susceptible to a bowel disorder.
EXAMPLES
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BOS2 775861 1 Embodiments of the invention are based, in part, on the demonstration that rifaximin is differentially absorbed in subjects having other clinical conditions, e.g., hepatic encephalopathy. It should be appreciated that the invention should not be construed to be limited to the examples that are now described; rather, the invention should be construed to include any and all applications provided herein and all equivalent variations within the skill of the ordinary artisan.
Example 1
Clinical Study of Rifaximin Administration to Subjects with Impaired Liver Function To determine the effect of impaired liver function on rifaximin efficacy, tests were preformed on subjects having hepatic encephalopathy (HE). HE, also known as hepatic coma or portal- systemic encephalopathy, is a serious, rare, complex, potentially reversible, neuropsychiatric syndrome associated with advanced liver disease. Nitrogenous substances, most notably ammonia, gain access to the systemic circulation as a result of decreased hepatic function or portal- systemic shunts. Once in brain tissue, the compounds produce alterations of neurotransmission that affect consciousness and behavior. There are four progressive stages of impairment associated with HE that are defined by using the West Haven criteria (or Conn score) which range from Stage 0 (lack of detectable changes in personality) to Stage 4 (coma, decerebrate posturing, dilated pupils). Management of patients with chronic HE includes: 1) provision of supportive care,
2) identification and removal of precipitating factors, 3) reduction of nitrogenous load from the gut, and 4) assessment of the need for long term therapy. The nitrogenous load from the gut is typically reduced using nonabsorbable disaccharide (lactulose) and/or antibiotics. Although lactulose is considered a first-line treatment in the United States, it is not currently approved for either the treatment or prevention of HE. Rifaximin is an attractive therapy for the treatment of patients with HE because of its demonstrated effectiveness and because of disadvantages of systemic antibiotics and nonabsorbable disaccharides. Disadvantages of chronic systemic antibiotic therapy include nephrotoxicity and ototoxicity, and disadvantages of lactulose therapy include dehydration due to diarrhea (a precipitating factor of HE), overly sweet taste, and GI side effects.
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BOS2 775861 1 In this example, rifaximin was dosed in an outpatient setting at 550 mg BID (for a total daily dose of 1100 mg rifaximin). Subjects were dosed with 550 mg of rifaximin BID for at least 7 consecutive days prior to the day of pharmacokinetic sampling.
To ensure steady-state plasma concentrations, blood sampling for pharmacokinetic analyses was performed after at least 7 consecutive days of rifaximin 550 mg BID dosing.
Blood samples for pharmacokinetic analyses were collected on a single day at after at least 7 consecutive days of 100% compliance with the rifaximin 550 mg BID dosing regimen.
Multiple samples for pharmacokinetic analyses were collected over 12 hours (e.g., predose and at 1, 2, 4, 6, 8, 10 and 12 hours after dosing) to permit steady-state characterization of the plasma rifaximin concentration-time profile. Subjects fasted overnight (no food for approximately 10 hours) prior to administration of rifaximin and were given a standardized light meal 1 hour following administration of study drug (subsequent to the planned 1 hour plasma collection).
Pharmacokinetic parameters of rifaximin in plasma were calculated using noncompartmental methods (e.g., standard model-independent approach).
Pharmacokinetic sample collection occurred on a single day following at least 7 consecutive days of 100% compliance with the rifaximin 550 mg BID dosing regimen. A total of 8 blood samples were collected over 12 hours (e.g., predose and at 1, 2, 4, 6, 8, 10, and 12 hours after dosing) to permit characterization of the individual plasma rifaximin concentration-time profile over the 12-hour dosing interval.
Plasma concentrations of rifaximin were determined using a reversed-phase high performance liquid chromatographic method with tandem quadrupole mass spectrometric detection (LC/MS/MS) using a validated analytical procedure. The lower limit of quantification (LOQ), deviation of calibration standards from the theoretical value, and precision were established using standard methods.
Pharmacokinetic parameters of rifaximin in plasma were calculated using WinNonlin® Enterprise (Version 5.2).
Pharmacokinetic parameters were calculated using noncompartmental methods (e.g., standard model-independent approach). The following steady-state pharmacokinetic
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BOS2 775861 1 parameters for rifaximin in plasma were calculated using actual concentration-time profiles for each subject:
Figure imgf000036_0001
Other parameters such as apparent oral clearance (CL/F) and terminal or disposition half-life (V2) were estimated if adequate data was available. In addition to the planned analysis, the AUC from time 0 (pre-dose) to the last measurable concentration (AUCo-t) was also calculated.
Individual plasma concentration and pharmacokinetic parameters of rifaximin were summarized for the overall pharmacokinetic population and by hepatic impairment severity using Child-Pugh scores (A and B) with descriptive statistics (e.g., N, mean, SD, CV%, median, min, max, Geometric mean).
Demographics and other baseline characteristics were summarized for subjects by hepatic impairment severity using Child-Pugh scores (A and B) and Model End-Stage Liver Disease (MELD) score with descriptive statistics. Baseline characteristics included albumin, alkaline phosphate, alanine aminotransferase (ALT), aspartate aminotransferase (AST), international normalized ratio (INR), serum creatinine, and serum total bilirubin, where baseline was defined as last available assessment prior to the first dose of rifaximin.
Rifaximin pharmacokinetic parameters AUCτ and Cmax in subjects with Child-Pugh scores A and B (e.g., mild and moderate liver impairment) were compared using an analysis of variance (ANOVA) model.
A paired ANOVA was used to evaluate concentration values of rifaximin measured at predose and at 12 hours postdose to assess possible differences in steady-state rifaximin concentrations.
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BOS2 775861 1 A total of 25 subjects were included in the pharmacokinetic evaluable population and evaluated for safety.
Eighteen (18) of 25 subjects (72.0%) had mild hepatic impairment at baseline (e.g., Child-Pugh score A). The remaining 7 subjects (28.0%) had moderate hepatic impairment (e.g., Child-Pugh score B) at baseline.
Rifaximin pharmacokinetic parameters were compared to results from a separate study on healthy subjects with normal hepatic function.
Subject Demographics and Baseline Characteristics
Table 1 summarizes demographics for all enrolled subjects. A total of 25 subjects were enrolled in the study; 17 subjects (68.0%) were male and 8 subjects (32.0%) were female. The mean age among participating subjects was 58 years (range 45 to 68 years).
Twenty-two subjects (88.0%) were white, and the remaining 3 subjects (12.0%) were black.
Seven of 25 subjects (28.0%) were of hispanic ethnicity.
Eighteen (18) subjects had a Child-Pugh classification of A and 7 subjects had a Child-Pugh classification of B. Fifteen (15) subjects had a baseline MELD score of < 11 and
10 subjects had a baseline MELD score between 11 and 18 (inclusive). The majority of subjects participating had a Conn Score of 0 (22/25; 88.0%) at baseline for the pharmacokinetic substudy; 3 of 25 subjects (12.0%) had a Conn Score of 1 at baseline.
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BOS2 775861 1 Table l.Subject Demographics and Baseline Characteristics - AU Enrolled Subjects
Characteristic N = 25
N 25
Mean(± SD) age, years 58 (± 5.34)
Sex: n (%)
Male 17 (68.0)
Female 8 (32.0)
Race: n (%)
White 22 (88.0)
Black or African American 3 (12.0)
Child-Pugh Score: n (%)
A 18 (72.0)
B 7 (28.0)
MELD Score: n (%)
< 11 15 (60.0)
11 - 18 10 (40.0)
Conn Score
Grade 0 22 (88.0)
Grade 1 3 (12.0)
Abbreviations: MELD= model end-stage liver disease. Overall, demographic characteristics were comparable for Child-Pugh A and Child-
Pugh B subjects. Baseline demographics were also generally similar for subjects who had a baseline MELD score of < 11 and subjects who had a baseline MELD score between 11 and 18 (inclusive). A higher proportion of subjects with a MELD score between 11 and 18 were Hispanic (50.0% vs. 13.3%) compared with subjects with a MELD score < 10. Baseline laboratory findings were consistent with impaired liver function among subjects. Results of baseline liver function tests indicated greater hepatic impairment among subjects categorized as Child-Pugh B compared with subjects categorized as Child-Pugh A and greater hepatic impairment among subjects with a MELD score between 11 and 18 compared with subjects with a MELD score < 11. Specifically, Child-Pugh B subjects and subjects with a MELD score of 11-18 had noticeably higher baseline values for alkaline phosphatase, AST, and direct and total bilirubin at baseline.
On the day preceding the pharmacokinetic collection, the majority of subjects received their 2 rifaximin doses at an interval of approximately 12 hours apart. The shortest interval between doses for any subject was 10 hours; the longest interval for any subject was 13.55
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BOS2 775861 1 hours. The 2nd rifaximin dose was administered without regard to the evening meal, either before food (13 subjects) or after food (12 subjects).
On the day of pharmacokinetic sampling, the morning rifaximin dose was administered following at least 10 hours of overnight fasting. All subjects had a light meal served 1 hour postdose, subsequent to the 1 hour pharmacokinetic plasma sampling time point. The next rifaximin dose was taken immediately after the 12-hour pharmacokinetic plasma sampling time point, with 1 exception.
Mean plasma concentrations of rifaximin peaked at 1 hour after drug administration and then declined slowly over 12 hours (Figure 1). Rifaximin plasma concentrations were above the limit of quantification (LOQ) of the assay over the entire 12-hour sampling interval in all subjects. A total of 5 subjects displayed double peak plasma concentration profiles.
Rifaximin pharmacokinetic parameters at steady-state in subjects with hepatic impairment classifications of Child-Pugh A and Child-Pugh B
Table 2 summarizes pharmacokinetic parameters of rifaximin following at least 7 days of treatments in subjects with impaired liver function by Child-Pugh scores and for the overall pharmacokinetic population. A column including the values determined for the healthy subjects in a separate study is provided to facilitate comparison.
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BOS2 775861 1 Table 2. Mean (± SD) Plasma Pharmacokinetic Parameters of Rifaximin in Subjects with Liver Impairment
Hepatic Insufficient
Paramete Child-Pugh Child-Pugh
Healthy rs A B Volunteers (Mild) (Moderate) Overall N = 14 N = 18 N = 7 N = 25
AUCo-t 113 (68.2) 156 (93.0) 125 (76.4) 11.5 (6.44) (ng«h/mL)
AUCtau
118 (67.8)a 161 (101)b 130 (77.6)c 12.3 (4.76) (ng«h/mL)
*— max 19.5 (11.4) 25.1 (12.6) 21.1 (11.8) 3.41 (1.62)
(ng/mL)
*— mm 5.13 (1.04) 7.90 (5.35) 5.91 (4.49) 0.275
(ng/mL) (0.333) 967, 1.00 (0.933, 0.76 (0.50-
Tmax (h)d 1.00 (0.933, 1.00 (0. 10.0) 1.00) 10.0) 4.00) t/2 (h)e 8.12 (3.58/ 10.5 (1.50)ε 8.64 (3.63)h 4.17 (3.30)h
CL/F
122 (101)a 70.6 (29.2)b 109 (90.1)c 863 (364) (L/min) a n=17 b n=6
C n=23 d Median (Min, Max) e Harmonic mean (pseudo SD) f n=14 g n=5 h n=19
Comparisons between subjects with Child-Pugh A (mild impairment) versus Child-Pugh B (moderate impairment) and between subjects with MELD scores of < 11 (mild impairment) versus 11 to 18 (moderate impairment)
Mean AUCτ and Cmax values in subjects with Child-Pugh score B (161 ng*h/mL and 25.1 ng/mL, respectively) were approximately 36% and 29% higher than those observed in subjects with Child-Pugh score A (118 ng*h/mL and 19.5 ng/mL, respectively). The elimination rate of rifaximin in subjects with Child-Pugh B score was approximately 29% longer than that observed in subjects with Child-Pugh A score (10.5h vs. 8.12 h). The pharmacokinetics of rifaximin were characterized by an inter- subject coefficient of variability (CV%) for AUCτ and Cmax ranging from approximately 50 to 60%. This was in agreement with the variability previously observed in healthy subjects e.g., CV% of 45% to 60%.
Rifaximin pharmacokinetic parameters AUCτ and Cmax in subjects with Child-Pugh scores A and B (mild and moderate hepatic impairment, respectively) were compared using
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BOS2 775861 1 an ANOVA model. For cases where the AUCτ could not be calculated the corresponding AUCo-t values were used for inferential statistics.
The results of the one-way ANOVA analysis are summarized in Table 3. The ratio of AUCτ geometric LSM for Child-Pugh Score B to Child-Pugh Score A was 151.2% with 90% confidence intervals of 98.8% to 231.5% (p = 0.1092). The ratio of Cmax geometric LSM for Child-Pugh Score B to Child-Pugh Score A was 149.9% with 90% confidence intervals of 98.8% to 227.5% (p = 0.1096). Confidence intervals for the ratios of LSM were very large given the inter-subject variability in AUCτ and Cmax parameters in both populations.
Table 3. Effect of Hepatic Impairment Scores (Child-Pugh A versus Child-Pugh B) on Main Pharmacokinetic Parameters of Rifaximin
I Geometric
LSM Rat
Pharmac (ng/mL) io of Varian Int
90% CI okinetic P
LSM (B/A) ce er-Subject Parameter C (%) value
Chi Assumption CV (%) hild- (%) ld-Pugh B Pugh i
Child- 81.
AUCτ 9 139 151 (98.8, 0. Pugh A 8
(ng*h/mL) 2.44 .80 .2 231.5) 1092 Child- 49.
Pugh B 6
Child- 91.
^max 1 23. 149 (98.8, 0. Pugh A 5
(ng/mL) 5.41 11 .9 227.5) 1096 Child- 43.
Pugh B 6
Covariate analyses indicated that biochemical markers of impaired hepatic function, e.g., elevated albumin, total bilirubin, and international normalized ratio values correlated with elevated rifaximin systemic exposure (AUCtau and Cmax) and decreased oral clearance (CL/F).
The pharmacokinetics of rifaximin were evaluated in subjects with impaired liver function. After receiving the same dosing regimen (e.g., 550 mg BID), rifaximin systemic exposure values (AUCtau) at steady-state in subjects with Child-Pugh A and B were approximately 9.6- and 13.1-fold higher, respectively, than those observed in healthy subjects at steady-state.
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BOS2 775861.1 Systemic exposure was compared using a different method to assess liver function, MELD score. The ratios of geometric LSMs and 90% CIs for AUCτ and Cmax were determined for subjects with MELD score of < 11 (n = 15) versus MELD score of 11 to 18 (n = 10). Results of this analysis (see Table 4) showed that systemic exposure was statistically significantly higher (p < 0.05) in subjects with moderate hepatic impairment when compared with mild hepatic impairment when MELD score was used to rate hepatic function. The ratio of AUCτ for MELD score < 11 versus 11 to 18 was 168.22% with 90% CIs of 110.5% to 256.2% (p = 0.0451); and the ratio of Cmax ratio was 178.12% with 90% CIs of 116.7% to 271.8% (p = 0.0283). The correlation between MELD score and Child-Pugh category in the 25 subjects who participated in the substudy was mild (Correlation Coefficient: p = 0.399).
Table 4. Effect of Hepatic Impairment Scores (MELD score < 11 versus 11 to 18) on Main Pharmacokinetic Parameters of Rifaximin
Geometric LSM
Pharmacoki , , τ \ Ratio " o "-f ^ 9«0% "> netic (ng/mL) i LSβMM π (lil.-i1β8/n< 1i1^) m CI P
Parameter MEL MEL ( (%mΛ) ( r%%)ϊ value D < 11 D 11 to 18
AUQ 141.8 (110.5 0.045
( Ing A*lh.//mL T N) 04.3U 1. It)O. ZZ , „ 25.6,.2„,) 11
Cmax (ng/mL) 13.70 24.41 178.12 3 θ'°28
Figure imgf000042_0001
Rifaximin was rapidly absorbed, with peak plasma concentration observed at 1 hour post-dose in the vast majority of subjects. A total of 3 subjects in the Child-Pugh A group had delayed rifaximin absorption, with peak plasma concentration observed between 6 and 10 hours post dose.
Comparisons to subjects with normal hepatic function
Results from the current study were compared with historical data from subjects with normal hepatic function. Arithmetic mean (± SD) pharmacokinetic parameters of rifaximin 550 mg multiple-dose BID in healthy subjects are presented in Table 5.
Rifaximin exposure values (AUCτ) in subjects with Child-Pugh score A and B (118 and 161 ng*h/mL, respectively) were approximately 9.6- and 13.1 -fold higher than that
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BOS2 775861.1 observed in healthy subjects following twice daily oral doses of 550 mg (12.3 ng*h/mL), respectively. Except for ty2> intersubject variabilites in the pharmacokinetics of healthy subjects were generally similar to those measured in subjects with hepatic impairment.
Table 5. Arithmetic Mean (± SD) Pharmacokinetic Parameters of Rifaximin 550 mg Multiple-Dose BID in Healthy Subjects
Parameters Healthy Volunteers N = 14
AUCo-t (ng*h/mL) 11.5 (6.44)
AUCτ (ng*h/mL) 12.3 (4.76)
Cmax (ng/mL) 3.41 (1.62)
Cmin (ng/mL) 0.275 (0.333)
Tmax (h) a 0.76 (0.50-4.00) t/2 (h) b 4.17 (3.30)
CL/F (L/min) 863 (364)
1 Median (Mm, Max), Harmonic mean (pseudo SD)
Comparison of predose concentrations to 12 hours postdose on the day of the pharmacokinetic substudy Results of the paired ANOVA for the assessment of predose concentrations at 0 and
12 hours are presented in Table 6.
These results indicate that the 12-hour post-dose concentration values of rifaximin were reduced by 37.8% as compared to the morning pre-dose concentration (p < 0.0001). Coadministration with a meal was reported to increase rifaximin extent of absorption by approximately 2-3-fold. The morning dose was administered under fasting conditions.
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BOS2 775861 1 Table 6. Paired Analysis of Variance (ANOVA) Evaluation of In-Transformed Concentrations of Rifaximin at Predose and at 12 Hours Post-Dose
„. Geometri Ratio of n(ϊ(V ^τ Inter- o ff Sβamp VleZ (h) LSM ( c ng/mL) LSM (% ^) (12 h / 0 90 (^%)CI va .lue P Subj Qeyct (%)
0 7.72 (52 0 0 00 62.2 _ . XZ-V' ΠI υ'υυ 38.4
12 4.80 74-4) 01
Covariate analyses
A multivariate linear regression model was developed to evaluate the effect of various covariates on the rifaximin AUCτ, Cmax, and CL/F. The following covariates were tested in the model: Child-Pugh score and laboratory test results (albumin, alkaline phosphatase, ALT, AST, creatinine clearance, serum creatinine, INR, and total bilirubin). The covariates chosen for the analysis are known indicators of hepatic and renal function. A visual diagnostic was performed to detect potential trends between covariates of interest and AUCτ, Cmax, and CL/F.
Results are presented in Tables 7-9 below.
The covariate analyses indicated that biochemical markers of impaired hepatic function, e.g., elevated albumin, total bilirubin, and INR values correlated with elevated rifaximin systemic exposure (AUCτ and Cmax) and decreased oral clearance (CL/F) in this study.
The model with the highest R included albumin, total bilirubin, INR, and ALT (R2=53.6%, Cp=4.4101). Based on the analyses of the models, it was decided that the parsimonious model would include only albumin, total bilirubin, and INR. The final model for AUCτ is presented in Table 7.
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BOS2 775861 1 Table 7. Relationship Between AUCτ of Rifaximin and Covariates - Parsimonious Model
Final Multivariate Model
Effect Estimat Standard
95% CI p value e -Error
8.4175 (5.0768 ; <0.000 1.6064
Intercept 11.7582) 1
-0.0573 (-0.1130 ; - 0.0440
Albumin 0.0268 0.0017)
Total 0.0173 (-0.0035 ; 0.0988 0.0100 Bilirubin 0.0381)
-1.7432 (-3.1909 ; - 0.0206 0.6961
INR 0.2956)
The model with 3 parameters having the highest R included total bilirubin, INR, and ALT (R2=39.1%, Cp=3.7193). Within the subset of models with 4 parameters; the model with the highest R2 included albumin, total bilirubin, INR, and ALT (R2=46.9%, Cp=3.0598). Given that the R was higher for the model with 4 parameters; it was decided that the parsimonious model would include 4 parameters: albumin, total bilirubin, INR, and ALT. The final model is presented in Table 8.
Table 8. Relationship Between Cmax of Rifaximin and Covariates - Parsimonious Model
Final Multivariate Model
Effect Estimat Standard-
95% CI p value e Error
6.5350 (2.7734 ; 0.0017 1.8033
Intercept 10.2966)
-0.0515 (-0.1140 ; 0.1016 0.0300
Albumin 0.0111)
Total 0.0207 (-0.0022 ; 0.0742 0.0110 Bilirubin 0.0435)
-2.0654 (-3.7205 ; - 0.0170 0.7934
INR 0.4104)
0.0031 (-0.0004 ; - 0.0819 0.0017
ALT 0.0066)
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BOS2 775861 1 Within the subset of models with 4 parameters; the model with the highest R included albumin, total bilirubin, INR, and ALT (R2=54.9%, Cp=3.4103). Results of this model are presented in Table 9.
Table 9. Relationship Between CL/F of Rifaximin and Covariates - Parsimonious Model
Final Multivariate Model
Effect Estimat
95% CI P Standard- e value Error
-0.8934 (-4.6780 ; 0.625 1.8014
Intercept 2.8911) 9
0.0783 (0.0185 ; 0.013 0.0285
Albumin 0.1381) 1
Total -0.0185 (-0.0390 ; 0.073 0.0097 Bilirubin 0.0019) 2
2.5949 (0.8604 ; 0.005 0.8256
INR 4.3295) 6
-0.0028 (-0.0060 ; 0.092 0.0016
ALT 0.0005) 5
EXAMPLE 2:
A Randomized, Double-Blind, Dose Finding Study to Evaluate the Efficacy, Tolerability and Safety of Rifaximin in Patients with Grade I, II or III Hepatic Encephalopathy
A pharmacokinetic investigation was performed in subjects with HE in a dose-finding study. A total of 54 subjects (32 male, 22 female, age 32 through 82 years) were included in the study and received 200, 400, or 800 mg rifaximin TID (200 mg tablets) corresponding to daily doses of 600, 1200, and 2400 mg, respectively, for 7 consecutive days. Rifaximin plasma and urine concentrations were measured by LC-MS/MS (LLOQ = 0.5 ng/mL).
The urine recovery of rifaximin is provided in Table 10.
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BOS2 775861 1 Table 10: Urinary Recovery of Rifaximin During the 24-Hour Collection Interval After Last Dose
Mean
Numb Drug Recovery Dosage er of Subjects (mg) Mean (Range) % Recovery
200 mg ; TID x
18 0.37
7 days 0.061% (0.003-0.229%)
400 mg ; TID x
19 1.20
7 days 0.100% (0.002-0.295%)
800 mg ; TID x
17
7 days 1.35 0.056% (0.002-0.320%)
There was no relationship between the administered dose and the amount of rifaximin recovered in urine. In the 24-h urine collected after the last (third) 200, 400, and 800 mg dose on the last administration day, Day 7, the mean (SD) amount of rifaximin recovered in the urine ranged from 0.06% (+ 0.66%) through 0.1% (+ 0.093%) of dose and these values are consistent with the rifaximin recovered (e.g., 0.030% + 0.020% dose) after a single 400 mg radiolabeled dose.
Mean maximum rifaximin plasma concentrations of 2.7, 10.5, and 13.5 ng/mL were measured 3 h after the first single dose of 200, 400, and 800 mg rifaximin, respectively.
EXAMPLE 3 Rifaximin Absorption
A study was performed in hepatically impaired subjects. Mean AUCtau and Cmax values in subjects with Child- Pugh score B (161 ng»h/mL and 25.1 ng/mL, respectively) were approximately 36% and 29% higher than those observed in subjects with Child-Pugh score A (118 ng»h/mL and 19.5 ng/mL, respectively). The elimination t/2 of rifaximin in subjects with Child-Pugh B score was approximately 29% longer than that observed in subjects with Child- Pugh A score (10.5h vs. 8.12 h). Rifaximin pharmacokinetic parameters had inter-subject coefficient of variability percentages (CV%) for AUCo-tau and Cmax ranging from approximately 50% to 60% in both subpopulations. This was in agreement with the variability previously observed in healthy subjects, e.g., CV% of 45% through 60%.
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BOS2 775861 1 Rifaximin was rapidly absorbed, with peak plasma concentration observed at 1 h post- dose in the vast majority of subjects. A total of 3 subjects in the Child-Pugh A group had delayed rifaximin absorption, with peak plasma concentration observed between 6 and 10 h post-dose. Several subjects displayed flat or double-peak plasma concentration profiles of rifaximin. Abnormalities of gastrointestinal motility and of bile secretion in subjects with cirrhosis and HE may potentially explain delayed/prolonged rifaximin absorption observed in this study.
Results of the multiple linear regression models showed that biochemical markers of hepatic function, e.g., elevated albumin, total bilirubin, and International Normalized Ratio, correlated with increased rifaximin systemic exposure (AUCtau and Cmax) and decreased oral clearance (CL/F). A positive correlation between baseline alanine aminotransferase and Cmax was also observed.
In a separate study, the pharmacokinetic parameters were studied. This population included 18 subjects (72%) with mild hepatic impairment (Child-Pugh A) and 7 subjects with moderate hepatic impairment (Child-Pugh B). The healthy subject study included 28 subjects.
Rifaximin exposure values (AUCtau) in subjects with Child-Pugh score A and B (118 and 161 ng»h/mL, respectively) were approximately 9.6- and 13.1-fold higher, respectively, than those observed in healthy subjects following twice daily oral doses of 550 mg (12.3 ng»h/mL). Except for t/2 intersubject variability in the pharmacokinetics of healthy subjects were generally similar to those measured in subjects with hepatic impairment.
Example 4 Phase 3 Studies
A phase 3 randomized, double-blind, placebo-controlled multicenter study (Study A) to evaluate the efficacy and safety of rifaximin in patients currently in remission from previously demonstrated HE was conducted. The study consisted of a screening period (4 days), observation period (3 days), baseline visit, and treatment period (6 months). After determining eligibility, patients underwent a baseline assessment period prior to randomization. This period was 7 days in duration and was used to determine the patient's eligibility, provide adequate instructions to caregivers and establish baseline mental status
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BOS2 775861 1 and neuromuscular function before entering the double-blind period. Patients were randomized to received rifaximin 550-mg tablet BID or matching placebo tablet BID for 6 months. Subjects had the option to use lactulose as a concomitant medication, and 91% of subjects in both groups were taking lactulose during the course of the study. Subjects underwent extensive evaluations of mental status (Conn score) and neuromuscular functioning (asterixis grade) for determination of the occurrence of a breakthrough overt HE episode by the investigators and site personnel at each in-person study visit, telephone interviews, caregiver reports, and from subject diaries. Subjects were discontinued from the study at the time of breakthrough overt HE episode. After participation in the study subjects had the option to enroll in the open-label, treatment-extension study (Study B).
Rifaximin Dose
The dosage regimen used (550 mg BID) in Study A was based on past clinical experience with rifaximin in patients with HE and other subject populations. In several previous studies, rifaximin was safe and effective in subjects with HE at a dose of 1200 mg per day (2 x 200 mg tablets TID) with or without concomitant lactulose. In a 6-month study of rifaximin versus neomycin, rifaximin 1200 mg/day and neomycin (3 g/day) had comparable efficacy in patients with HE. In the 3-month studies of rifaximin versus lactitol, subjects who received rifaximin 1200 mg daily (2 x 200 mg tablets TID) showed significant improvements in HE endpoints. In a dose-ranging study in subjects with active symptoms of HE, there was a dose- dependent trend in improvement in the PSE index up to 1200 mg (2 x 200 mg tablets TID). Similar results were observed for the 1200 mg and 2400 mg doses (4 x 200 mg tablets TID) (Table 11). In a dose-response analysis, the Jonckheere-Terpstra test indicated a trend in improvements in PSE index across dose groups (p = 0.0586).
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BOS2 775861 1 Table 11 Change from Baseline in PSE Index (ITT population)
Study C (N=54)
Rifaximin
600 mg/day 1200 mg/day 2400 mg/day
PSE index" N= 18 N= 18 N= 18
End-of-treatment (Day 7) minus baseline
14 16 16
Mean (standard deviation) -0.064 (0.137) -0.103 (0.137) -0.107 (0.149)
Abbreviations: PSE: portal systemic encephalopathy; EEG: electroencephalogram. a PSE index was calculated as follows: [Mental State (Conn score) X 3 + asterixis grade X l + NCT grade X l + ammom grade X 1 + EEG grade X 1 (if available) / 24 (or 28 if EEG is available)]. (24 [or 28 if EEG results are included] is the highe possible score and higher scores are indicative of worse symptoms of HE.)
Study Population For Study A, male or female subjects aged 18 years and older were eligible for the study if they met the following inclusion criteria: o Conn score 0 or 1 o History within 6 months of > 2 episodes of overt HE associated with chronic liver disease (eg, cirrhosis or portal hypertension) with a documented severity equivalent to Conn score > 2 prior to screening (ie, subjects had documented recurrent, overt HE). At least 1 prior episode was verified from medical records. Hepatic encephalopathy episodes primarily attributed to GI hemorrhage, medications (eg, narcotics, tranquilizers, sedatives), renal failures requiring dialysis, or CNS insult such as a subdural hematoma were not counted as prior, qualifying episodes of HE. o MELD score of < 25, o TIPS placement or revision > 3 months prior to screening (if present) and o Had a close family or other personal continuing oversight and be available to the subject during the study. Subjects were excluded from the study if the following criteria applied: o Expected to receive a liver transplant within 1 month of screening
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BOS2 775861 1 o Consume alcohol within 14 days of screening, sedatives within 7 days or evidence of drug dependence o HF/ as determined by medical history o History of TB infection or treatment for a TB infection o Active SBP or daily prophylactic antibiotic therapy o GI bleeding requiring hospitalization and blood transfusion < months of screening o Presence of intestinal obstruction or had inflammatory bowel disease o Renal insufficiency (serum Cr > 2.0 mg/dL) o Anemia (HgB < 8 gm/dL) o Hypovolemia or electrolyte abnormality (Na+ < 125 mEq/L, Ca++ > 10 mg/dL, K+ < 2.5 mEq/L o Required prohibited concurrent medications
Efficacy Endpoints Definitions The primary endpoint in Study A was the time to first breakthrough overt HE episode.
A breakthrough overt HE episode was defined as an increase of Conn score to Grade > 2 (ie, 0 or 1 to > 2) or an increase in Conn and asterixis score of 1 grade each for those subjects who entered the study with a Conn score of 0. Time to breakthrough overt HE episode was the duration from first dose of study drug to the first breakthrough overt HE episode. Key secondary endpoints are listed below:
1. Time to first HE-related hospitalization.
2. Time to any increase from baseline in Conn score (mental state grade).
3. Time to any increase from baseline in asterixis grade.
4. Mean change from baseline in fatigue domain scores on the CLDQ at end of treatment.
5. Mean change from baseline in venous ammonia concentration at end of treatment.
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BOS2 775861 1 Details of the treatment group for Study A are presented below in Tables 12-13.
Table 12 Demographic Characteristics by Treatment Group (ITT Population)
Characteristic Placebo Rifaximin Total Category or statistic N = 159 N = 140 N = 299
Age (years) n 159 140 299
Mean (SD) 56.8 (9.18) 55.5 (9.57) 56.2 (9.38)
Median (Min, max) 57.0 (21, 78) 55.0 (26, 82) 56.0 (21, 82)
Age group - n (%)
< 65 128 (80.5) 113 (80.7) 241 (80.6)
> 65 31 (19.5) 27 (19.3) 58 (19.4)
Sex - n (%)
Male 107 (67.3) 75 (53.6) 182 (60.9)
Female 52 (32.7) 65 (46.4) 117 (39.1)
Ethnicity - n (%)
Hispanic or Latino 28 (17.6) 21 (15.0) 49 (16.4)
Not Hispanic or Latino 131 (82.4) 119 (85.0) 250 (83.6)
Race
American Indian/Alaskan native 3 (1.9) 5 (3.6) 8 (2.7)
Asian 8 (5.0) 4 (2.9) 12 (4.0)
Black/African American 5 (3.1) 7 (5.0) 12 (4.0)
Native Hawaiian/Pacific islander 1 (0.6) 2 (1.4) 3 (1.0)
White 139 (87.4) 118 (84.3) 257 (86.0)
Other 3 (1.9) 3 (2.1) 6 (2.0)
Missing 0 1 (0.7) 1 (0.3)
Country - n (%)
United States 112 (70.4) 93 (66.4) 205 (68.6)
Canada 6 (3.8) 8 (5.7) 14 (4.7)
Russia 41 (25.8) 39 (27.9) 80 (26.8)
Table 13 Demographics in Studies A and B
Long Term Rifaximin
Experience Population
RCT Study Population (Study A) (Study A+Study B)
Rifaximin
Placebo 550 mg BID AU Rifaximin Subjects
(N = 159) (N = 140) (N = 348)
Category n (%) n (%) n (%)
Sex, n (%) Male 107 (67) 75 (54) 203 (58) Female 52 (33) 65 (46) 145 (42)
Age, yr Mean (SD) 57 (9.2) 56 (9.6) 57 (9.3) < 65 yr , n (%) 128 (81) 113 (81) 277 (80) > 65 yr , n (%) 31 (19) 27 (19) 71 (20)
Race (n, %) Asian 1 (5) 4 (3) 9 (3)
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BOS2 775861 1 Long Term Rifaximin
Experience Population
RCT Study Population (Study A) (Study A+Study B)
Rifaximin
Placebo 550 mg BID AU Rifaximin Subjects
(N = 159) (N = 140) (N = 348)
Category n (%) n (%) n (%)
Black/African- American 5 (3) 7 (5) 16 (5)
White 139 (87) 118 (84) 310 (89)
Ethnicity, n (%)
Hispanic or Latino 28 (18) 21 (15) 45 (13)
Not Hispanic or Latino 131 (82) 119 (85) 303 (87)
Hispanic or Latino 28 (18) 21 (15) 45 (13)
Geographic region, n (%)
United States 112 (70) 93 (66) 269 (77)
Canada 6 (4) 8 (6) 15 (4)
Russia 41 (26) 39 (28) 64 (19)
Baseline Characteristics
Hepatic encephalopathy baseline characteristics in the ITT population such as HE severity for recent episodes of overt HE (Conn scores and asterixis grades) and time since last HE episode are summarized in
Table 4. Liver disease characteristics and other characteristics of subjects at baseline in the ITT population such as disease severity (MELD score), time since first diagnosis of advanced liver disease and etiology of liver disease are summarized in Tables 15, 16 and 17. Baseline characteristics were generally comparable across the treatment groups.
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BOS2 775861 1 Table 14 Hepatic Encephalopathy Baseline Characteristics by Treatment Group (ITT Population)
Placebo Rifaximin Total
Characteristic N = 159 N = 140 N = 299
Time since first diagnosis of hepatic encephalopathy (months) n 159 139 298
Mean (SD) 21.9 (26.4) 20.8 (23.13) 21.4 (24.9)
Median (min, max) 11.0 (0.6, 179.4) 11.8 (0.5, 125.1) 11.5 (0.5, 179.4)
Number of HE episodes within the past 6 months - n (%)
2 111 (69.8) 97 (69.3) 208 (69.6)
3 35 (22.0) 29 (20.7) 64 (21.4)
4 8 (5.0) 5 (3.6) 13 (4.3)
5 1 (0.6) 7 (5.0) 8 (2.7)
>6 3 (1.9) 2 (1.4) 5 (1.6)
Missing 1 (0.6) 0 1 (0.3)
Past HE severity (Conn score at most recent episode prior to study) - n (%)
Grade 1 2 (1.3) 1 (0.7) 3 (1.0)
Grade 2 130 (81.8) 115 (82.1) 245 (81.9)
Grade 3 24 (15.1) 20 (14.3) 44 (14.7)
Grade 4 2 (1.3) 3 (2.1) 5 (1.7)
Missing 1 (0.6) 1 (0.7) 2 (0.7)
Duration of verified current remission (taking qualifying HE episodes into account) (days) n 158 139 297
Mean (SD) 73.1 (51.33) 68.8 (47.68) 71.1 (49.62)
Median (min, max) 61.0 (12, 205) 55.0 (8, 222) 57.0 (8, 222)
Duration of verified current remission categories - n (%)
< 90 days 110 (69.2) 100 (71.4) 210 (70.2)
> 90 days 48 (30.2) 39 (27.9) 87 (29.1)
Missing 1 (0.6) 1 (0.7) 2 (0.7)
Conn score - n (%) (at Baseline, subjects were in remission)
Grade 0 107 (67.3) 93 (66.4) 200 (66.9)
Grade 1 52 (32.7) 47 (33.6) 99 (33.1)
Asterixis grade - n (%)
Grade 0 108 (67.9) 96 (68.6) 204 (68.2)
Grade 1 45 (28.3) 41 (29.3) 86 (28.8)
Grade 2 5 (3.1) 2 (1.4) 7 (2.3)
Grade 3 1 (0.6) 1 (0.7) 2 (0.7)
Average critical flicker frequency (Hz) n 159 140 299
Mean (SD) 37.4 (6.03) 36.9 (5.47) 37.2 (5.77)
Median (min, max) 37.5 (15, 50) 37.2 (18, 48) 37.3 (15, 50)
Average Venous Ammonia Concentration (μmol/L) n 146 132 278
Mean (SD) 90.3 (52.48) 87.9 (47.76) 89.2 (50.22)
Median (min, max) 84 (20, 465) 76.5 (20, 290) 79.5 (20, 465)
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BOS2 775861 1 Placebo Rifaximin Total
Characteristic N = 159 N = 140 N = 299
Prior lactulose use- n (%)
Yes 145 (91.2) 128 (91.4) 273 (91.3)
No 14 (8.8) 12 (8.6) 26 (8.7)
Lactulose daily dose at Baseline (cups/day)a n 145 128 273
Mean (SD) 3.7 (2.54) 3.5 (3.24) 3.6 (2.88)
Median (min, max) 3.0 (0, 13) 2.8 (0, 30) 2.9 (0, 30) a One cup = 15 mL lactulose at 10 g/15 mL.
Table 15 Liver Disease Characteristics and Other Characteristics at Baseline by Treatment Group (ITT Population)
Placebo Rifaximin Total
Characteristic N = 159 N = 140 N = 29
Time since first diagnosis of advanced liver disease (months) n 159 140 299
Mean (SD) 60.5 (64.89) 51.2 (49.2) 56.2 (58
Median (min, max) 39.0 (2, 323.4) 38.0 (1.7, 260.5) 38.3 (1.7, 3
Model end-stage liver disease (MELD) score n 158 140 298
Mean (SD) 12.7 (3.94) 13.1 (3.64) 12.9 (3.1
Median (min, max) 12.4 (6, 23) 13.1 (6, 24) 12.6 (6,
Model end-stage liver disease (MELD) score category - n (%)
< 10 48 (30.2) 34 (24.3) 82 (27.-
11 - 18 96 (60.4) 94 (67.1) 190 (63
19 - 24 14 (8.8) 12 (8.6) 26 (S.1
> 25 0 0 0
Missing 1 (0.6) 0 1 (0.3
Diabetes at baseline - n (%)
Yes 56 (35.2) 44 (31.4) 100 (33
No 103 (64.8) 96 (68.6) 199 (66
Table 16 Cirrhosis Etiology in Study A
RCT Study Population Study A Placebo Rifaximin 550 mg BID
(N = 159) (N = 140)
System Organ Class n (%) n (%)
Etiology
Hepatitis C 67 (42) 61 (44)
Alcohol 57 (36) 47 (34)
Hepatitis C + Alcohol 10 (6) 18 (13)
Other:
NAFLD/NASH 17 (11) 13 (9) Hepatitis B 13* (8) 11 (8) Cryptogenic 11 (7) 9 (6) Autoimmune Hepatitis 1 (1) 9 (6) Primary Biliary cirrhosis 5 (3) 4 (3) Drug/chemical induced 1 (1) 2 (1) Genetic 2 (1) 0
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BOS2 775861 1 RCT Study Population Study A
Placebo Rifaximin 550 mg BID
(N = 159) (N = 140)
System Organ Class n (%) n (%)
*The cirrhosis etiology was alcohol and hepatitis B for r of these 13 subjects.
Table 17 Medical History in Study A or Study B
Long Term Rifaximin Experience Population
RCT Study Population (Study A) (Study A+Study B)
Rifaximin
Placebo 550 mg BID AU Rifaximin Subjects (N = 159) (N = 140) (N = 348)
System Organ Class n (%) n (%) n (%)
Any Organ Class 159 (100) 140 (100) 348 (100)
Blood and lymphatic system 59 (37) 63 (45) 176 (51)
Cardiac 35 (22) 34 (24) 80 (23)
Endocrine 11 (7) 18 (13) 39 (11)
Gastrointestinal 145 (91) 122 (87) 324 (93)
Study B Design
Study B is an ongoing phase 3, multicenter, open-label, treatment-extension study evaluating the long-term safety of rifaximin 550 mg BID in subjects with a history of recurrent, episodic, overt HE. All eligible subjects had a history of overt HE episodes with a documented severity of Conn score > 2 within 12 months prior to screening, a Conn score of < 2 at enrollment, and either had participated in Study A or were new subjects. Treatment with rifaximin 550 mg tablet BID is planned for at least 24 months or until regulatory approval. Concomitant therapy with lactulose is optional.
Although Study B was primarily designed to evaluate the long-term safety of rifaximin 550 mg, additional efficacy assessments of Conn score and asterixis grade were collected during the study. In Study B, breakthrough overt HE was defined as an increase of Conn score to Grade > 2, an increase in Conn and asterixis score of 1 grade each for those subjects who entered the study with a Conn score of 0, and an increase in Conn score to > 3 for subjects who had a Conn score of 2 at study entry.
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BOS2 775861 1 Studies C, D, and E Design
Study C was a double-blind, dose-ranging study in subjects with Grade 1-3 HE enrolled at 5 centers in the United Kingdom. Subjects were randomized to rifaximin at daily doses of 600 mg (200 mg TID), 1200 mg (400 mg TID), or 2400 mg (800 mg TID) for 7 days. Planned enrollment was 54 subjects (18 per group).
Study D was a double-blind, double-dummy, comparative, phase 3 study of rifaximin 1200 mg/day and lactitol 60 g/day for up to 10 days of treatment in hyperammonemic, cirrhotic subjects with Grade 1-3 HE enrolled at 16 centers in Spain. Planned enrollment was 120 subjects (60 per group).
Study E was a phase 3, international, multicenter, randomized, double-blind, placebo- controlled, parallel-group study comparing 14 days of rifaximin 400 mg TID to placebo in cirrhotic subjects with mild to moderate hepatic encephalopathy who were intolerant to the GI side effects of lactulose or lactitol. The study was conducted in the United States, Poland, Hungary, and the United Kingdom. Planned enrollment was 112 subjects (56 per group)
Primary efficacy endpoint definition
Mental state (Conn score) and neuromuscular function (asterixis grade) were assessed in studies C, D and E using the same criteria as described above for studies A and B.
Venous ammonia levels, NCT scores, and EEG results were graded according to increasing severity.
Study C: The primary efficacy endpoint for study C was the PSE index at the end of study. The PSE index was a component score that included scores for mental state (Conn score), asterixis, venous ammonia levels, NCT, and EEG.
The differences in PSE index at end of study across rifaximin 600 mg, 1200 mg, and 2400 mg daily treatment groups were evaluated by analysis of covariance.
Study D: Four primary efficacy endpoints were defined:
1. Improvement in mental state (Conn score)
2. PSE index.
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BOS2 775861 1 3. Decrease in venous ammonia levels
4. Decrease in PSE index
Study E: The primary efficacy endpoint was the overall response rate, defined as the proportions of subjects who showed improvement in mental state (Conn score) by at least 1 level (eg, change from Conn score 2 to Conn score 1 or 0) after completing treatment when compared to baseline.
Demographics and Baseline Characteristics
In study C, mean ages were 55.2 years, 52.3 years, and 55.3 years in the 600 mg, 1200 mg, and 2400 mg groups, respectively. In study D, mean ages were 61.6 years and 62.9 years in the rifaximin and lactitol groups, respectively. In study E, mean ages were 53.6 years and 53.3 years in the rifaximin and placebo groups, respectively.
Demographic characteristics were generally similar across treatment groups in studies C, D, and E.
Table 8 presents a summary of baseline characteristics for studies C, D, and E. Subjects in study D had more severe HE symptoms, as measured by mental status/Conn scores, asterixis grades, and PSE index, than subjects in study E. Also, disease severity was greater in D compared with C. For example, the proportions of subjects with mental status/Conn scores of >2 at baseline were 70% (rifaximin) and 60.3% (lactitol) in D, 14.6% (rifaximin) and 4.4% in E, and 16.7%, 31.6%, and 23.5% in the 600 mg, 1200 mg, and 2400 mg groups in C. Time since diagnosis of the HE condition (ie, duration of HE) was substantially longer in the Study D than in Study E and Study C (see Table 8).
Table 18 Studies C, D, and E: Summary of Baseline Characteristics (ITT population)
Figure imgf000058_0001
Duration of hepatic encephalopathy (years) n 18 19 17 46 49 48 45
Mean (SD) 0.4 (0.9) 0.9 (2.1) 0.8 (2.9) 3.7 (4.3) 4.4 (5.0) 1.49(1.82) 1.56(2.2
Min, max 0, 18 8, 19 12, 17 0.003, 15 0,20 0,7.3 0,9.0
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BOS2 775861 1
n <
I)s
Figure imgf000059_0001
Mental state/Conn score - n (%)
0 1 (5.6) 1 (5.3) 0 0 1 (1.9) 5 (10.4%) 3 (6.7%
1 14 (77.8) 12 (63.2) 13 (76.5) 15 (30.0) 20 (37.7) 36 (75.0%) 40 (88.99
2 3 (16.7) 5 (26.3) 4 (23.5) 29 (58.0) 20 (37.7) 7 (14.6%) 2 (4.4%
3 0 1 (5.3) 0 6 (12.0) 12 (22.6) 0 0
Asterixis grade - n (%)
0 2 (11 D 4 (21.1) 3 (17.7) 5 (10.2) 1 (1.9) 19 (39.6%) 22 (48.99
1 10 (55 •6) 10 (52.6) 5 (29.4) 5 (10.2) 8 (15.4) 21 (43.6%) 18 (40.09
3 (16 7) 4 (21.1) 8 (47.1) 10 (20.4) 17 (32.7) 5 (10.4%) 5 (11.1%
3 (16 7) 0 1 (5.9) 18 (36.7) 14 (26.9) 2 (4.2%) 0
4 0 1 (5.3) 0 11 (22.5) 12 (23.1) 1 (2.1%) 0
PSE index n 14 16 16 43 38 46 43
Mean (SD) 0.38 (0.11) 0.38 (0.14) 0.42 (0.085) 0.56 (0.13) 0.56 (16) 0.30 (0.14) 0.29 (0 1
Venous ammonia level (US/dL) n 14 16 16 50 51 48 44
Mean (SD) 132.8 (108 •9) 143 5 183 3 131.5 150.7 95 1 (60.07) 85.2 (139 8) (155 9) (68.9) (104.0) (37.66)
Patient Disposition
At the time of the 120 Day safety update, 280 subjects were enrolled at 60 study sites. A total of 152 (54.3%) of these subjects rolled over from the lead-in study (Study A) and 128 (45.7%) were new subjects. A total of 187 subjects (66.8%) are still ongoing in the study. Ninety-three subjects (33.2%) discontinued treatment early, and primary reasons were death, liver transplant, subject request, and adverse events.
Baseline characteristics
Baseline characteristics were generally similar between subjects in Study A and subjects in Study B. Demographics are presented in and baseline characteristics are presented in for new rifaximin subjects in Study B.
Differences between baseline characteristics between Study A subjects and Study B were related to differences in entry criteria. Subjects had > 1 verifiable episode of HE within 12 months prior to screening for study Study B versus > 2 HE episodes within 6 months prior
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BOS2 775861 1 to screening for Study A. Consistent with these differences, when compared with study Study A, subjects in Study B had longer durations of current verified remission from HE and lower proportions of subjects with 2 or 3 verifiable HE episodes prior to study entry.
Subgroup Analyses for Time to Breakthrough Overt HE Rifaximin treatment reduced the risk of experiencing breakthrough overt HE episodes across all subgroups examined.
Hazard ratios for the risk of experiencing breakthrough overt HE in the rifaximin group relative to the placebo group (primary efficacy endpoint), 95% CIs, and p-values from the Cox proportional hazards model are presented in Figure 2. Hazard ratios of less than 1 indicate that the outcome favors rifaximin and greater than 1 favors placebo.
Time to first breakthrough overt HE episode results across Child-Pugh classifications at baseline are presented in Table 9. The Child-Pugh subscores, total scores and classifications were obtained post study. Rifaximin treatment resulted in significant reductions in the risk of experiencing breakthrough overt HE episode when compared to placebo, across Child-Pugh A, B or C classes. A statistically significant rifaximin treatment effect in reducing the risk of experienced breakthrough overt HE was observed in Child-Pugh A (5-6), B (7-9), and C (10-15) classifications.
Table 19 Study A - Breakthrough Overt HE Episodes by Child-Pugh Class
Placebo Rifaximin N = 159 N = 140 Hazard ratios
Classification (score) n (%) n (%) (95% CI)a p-value
Child-Pugh A (5-6), n 56 46 Breakthrough overt HE, n (%) 26 (46.4) 8 (17.4) 0.339 (0.153, 0.749) 0.0050 No breakthrough overt HE, n (%) 30 (53.6) 38 (82.6)
Child-Pugh B (7-9), n 72 65 Breakthrough overt HE, n (%) 32 (44.4) 15 (23.1) 0.442 (0.239, 0.816) 0.0073 No breakthrough overt HE, n (%) 40 (55.6) 50 (76.9)
Child-Pugh C (10-15), n 14 17 Breakthrough overt HE, n (%) 9 (64.3) 5 (29.4) 0.345 (0.115, 1.037) 0.0474 No breakthrough overt HE, n (%) 5 (35.7) 12 (70.6)
Missing, n 17 12 Breakthrough overt HE, n (%) 6 (35) 3 (25) 0.595 (0.149, 2.384) 0.4587 No breakthrough overt HE, n (%) 11 (65) 9 (75)
Source: Table 2 - analysis by Child-Pugh class (18 Dec 2009 submission to FDA); Abbreviations: BID = twice daily; CI=confidenc( interval. a Hazard ratio, 95% CI determined from time to breakthrough HE analysis using Cox proportional hazards model with effe for treatment and stratified by analysis region. P-value determined from Log Rank test stratified by analysis region.
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BOS2 775861 1 Study A Secondary Efficacy Analyses
Rifaximin treatment resulted in a 50% reduction, when compared with placebo, in the risk of HE-related hospitalization (ie, hospitalization directly resulting from HE or HE events occurring during hospitalization) during the 6-month treatment period (hazard ratio=0.500, 95% CI: 0.287 to 0.873, p=0.0129). Hepatic encephalopathy-related hospitalizations were reported for 19 of 140 subjects and 36 of 159 subjects in the rifaximin and placebo groups, respectively. After normalization to exposure, the HE-related hospitalization rate was 51% lower (0.38 event/PEY, rifaximin versus 0.78 event/PEY, placebo) in the rifaximin group.
Subjects in the rifaximin group had a 56% reduction in the risk of HE-caused hospitalization (ie, hospitalization directly resulting from HE only) during the 6-month treatment period when compared with placebo (hazard ratio=0.438, 95% CI: 0.238 to 0.807, p = 0.0064). HE-caused hospitalizations were reported for 15 of 140 subjects and 33 of 159 subjects in the rifaximin and placebo groups, respectively. The HE-caused hospitalization rate was 0.30 events/PEY in the rifaximin group versus 0.72 event/PEY in the placebo group.
Changes from baseline in CLDQ fatigue domain scores at end of treatment of Study A
Health related quality of life assessments were performed through the use of the validated Chronic Liver Disease Questionnaire (CLDQ) for subjects with chronic liver disease.
Traditionally, CLDQ analyses are performed by comparing the changes from baseline to the last assessment in CLDQ overall and domain scores between the 2 treatment groups. However, in this study using a simple change from baseline analysis has the following limitations. Firstly, the questionnaire measures the subject's quality of life status over the 2 weeks prior to completing the questionnaire. By comparing results in the 2 weeks prior to last assessment to the 2 weeks prior to baseline (change from baseline analysis), changes over the entire course of the study are not captured in the analysis. Secondly, most subjects in the study also had comorbidities associated with hepatic cirrhosis that can potentially skew results, depending on the timing of complication, and if it occured at or near the first or last assessment. Finally, subjects who experienced an overt HE breakthrough episode were
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BOS2 775861 1 withdrawn from the study per protocol, and completed the last CLDQ assessment during the end of study visit, which often occured after the resolution of the HE event. Therefore, for these subjects, the CLDQ results may have been similar to baseline levels. To address these limitations an AUC analysis using a Twa (AUC adjusted for exposure time in study) was performed since it allows for inclusion of CLDQ results over the subject's complete time of participation in the study especially prior to breakthrough HE episode.
When CLDQ results were analyzed using the Twa, subjects in the rifaximin group had significantly less fatigue and significantly greater overall quality of life than subjects in the placebo group. CLDQ results in favor of the rifaximin group were also observed for the overall CLDQ domain score (p = 0.0093), and for each of the other component domains of the CLDQ, including abdominal symptoms (p = 0.0090), systemic symptoms (p = 0.0160), activity (p = 0.0022), emotional function (p = 0.0065), and worry (p = 0.0436).
The CLDQ results were shown to be predictive of breakthrough overt HE episodes as defined by the primary endpoint (Figure 4). There were significant differences in frequency distributions of Twa (AUC normalized by exposure time) for all domains of the CLDQ between subjects who had breakthrough overt HE and subjects without breakthrough overt HE. The mean Twa for each domain and overall correlated with presence or absence of breakthrough overt HE episode.
Long-Term Efficacy (Study A and Study B) Although Study B was primarily designed to evaluate the long-term safety of rifaximin 550 mg additional efficacy assessments of Conn score and asterixis grade were collected at each visit and at the time of an overt HE breakthrough. Kaplan Meier analyses of time to first breakthrough overt HE episode demonstrated consistency, durability, and repeatability of the protective effect of rifaximin compared with placebo as noted in Study A.
Time to Breakthrough Overt HE in Study B - Consistency with Study A Results
The Kaplan-Meier estimates of time to first breakthrough overt HE episode were similar between the rifaximin group in study Study A (rifaximin PEY=50) and new rifaximin subjects in Study B (rifaximin PEY=80) (p=0.800 for difference in relative risk). Also,
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BOS2 775861 1 similar proportions of subjects had breakthrough overt HE episodes in the rifaximin group of Study A (22%, 31 of 140 [rifaximin group]) and in the new rifaximin group of Study B (20.5%, 43 of 210). Adjusted for exposure, rates of breakthrough overt HE episodes were 0.62 events/PEY in the rifaximin group from Study A compared to 0.5 events/PEY for new rifaximin subjects in Study B.
Time to Breakthrough Overt HE Episode in Placebo Subjects in Study A Who Crossed Over to Rifaximin Therapy in Study B
Placebo treated subjects from Study A who crossed over into Study B were followed during open-label study (n=82). The comparison of Kaplan Meier estimates of time to first breakthrough overt HE episode between the placebo experience in Study A and during the first 6 months of rifaximin treatment in Study B is shown in Figure 5. The ratio of the incidence of breakthrough overt HE episode for rifaximin treatment relative to placeo treatment was 0.2112 (95% CI: 0.1006 to 0.4432, p < 0.0001 for between group difference in relative risk). This result represents 79% reduction in risk of experiencing breakthrough overt HE during rifaximin treatment in Study B when compared with their prior placebo experience in Study A. Breakthrough overt HE was experienced by 14 of 82 during 6 months of rifaximin treatment in Study B versus 39 of 82 during placebo treatment in Study A. Rates of breakthrough HE episodes were 1.5 events/PEY during placebo experience in Study A and 0.4 events/PEY during rifaximin experience in Study B. Collectively these results demonstrate that the placebo crossover subjects in Study B experienced a similar protective effect against breakthrough HE episodes compared with rifaximin-treated subjects in Study A and the continuing rifaximin group in Study B.
PSE Index during Short-Term Treatment
Improvements (ie, decreases) in PSE index were observed in all treatment groups from baseline to end of treatment in the dose-ranging study, Study C. Mean changes from baseline in PSE index at end of treatment was -6.4%, -10.3%, and -10.7% in the 600 mg, 1200 mg, and 2400 mg rifaximin daily dose groups, respectively. In Study D, which compared rifaximin 1200 mg daily to lactitol, there was a significant reduction in PSE index in the rifaximin group when compared with lactitol group (p = 0.0103). Also in Study D, the
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BOS2 775861 1 PSE efficacy index showed significant improvements in the rifaximin group compared to the lactitol group (p = 0.0083). Changes in PSE index were similar between rifaximin and placebo groups in Study E.
Figure 6 illustrates PSE index results at baseline and at end of studies C, D, and E.
Improvements in Conn Score during Short-Term Treatment
In study C (dose-ranging study), there was evidence of a statistical trend showing greater proportions of subjects who had improvements in mental state (Conn score) in the 1200 mg group when compared with the 600 mg group (p = 0.099 by using the proportional odds model). Additionally, at the 2400 mg daily dose, a higher proportion of subjects had improvements in Conn score when compared to the 600 mg daily dose (31.3% versus 26.7% had Conn score changes of -1 or -2).
Improvements in mental state (Conn score), were not notably different between rifaximin and lactitol groups in Study D; however, 3 of the Study D primary efficacy endpoints; decrease in PSE index, improvement in PSE efficacy index, and decrease in venous ammonia levels; showed significant, favorable effects of rifaximin. The absence of a significant rifaximin effect in improvements in Conn score in Study D may have been due to the short duration of study drug therapy (10 days).
In Study E, the lack of a rifaximin effect on improvements in Conn score may have been due to short duration of therapy in this study (15 days) and the mild HE symptoms at baseline. Subjects in study Study E had mild HE symptoms, as measured by mental status/Conn scores, asterixis grades, and PSE index, when compared with subjects in study Study D or Study C.
Asterixis Grade, NCT Results, and Global response During Short-Term Treatment
The percentages of subjects who had improvements in asterixis grade while on drug increased with higher rifaximin doses in Study C. In Study D (rifaximin versus lactitol), the proportions of subjects who had improvements in asterixis grade were similar between groups. In the rifaximin versus placebo study, Study E, a greater frequency of subjects had
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BOS2 775861 1 improvements in asterixis grade in the rifaximin group compared to the lactitol group (39.1% versus 9.3%; p = 0.0097 for between-group difference in favor of rifaximin).
The changes in NCT scores were generally similar across groups in each of the 3 studies. The overall global response to treatment was evaluated in Study D. The percentages of subjects who were considered cured (venous ammonia normalized and mental state/Conn score of 0) by end of study were higher in the rifaximin group when compared with the lactitol group (53.1% versus 39.2%).
Summary of Results for Short-Term Treatment Studies C, D, and E In Study C, a dose-dependent trend in improvement of PSE index (p = 0.056) and mental state/Conn score were observed, and results from this study showed the effectiveness of 1200 mg rifaximin daily dose (400 mg TID). These data, together with results from published studies of rifaximin 1200 mg/day in the treatment of HE, provided a rationale for dose selection for the phase 3 studies Study A and Study B. In Study D, there were significant between-group differences in the changes in PSE index and venous ammonia levels (both of which were primary endpoints) in favor of the rifaximin group when compared with lactitol; and higher proportion of rifaximin subjects were considered cured at end of treatment (venous ammonia normalized and mental state/Conn score of 0). In Study E, a significant larger proportion of rifaximin subjects had improvements in asterixis grade when compared with placebo subjects; however, results for the primary endpoint, the proportion of subjects who had improvements in Conn score, were not significantly different between groups. Subjects in study E had mild HE symptoms when compared with subjects in Study D.
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BOS2 775861 1 Incorporation by Reference
The contents of all references, patents, pending patent applications and published patents, cited throughout this application are hereby expressly incorporated by reference.
Equivalents
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments provided herein described herein. Such equivalents are intended to be encompassed by the following claims.
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BOS2 775861 1

Claims

WHAT IS CLAIMED IS:
1. A method of increasing rifaximin systemic exposure (AUCtau) in a subject after oral administration comprising:
selecting a subject comprising hepatic insufficiency; and
orally administering rifaximin to the subject comprising hepatic insufficiency, wherein systemic exposure to rifaximin is increased in the subject with hepatic insufficiency as compared to a subject without hepatic insufficiency.
2. The method of claim 1, wherein hepatic insufficiency in the subject comprises a model end stage liver disease (MELD) score of less than 11 for the subject.
3. The method of claim 1, wherein hepatic insufficiency in the subject comprises a model end stage liver disease (MELD) score of 11 to 18 for the subject.
4. The method of claim 1, wherein hepatic insufficiency in the subject comprises a Child-Pugh A diagnosis for the subject.
5. The method of claim 1, wherein hepatic insufficiency in the subject comprises a Child-Pugh B diagnosis for the subject.
6. The method of claim 1, wherein the rifaximin systemic exposure in the subject suffering from hepatic insufficiency comprises exposure at least 5-fold higher than in the subject not comprising hepatic insufficiency.
7. The method of claim 1, wherein the rifaximin systemic exposure in the subject suffering from hepatic insufficiency comprises exposure at least 9.6-fold higher than in the subject not having hepatic insufficiency.
8. The method of claim 1, wherein the rifaximin systemic exposure in the subject suffering from hepatic insufficiency comprises exposure at least 13.1 -fold higher than in the subject not having hepatic insufficiency.
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9. The method of claim 1, wherein the rifaximin systemic exposure in the subject suffering from hepatic insufficiency comprises exposure between about 5 fold and about 13.1 -fold higher than in the subject not having hepatic insufficiency.
10. The method of claim 1, wherein the subject suffering from hepatic insufficiency comprises a subject suffering from hepatic encephalopathy.
11. The method of claim 1 , further comprising administration of rifaximin with food.
12. The method of claim 11, wherein the rifaximin systemic exposure in the subject suffering from hepatic insufficiency comprises exposure at least 10-fold higher than in the subject not comprising hepatic insufficiency.
13. The method of claim 11, wherein the rifaximin systemic exposure in the subject suffering from hepatic insufficiency comprises exposure at least 2-fold higher than in the subject not comprising hepatic insufficiency.
14. The method of claim 11, wherein the rifaximin systemic exposure in the subject suffering from hepatic insufficiency comprises exposure at least between about 2-fold to about 10-fold higher than in the subject not comprising hepatic insufficiency.
15. The method of claim 1, further comprising selecting a subject susceptible to or suffering from Travelers' diarrhea.
16. The method of claim 15, further comprising informing the subject that the elimination rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency.
17. A method of increasing rifaximin plasma concentrations (Cmax) in a subject after oral administration comprising:
selecting a subject comprising hepatic insufficiency; and
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BOS2 775861 1 orally administering rifaximin to the subject comprising hepatic insufficiency, wherein plasma concentrations of rifaximin are increased in the subject with hepatic insufficiency as compared to a subject without hepatic insufficiency.
18. The method of claim 17, wherein the subject comprising hepatic insufficiency comprises an elevated alanine aminotransferase (ALT).
19. The method of claim 17, wherein the rifaximin plasma concentrations in the subject suffering from or susceptible to hepatic insufficiency comprises exposure at least 2- fold higher than in the subject not comprising hepatic insufficiency.
20. The method of claim 17, further comprising administration of rifaximin with food wherein time to reach maximum plasma concentration is delayed.
21. The method of claim 17, further comprising selecting a subject susceptible to or suffering from Travelers' diarrhea.
22. The method of claim 21, further comprising informing the subject that the elimination rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency.
23. A method of decreasing rifaximin elimination rate in a subject after oral administration comprising:
selecting a subject comprising hepatic insufficiency; and
orally administering rifaximin to the subject comprising hepatic insufficiency, wherein elimination rate of rifaximin is decreased in the subject with hepatic insufficiency as compared to a subject without hepatic insufficiency.
24. The method of claim 23, wherein the rifaximin elimination rate is decreased by at least 25% in the subject with hepatic insufficiency as compared to the subject without hepatic insufficiency.
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BOS2 775861 1
25. The method of claim 23, wherein hepatic insufficiency in the subject comprises a Child-Pugh A score.
26. The method of claim 23, wherein hepatic insufficiency in the subject comprises a Child-Pugh B score.
27. The method of claim 23, wherein decreasing the elimination rate further comprises increasing bioavailablity of rifaximin in the subject with hepatic insufficiency.
28. The method of claim 23, wherein the subject comprising hepatic insufficiency comprises a subject comprising at least one sign, symptom or episode of hepatic encephalopathy.
29. The method of claim 23, wherein the subject comprising hepatic insufficiency comprises at least one portal systemic shunt.
30. The method of claim 23, further comprising selecting a subject susceptible to or suffering from Traveler's diarrhea.
31. The method of claim 30, further comprising informing the subject that the elimination rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency.
32. A method of determining a therapeutically effective dose of rifaximin for a subject comprising:
selecting a subject comprising hepatic encephalopathy; and
determining a therapeutically effective dose in consideration of the subject having hepatic encephalopathy.
33. The method of claim 32, wherein the subject has Traveler's diarrhea.
34. The method of claim 32, wherein the subject is given a dosage that is increased as compared to a subject that has does not have hepatic encephalopathy.
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BOS2 775861 1
35. The method of claim 32, wherein the subject is given a dosage that is decreased as compared to a subject that has does not have hepatic encephalopathy.
36. The method of claim 32, further comprising informing the subject of one or more of:
elimination rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency,
systemic exposure to rifaximin is increased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency,
plasma concentration of rifaximin is increased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency, and
clearance rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency.
37. A method of determining a therapeutically effective dose of rifaximin for a subject comprising:
selecting a subject comprising hepatic insufficiency;
correlating hepatic insufficiency with one or more of increased systemic exposure to rifaximin, increased plasma concentration of rifaximin, or decreased clearance rate of rifaximin; and
determining the therapeutically effective dose in consideration of at least one of increased systemic exposure to rifaximin, increased plasma concentration of rifaximin, or decreased clearance rate of rifaximin in the subject associated with hepatic insufficiency.
38. The method of claim 37, wherein hepatic insufficiency in a subject comprises a Child-Pugh A diagnosis for the subject.
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BOS2 775861 1
39. The method of claim 37, wherein hepatic insufficiency in a subject comprises a Child-Pugh B diagnosis for the subject.
40. The method of claim 37, wherein hepatic insufficiency in the subject comprises a model end stage liver disease (MELD) score of less than 11 for the subject.
41. The method of claim 37, wherein hepatic insufficiency in the subject comprises a model end stage liver disease (MELD) score of 11 to 18 for the subject.
42. The method of claim 37, wherein hepatic insufficiency in the subject comprises an elevated ALT for the subject.
43. The method of claim 37, wherein hepatic insufficiency in the subject comprises at least one portal systemic shunt in the subject.
44. The method of claim 37, wherein hepatic insufficiency in the subject comprises at least one hepatic encephalopathy episode.
45. The method of claim 37, further comprising selecting a subject susceptible to or suffering from Traveler's diarrhea.
46. The method of claim 45, further comprising informing the subject of one or more of:
elimination rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency,
systemic exposure to rifaximin is increased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency,
plasma concentration of rifaximin is increased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency, or
clearance rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency.
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BOS2 775861 1
47. A method of treating Travelers' Diarrhea (TD), comprising:
selecting a subject suffering from or susceptible to TD;
instructing the subject to orally administer rifaximin; and
informing the subject of one or more of:
elimination rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency,
systemic exposure to rifaximin is increased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency,
plasma concentration of rifaximin is increased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency, or
clearance rate of rifaximin is decreased in a population of subjects with hepatic insufficiency as compared to population of subjects without hepatic insufficiency.
48. The method of claim 47, wherein hepatic insufficiency in the subject comprises a model end stage liver disease (MELD) score of less than 11 for the subject.
49. The method of claim 47, wherein hepatic insufficiency in the subject comprises a model end stage liver disease (MELD) score of 11 to 18 for the subject.
50. The method of claim 47, wherein hepatic insufficiency in the subject comprises a Child-Pugh A diagnosis for the subject.
51. The method of claim 47, wherein hepatic insufficiency in the subject comprises a Child-Pugh B diagnosis for the subject.
52. The method of claim 47, wherein the subject having hepatic insufficiency comprises a subject having hepatic encephalopathy.
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53. The method of claim 47, further comprising identifying subjects having hepatic insufficiency.
54. The method of claim 53, wherein the subject is tested for hepatic insufficiency.
55. The method of claim 47, further comprising altering the amount of rifaximin administered based on the subject having hepatic insufficiency as compared to a subject without hepatic insufficiency.
56. The method of claim 47, further comprising altering the dosing regime of rifaximin based on the subject having hepatic insufficiency as compared to a subject without hepatic insufficiency.
57. The method of claim 47, further comprising informing the subject that systemic exposure or plasma concentrations of rifaximin is altered with food.
58. A kit comprising rifaximin, or a pharmaceutical composition thereof, and instruction for administering to a subject with hepatic insufficiency.
59. The kit of claim 58, wherein the kit comprises instructions for administering rifaximin to a subject having hepatic encephalopathy.
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BOS2 775861 1
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9271968B2 (en) 2005-03-03 2016-03-01 Alfa Wassermann S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
US10285944B2 (en) 2005-03-07 2019-05-14 Alfasigma S.P.A. Gastroresistant pharmaceutical formulations containing rifaximin

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021152587A1 (en) 2020-01-30 2021-08-05 Yeda Research And Development Co. Ltd. Treating acute liver disease with tlr-mik inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090028940A1 (en) * 2007-07-06 2009-01-29 Lupin Ltd. Pharmaceutical compositions of rifaximin

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2420226B1 (en) * 2007-07-06 2020-03-04 Lupin Limited Pharmaceutical compositions of rifaximin
US20110035232A1 (en) * 2008-10-02 2011-02-10 Salix Pharmaceuticals, Ltd. Methods of treating hepatic encephalopathy
CA2739436C (en) * 2008-10-02 2019-08-27 Salix Pharmaceuticals, Ltd. Use of rifaximin for treating hepatic encephalopathy
AU2010271070A1 (en) * 2009-06-02 2012-01-12 Salix Pharmaceuticals, Ltd. Methods of treating hepatic encephalopathy

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090028940A1 (en) * 2007-07-06 2009-01-29 Lupin Ltd. Pharmaceutical compositions of rifaximin

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHARI ET AL.: "Treatment of Hepatic Failure with ex Vivo Pig-Liver Perfusion Followed by Liver Transplantation", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 331, no. 4, 28 July 1994 (1994-07-28), pages 235, XP008150608 *
GIONCHETTI ET AL.: "Antibiotic treatment in inflammatory bowel disease: rifaximin a new possible approach", EUROPEAN REVIEW FOR MEDICAL AND PHARMACOLOGICAL SCIENCES, vol. 3, 1999, pages 27 - 30, XP002603353 *
See also references of EP2442803A4 *
TAYLOR ET AL.: "Systemic Pharmacokinetics of Rifaximin in Volunteers with Shigellosis", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 52, no. 3, March 2008 (2008-03-01), pages 1179 - 1181, XP008150594 *
VIGNALI ET AL.: "TIPS with Expanded Polytetrafluoroethylene overed Stent': Results of an Italian Multicenter Study", AMERICAN ROENTGEN RAY SOCIETY, vol. 185, August 2005 (2005-08-01), pages 472 - 480, XP008150596 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9271968B2 (en) 2005-03-03 2016-03-01 Alfa Wassermann S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
US10285944B2 (en) 2005-03-07 2019-05-14 Alfasigma S.P.A. Gastroresistant pharmaceutical formulations containing rifaximin

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NZ597080A (en) 2014-02-28
EP2442803A4 (en) 2012-11-28
RU2012101310A (en) 2013-07-27
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