KR20120030542A - Modulation of systemic exposure to rifaximin - Google Patents

Abstract

The present invention relates to the effect of liver failure on pharmacokinetics of rifaximin. Also provided are methods for determining the appropriate amount of rifaximin for a subject suffering from liver failure. Also provided is a method of treating a subject with liver dysfunction or susceptible to liver dysfunction, which is treated by rifaximin.

Description

Modulation of systemic exposure to rifaximin

This application claims the benefit of US Provisional Application No. 61 / 187,251, filed June 15, 2009 and US Provisional Application No. 61 / 297,696, filed January 22, 2010. Each of which is incorporated herein by reference in its entirety.

Rifaximin (INN) (see The Merck Index, XIII Ed., 8304) is an antibiotic belonging to a rifamycin antibiotic group, such as pyrido-imidazo rifamycin. Rifaximin is characterized by its negligible systemic absorption, due to its chemical and physical properties (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 patents IT 1154655 and EP 0161534, both of which are incorporated herein by reference in their entirety for all purposes. EP 0161534 describes a process for preparing rifaximin using rifamycin O as starting material (The Merck Index, XIII Ed., 8301).

It is provided herein that rifaximin exhibits different pharmacokinetics in individuals with hepatic insufficiency, as compared to individuals with normal liver systems. Thus, in one aspect, a method of increasing a rifaximin systemic exposure (AUCtau) in an individual following oral administration, by selecting an individual with liver failure and orally administering rifaximin to the individual, wherein the rifax Systemic exposure to citizens is increased in individuals with hepatic insufficiency, as compared to individuals without hepatic insufficiency).

In a related aspect, an individual with liver failure has a model end stage liver disease (MELD) score of less than 11 for that individual. In another related aspect, an individual with liver dysfunction has a model terminal liver disease (MELD) score of 11 to 18 for that individual.

In another embodiment, the subject with liver failure has a Child-Pugh A score. In another embodiment, the individual with liver failure has a Child-Pugh B score.

In another embodiment, rifaximin systemic exposure in a subject with liver failure comprises at least 5 times higher exposure than in a subject without liver failure. In another embodiment, rifaximin systemic exposure in an individual suffering from liver failure comprises at least 9.6 times higher exposure than in an individual without liver failure. In another embodiment, rifaximin systemic exposure in an individual suffering from liver failure comprises at least 13.1 times higher exposure than in an individual without liver failure. In another embodiment, rifaximin systemic exposure in an individual with liver failure comprises about 5 to about 13.1 times higher exposure than in an individual without liver failure.

In one particular embodiment, the individual with liver failure has hepatic encephalopathy

In another embodiment, the methods provided herein further comprise administering rifaximin with food.

In one embodiment, the food delays the time to reach maximum plasma concentration.

In another aspect, the methods provided herein further comprise selecting an individual susceptible to or suffering from traveler's diarrhea.

In another related aspect, the methods provided herein further comprise informing the individual that the rate of removal of rifaximin is reduced in the population of individuals with liver dysfunction compared to the population of individuals without liver dysfunction. .

In another aspect, a method of increasing a rifaximin plasma concentration (C _max ) in an individual following oral administration by selecting an individual comprising hepatic insufficiency and orally administering rifaximin to the individual with hepatic insufficiency. Provided herein is wherein the plasma concentration of rifaximin is increased in individuals with hepatic insufficiency, as compared to individuals without hepatic insufficiency.

In one embodiment, the individual with liver dysfunction has increased alanine aminotransferase (ALT).

In one embodiment, the rifaximin plasma concentration in an individual suffering from liver failure comprises at least two times higher exposure than in an individual that does not comprise liver failure.

In another embodiment, the methods provided herein further comprise delaying the time to maximum plasma concentration by administering rifaximin with food.

In another embodiment, the method further comprises selecting an individual susceptible to or suffering from traveler's diarrhea.

In another related aspect, the methods provided herein further comprise informing the subject that the rate of elimination of rifaximin is reduced in a population of individuals with hepatic insufficiency, relative to a population of individuals without hepatic insufficiency. do.

In another aspect, a method of reducing the rate of rifaximin removal in an individual following oral administration by selecting an individual comprising liver failure and orally administering rifaximin to said individual with liver failure. The rate of elimination of rifaximin is reduced in individuals with hepatic insufficiency as compared to individuals without hepatic insufficiency).

In one embodiment, the rifaximin removal rate is reduced by at least 25% in individuals with hepatic insufficiency, as compared to individuals without hepatic insufficiency.

In another embodiment, the subject with liver failure has a Child-Pugh A score. In another embodiment, the individual with liver failure has a Child-Pugh B score.

In another embodiment, the reduction in clearance further comprises an increase in bioavailability of rifaximin in the subject with liver failure.

In another embodiment, the individual with hepatic insufficiency is an individual with at least one sign, symptom or episode, or at least one portal systemic shunt of hepatic encephalopathy. In another embodiment, the subject is susceptible to traveler's diarrhea or suffers from traveler's diarrhea.

In another related aspect, the methods provided herein further comprise informing the individual that the rate of removal of rifaximin is reduced in the population of individuals with liver dysfunction compared to the population of individuals without liver dysfunction. .

In another aspect, provided herein is a method of determining a therapeutically effective amount of rifaximin for a subject by selecting the subject comprising hepatic encephalopathy and determining a therapeutically effective amount in view of the subject with hepatic encephalopathy. .

In one embodiment, the subject has or is susceptible to tourist diarrhea.

In another embodiment, an increased dose is presented to the individual compared to the dose administered to an individual who is free of or does not have hepatic encephalopathy.

In another embodiment, a reduced dose is presented to the subject as compared to the dose administered to the subject without hepatic encephalopathy or not susceptible to hepatic encephalopathy.

In another embodiment, the method further comprises: the rate of elimination of rifaximin is reduced in a population of individuals with liver dysfunction compared to a population of individuals without liver dysfunction; Systemic exposure to rifaximin is increased in a population of individuals with hepatic insufficiency compared to a population of individuals without hepatic insufficiency; That the plasma concentration of rifaximin is increased in the population of individuals with liver dysfunction compared to the population of individuals without liver dysfunction; And / or informing the subject of one or more of that the clearance rate of rifaximin is reduced in the population of individuals with hepatic insufficiency compared to the population of individuals without hepatic insufficiency.

In another aspect,

At least one of increased systemic exposure to rifaximin, increased plasma concentrations of rifaximin, or reduced clearance of rifaximin is associated with liver failure,

Determining the therapeutically effective amount in consideration of one or more of increased systemic exposure to rifaximin, increased plasma concentrations of rifaximin, or reduced clearance of rifaximin in a subject associated with liver failure.

Provided herein are methods for determining a therapeutically effective amount of rifaximin for an individual by selecting an individual who has or is susceptible to liver failure.

In another embodiment, the subject with liver failure has a Child-Pugh A score. In another embodiment, the individual with liver failure has a Child-Pugh B score.

In a related embodiment, the subject has a model terminal liver disease (MELD) score of less than 11. In another related aspect, the subject has a model terminal liver disease (MELD) score of 11 to 18.

In another aspect, the subject has increased ALT levels.

In another aspect, the subject has at least one contextual paragraph. In another embodiment, the subject has at least one episode of hepatic encephalopathy. In another embodiment, the subject has at least one episode of hepatic encephalopathy within the preceding six months. In another embodiment, the subject has at least two episodes of hepatic encephalopathy within the preceding six months.

In another aspect, the method further comprises the selection of an individual susceptible to or suffering from traveler's diarrhea.

In another aspect,

Select objects that have liver failure or are prone to liver failure,

At least one of increased systemic exposure to rifaximin, increased plasma concentrations of rifaximin, or reduced clearance of rifaximin is associated with liver failure,

Determining a therapeutically effective amount in consideration of at least one of increased systemic exposure to rifaximin, increased plasma concentrations of rifaximin, or reduced clearance of rifaximin in a subject associated with liver failure.

Provided herein are methods for determining a therapeutically effective amount of rifaximin for a subject.

In another aspect, selecting an individual suffering from or susceptible to traveler diarrhea (TD); Instructing the subject to orally administer rifaximin; In said subject, the rate of elimination of rifaximin is reduced in the population of individuals with hepatic insufficiency compared to the population of individuals without hepatic insufficiency, and systemic exposure to rifaximin is in the population of individuals without hepatic insufficiency. By comparison, increased in a population of individuals with hepatic insufficiency, plasma concentrations of rifaximin are increased in a population of individuals with hepatic insufficiency, and / or rifaximin compared to a population of individuals without hepatic insufficiency Provided herein is a method of treating traveler diarrhea by informing one or more of the clearance rate of is reduced in a population of individuals with liver failure, as compared to a population of individuals without liver failure.

In another embodiment, the subject with liver failure has a Child-Pugh A score. In another embodiment, the individual with liver failure has a Child-Pugh B score.

In a related embodiment, the subject has a model terminal liver disease (MELD) score of less than 11. In another related embodiment, the subject has a model terminal liver disease (MELD) score of 11-18.

In a related aspect, liver failure includes hepatic encephalopathy.

In another embodiment, the method further comprises identifying a subject with liver failure. In a related aspect, the method further comprises testing the subject for liver failure.

In another embodiment, the method further comprises varying the amount of rifaximin administered based on the individual with liver failure as compared to the individual without liver failure.

In another embodiment, the method further comprises changing the dosing regimen of rifaximin based on the subject with liver failure as compared to the subject without liver failure.

In another embodiment, the method further comprises informing the subject that systemic exposure to rifaximin and / or plasma concentrations of rifaximin are changed by food.

In another aspect, provided herein is a kit comprising rifaximin or a pharmaceutical composition thereof and instructions for administering to an individual with liver failure. In one embodiment, the kit comprises instructions for administering rifaximin to a subject with hepatic encephalopathy.

Other aspects and aspects are described below.

1 is a graph showing the mean + SD of the plasma concentration-time profile of rifaximin on a linear scale.
FIG. 2 shows the time for the first breakthrough overt HE episode by subgroup.
3 shows the CLDQ overall and individual domain T _wa results by treatment group (ITT population).
4 shows the CLDQ overall and individual domain T _wa results by breakthrough overt HE state.
5 shows a comparison of Kaplan-Meier Estimates of time for the first breakthrough overt HE episode. Placebo experiences versus rifaximin experience in placebo crossover individuals up to 6 months of treatment are shown.
6 shows mean PSE values at baseline in clinical studies and at the end of treatment.

Embodiments provided herein relate to the discovery of differences in systemic exposure, plasma concentrations, and final clearance rate constants of rifaximin in individuals with hepatic insufficiency compared to individuals with normal liver function. The present invention also relates to the discovery of a food effect over time up to the maximum plasma concentration of rifaximin in a subject.

The main pathogenesis of HE is related to nitrogenous substances derived from the intestines that adversely affect brain function. The most influential these compounds are believed to be ammonia, a proteolytic byproduct that is typically detoxified by the liver. However, the correlation between blood levels and mental state in cirrhosis is some inaccuracy because the blood-brain barrier permeability to ammonia is increased in patients with HE. Other visceral-induced toxins have also been shown to be responsible for HE.

In patients with chronic liver disease, the development of hepatic encephalopathy is associated with a lower quality of life compared to age-related patients without HE. Overt HE episodes are weakened, can be present without warning, render the patient unself-protective, and often lead to hospitalization. Patients with HE had fatigue, daytime sleepiness and lack of awareness (Conn score 1); And symptoms of confusion and disorientation (Conn score 2), which significantly interfere with daily functioning and reduce self-protection ability. Often, this lack of self-protection leads to inadequate effects, prevents adherence to treatment, and also results in more severe symptoms such as increased sleep, loss of overall direction and confusion (Conn score 3) or coma (Conn score 4). Is enlarged.

The history of overt HE episodes and the severity of HE episodes have also been found to predict reduced survival in patients with chronic liver disease. In patients with cirrhosis and overt HE episodes, the survival probability is 42% after one year of experience and 23% after 3 years. In another analysis, the incidence of HE episodes with Conn score 2 in patients with cirrhosis is associated with a four-fold increase in the risk of death.

These toxic compounds gain access to systemic circulation as a result of reduced liver function or portal systemic short circuits. Once in brain tissue, the compound causes changes in neurotransmission that affect consciousness and behavior. HE is due to general central nervous system depression from nitrogen compounds that cause excitation of gamma-aminobutyric acid (GABA) and reduced pretransmission of glutamate.

Factors involved were nitremia (29%), sedatives, neurostabilizers, analgesics (24%), gastrointestinal bleeding (18%), excess dietary protein (9%), metabolic alkalosis (11%), infection (3%) , Constipation (3%). Surgery, particularly transvenous hepatic intravenous-vein shortening (TIPS) treatment, may also be involved in HE. HE due to unknown causes reaches only 2% of cases.

Early signs are asymptomatic and require mental testing to be diagnosed. As discussed in more detail below, the West Haven criteria (or Conn score), which ranges from stage 0 (lack of detectable change in nature) to stage 4 (coma, cerebral posture, pupil dilation) There are four progressive stages of damage known as.

HE appears in serious forms such as psychomotor dysfunction, impaired memory, increased reaction time, paresthesia, decreased concentration, and coma. Changes can be observed in personality, consciousness, behavior and neuromuscular function. Neurological signs may include hyperreflection, stiffness, myoclonus, and inability to fix posture (coarse "flapping" muscle tremor). Cognitive tasks (eg, the connection of numbers and lines) can be abnormal. Feather hepaticus (sweet breath odor) may be present. Electroencephalogram (EEG) tracings are slow, nonspecific and predominantly nonspecific, mainly for the frontal head. Prothrombin time can be prolonged and cannot be corrected with vitamin K. Computed tomography scans of the head may be normal or may indicate general muscular atrophy. Finally, signs of liver disease such as jaundice and ascites can be noted.

The diagnosis of HE is based on medical history and physical and mental state tests, involvement factor (s), and / or prior history of HE by the necessary clinical factors that become knowledge of existing liver disease. EEG can exhibit slow-wave action, even in mild cases. Increased serum ammonia levels are characteristic but not essential and have little correlation with the levels of encephalopathy.

Management of patients with chronic HE includes 1) providing sustained protection, 2) identifying and eliminating factors involved, 3) reducing nitrogen loading from the intestines, and 4) evaluating the need for long-term treatment. Nitrogen loading from the intestines is typically reduced using non-absorbable disaccharides (lactulose) and / or antibodies.

Lactulose is considered the first-line therapy in the United States, but is not currently approved in the United States for the treatment or prevention of HE. Lactulose is metabolized by the intestinal bacteria of the colon, which induces reduced fecal pH, then induces a laxative effect, and finally induces fecal clearance. Reduced fecal pH ionizes ammonia (NH ₃ ) to ammonium ions (NH ₄ ⁺ ), which is used by bacteria for amino acid and protein synthesis. This lowers serum ammonia levels and improves mental function.

Conventional therapies aim at reducing the production and absorption of ammonia. Lactulose is typically used at a dose of 30 to 60 g / day. However, this dose may be titrated up to 20-40 g TID-QID to perform semi-formed bowel movements 2-3 times a day. Lactulose may be presented as a 300 cc (200 g) retention enema if, for example, it cannot be administered orally or along the nasogastric tube to a patient with stages 3 and 4 HE.

In acute encephalopathy, lactulose may be administered orally, orally or via nasogastric tube, or through retention enemas. A typical oral dose is 30 g, then every 1 or 2 hours until excretion occurs. Dosing is then adjusted to obtain two or three gentle bowel movements per day.

Lactulose is readily available without a prescription. Often the commercial reference formulations in convenient and relatively mumat that a "lactulose powder for oral solution (lactulose powder for oral solution)", for example, 10 and a 20g packet of Kristalose ^RTM Bertek Pharmaceutical (Sugarland, Tex. It is available from). Commercially available lactulose syrups as laxatives include Cephulac ^RTM , Chronulac ^RTM , Cholac ^RTM And Enulose ^RTM . These syrups can replace lactulose powder by using sufficient syrup to provide the desired dose of lactulose, and the commonly named syrup contains about 10 gm of lactulose in 15 ml of syrup.

A broad spectrum of GI-active antibiotics, including neomycin, metronidazole, vancomycin and paromomycin, has been used in the presence or absence of lactulose. A typical criterion is presented by neomycin 1-2 g / day or metronidazole 250 by periodic kidney and annual auditory monitoring. Lactulose can induce diarrhea by inducing diarrhea, a factor involved in HE. In addition, compliance with lactulose is limited to patients who dislike its excessively sweet taste. In addition, dosing schedules associated with intestinal habits and intestinal gasogenesis, bloating, diarrhea (which leads to dehydration), and side effects of acidemia make lactulose difficult to use for a long time.

Antibiotic use in the treatment of HE is hampered by the toxicity associated with long-term use. In particular, systemic absorption of neomycin, metronidazole, and ampicillin is known as nephrotoxic, toxic, S. aureus. Rare cases such as the development of S. enterocolitis and / or resistant bacterial strains. Neomycin also inhibits only aerobic bacteria. Metronidazole is slowly metabolized in patients with liver dysfunction, has potential for alcohol interaction (disulfiram-like effect), and high blood levels can cause seizures.

One gastrointestinal specific antibiotic is rifaximin. Rifaximin is a nonaminoglycoside, semisynthetic antibiotic derived from rifamycin O. It is a non-systemic, non-absorbable, broad spectrum oral antibiotic that is specific for enteric pathogens of the GI tract. Rifaximin has been found to be useful in the treatment of HE, compared to previously used antibiotics, and has, for example, negligible systemic absorption (<0.4%), regardless of food intake or the presence of GI disease, It does not show plasma accumulation by dose. Lack of systemic absorption makes rifaximin safe and well tolerated, thereby improving patient compliance and reducing the side effects commonly associated with known therapies.

Rifaximin (INN) (The Merck Index, XIII Ed., 8304) is an antibiotic belonging to a rifamycin antibiotic group, such as pyrido-imidazo rifamycin. Rifaximin exhibits its broad antibacterial activity in the gastrointestinal tract, for example, against local gastrointestinal bacteria that cause infectious diarrhea, irritable bowel syndrome, small intestinal bacterial hyperproliferation, Crohn's disease and / or pancreatic insufficiency. Rifaximin has been reported to be characterized by negligible systemic absorption due to its chemical and physical properties (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 patents IT 1154655 and EP 0161534. EP patent 0161534 describes a process for the preparation of rifaximin using rifamycin O as starting material (The Merck Index, XIII Ed., 8301). US 7,045,620 B1 describes the polymorphic form of rifaximin. The patent applications and patents mentioned in this specification are hereby incorporated by reference in their entirety for all purposes.

Embodiments provided herein also relate to the administration of a medical agent to an individual in need thereof with a composition such as rifaximin.

Rifaximin is a compound of the rifamycin antibiotic group. Rifaximin is a compound of Formula I:

Formula I

In one embodiment, rifaximin is a molecule that is poorly absorbed in certain individuals. This is suggested in clinical pharmacokinetic studies in normal individuals demonstrating that rifaximin is poorly absorbed from the gastrointestinal tract with single and multiple oral administrations (eg, less than 1% of the drug is absorbed after oral administration). do. Only trace amounts of the parent drug and metabolites are detected in urine, while there is a high stool recovery of rifaximin as an unchanged drug. On repeated dosing, little or no systemic drug accumulation exists, and the time to steady state is short. Exceptionally, administration of a 1.5-fold higher daily dose in TID regimen does not cause a corresponding increase in total daily systemic exposure to rifaximin; The AUC _sum is only about 13% higher after TID than after BID.

As used herein, “rifaximin” includes solvates and polymorphs of molecules, including, for example, the α, β, γ, δ, ε, η, ζ and amorphous forms of rifaximin. These forms are described, for example, in US Pat. No. 11 / 873,841; USSN 11 / 658,702; EP 05 004 635.2, filed May 3, 2005; USPN 7,045,620; US 61 / 031,329; and GC Viscomi, et al. , Crys EngComm, 2008, 10, 1074-1081 (April 2008). Each of these documents is incorporated herein by reference in its entirety.

As used herein, "polymorphism" refers to the occurrence of different crystalline forms of a single compound in a unique hydrate state, for example the properties of some compounds and complexes. Thus, polymorphs are unique solids that share the same molecular formula, but each polymorph can have unique physical properties. Thus, a single compound can produce a variety of polymorphs, where each form is different and unique physical properties (eg, solubility profile, melting point temperature, hygroscopicity, particle morphology, density, flowability, compactness and / or X-ray diffraction peaks). Since the solubility of each polymorph can vary, the presence of the pharmaceutical polymorph is essential to provide the drug with a predictable solubility profile. It is desirable to study all solid state forms of the drug, including all polymorphs, and to determine the stability, dissolution and flow characteristics of each polymorph. Polymorphs of the compound can be distinguished in the laboratory by X-ray diffraction spectroscopy and by other methods (eg, infrared spectroscopy). For a general review of polymorphs and their pharmaceutical use, see GM Wall, Pharm Manuf. 3, 33 (1986); JK Haleblian and W. McCrone, J. Pharm. Sci., 58, 911 (1969 and JK Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference.

As used herein, "systemic exposure" is intended to mean the exposure of an individual to rifaximin by administration, and the subsequent plasma exposure of rifaximin in the individual according to its distribution through the body. Increased systemic exposure can be measured by determining the plasma concentration of rifaximin in a subject. In an exemplary embodiment, the increased systemic exposure may be due to a decrease in the rate of elimination of rifaximin.

Combinations of physiological pathologies may explain the increase in rifaximin exposure in individuals with HE history compared to healthy individuals. Hepatic encephalopathy episodes result from central nervous system accumulation of nitrogenous substances (mainly ammonia) derived from the intestines due to portal systemic short circuits and portal perfusion depression associated with cirrhosis. Individuals with minor and moderate impairment of liver function and history documented in episodes of hepatic encephalopathy are recorded in the study. Hepatic encephalopathy is a complication of cirrhosis resulting from portal hypertension, cerebrovascular expansion and liver failure. Recent studies indicate a high incidence of spontaneous portal systemic short circuits in persistent hepatic encephalopathy.

In chronic liver disease, a substantial portion of the portal circulation does not perfuse functional hepatocytes due to the presence of intrahepatic or extrahepatic anatomical short circuits. As a result, the initial passage clearance rate of the orally administered formulation is reduced and systemic bioavailability is increased. Higher exposure values of rifaximin appear to be due, in part, to the reduction of presystemic metabolism in the presence of portal systemic short circuit and / or portal perfusion depression. This possibility is due to the fact that despite the limited plasma exposure to rifaximin from the gastrointestinal tract (˜0.32% of the dose), only a small percentage of unchanged rifaximin is released from the urine (0.03% of the dose), so this less absorbed fraction Is supported by the hypothesis that it performs first-pass metabolism in healthy individuals (~ 90.6%). In addition, the rifaximin terminator t _1/2 is in the HE object compared to a healthy individual because of clinically important the longer statistically significant (about 2 fold), higher exposure found in HE systemic removal of the drug speed May be due to a decrease.

As used herein, an “individual” refers to an organism capable of suffering from intestinal disease or other disease that may be treated by rifaximin or otherwise may have other benefits from the administration of rifaximin products as described herein. For example, humans and non-human animals). The term “non-human animal” provided herein refers to all vertebrates, eg mammals, eg rodents (eg mice), and non-mammals, eg non-human primates (eg Sheep, dogs, cattle, chickens, amphibians, reptiles), and the like.

As used herein, "prone to enteric disease" refers to individuals at risk for developing intestinal disease, such as HE, individuals with immunosuppression, individuals exposed to other individuals with bacterial infections, family history of intestinal disease. Traveling to remote areas known as harbor bacteria that cause diarrhea, individuals with genetic profiles indicating the risk of disease or bowel disease, individuals with known susceptibility to bowel disease, doctors, nurses, and traveler diarrhea It includes an object to say.

As used herein, an individual suffering from hepatic insufficiency includes an individual diagnosed with a clinical decrease in liver function due to, for example, hepatic encephalopathy, hepatitis or cirrhosis. Liver dysfunction can be quantified using a number of scales, including model end-stage liver disease (MELD) scores, Child-Pugh scores, or Conn scores.

The MELD score uses the patient's value for the International Standard for Serum Bilirubin, Serum Creatinine, and Prothrombin Time (INR) to provide weighted values that correlate with expected survival. Grades 10-19 correlate with 27% mortality within 3 months, grades less than 10 correlate with 4% mortality within 3 months. Methods of measuring and analyzing MELD scores are well known in the art.

The Child-Pugh score (often Child-Turcotte-Pugh score), used to assess the prognosis of chronic liver disease, mainly cirrhosis, is a combination of five clinical measures, bilirubin, serum albumin, INR, ascites, and hepatic encephalopathy. Rating. Each marker assigns a value of 1 to 3, and the overall value is A (5 to 6 points), B (7 to 9 points) or C (10), which can be correlated with 1 and 2 year survival rates. To 15 points). Methods of measuring and analyzing Child-Pugh scores are well known in the art.

The change in mental state can be measured, for example, by a Conn score (also known as a West Haven score). The Conn score has been used extensively as a measure of mental state in HE studies and is based on Parsons-Smith's criteria as modified by Conn. Inability to fix posture is not taken into account when assessing a subject's condition using the Conn scoring criteria presented below.

The scale used for the Conn scoring system is provided below.

Grade 0 = No detected personality or behavioral abnormalities.

Grade 1 = slight lack of awareness, bliss or anxiety; Reduced attention span; Damage to poisoning or deduction.

Class 2 = lethargy; Disorientation of time; Obvious personality changes; Inappropriate behavior.

Grade 3 = mirror to semi-mixed, response to stimulation; confusion; Overall disorientation; Unusual behavior.

Grade 4 = coma; Unable to test mental state

The fixed posture impairment rating (advancing progression) can be measured by an individual keeping both arms and forearms extended, with the wrist dorsal flexed for> 30 seconds. Fixed posture impairment is measured for five grades of continuity, for example, grades 0 and 4, as shown below, respectively, are no abnormal movement versus nearly continuous flop behavior:

Grade 0 = no progress;

Class 1 = rare flip flop behavior;

Class 2 = optional, irregular flop;

Grade 3 = frequent flop; And

Grade 4 = nearly continuous flop action.

Efficacy associated with a fixed posture grade can be measured as the time from baseline to any increase in the fixed posture grade. The time for the increase in fixation postability rating was computerized as the number of days from the first dose of rifaximin to the initial occurrence of the increase from the baseline of fixation posture rating.

A “prophylactically effective amount” of a compound means an amount of a compound of Formula 1 provided herein or other compounds described herein that is effective at single or multiple dose administration to an individual in the prevention or treatment of a bacterial infection or HE.

The term “therapeutically effective amount” means an amount of agent that is effective upon single or multiple dose administration to an individual to provide a therapeutic benefit to the individual. In another embodiment, the therapeutic benefit is inhibition of bacterial infection, or prolongation of survival of an individual with bacterial infection beyond what is expected in the absence of such treatment.

Rifaximin exhibits broad antimicrobial activity in the gastrointestinal tract against local gastrointestinal bacteria causing infectious diarrhea, including anaerobic strains. Rifaximin has been reported to be characterized by negligible systemic absorption due to its chemical and physical properties (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 shown to have an effect upon plasma exposure of rifaximin in vivo. Thus, criteria that are considered by health care professionals (eg, physicians, nurses, nurse practitioners, pharmacists) are made when prescribing doses of rifaximin for the treatment of traveler's diarrhea or intestinal diseases such as IBS. Liver dysfunction leads to a clinically statistically significant increase in rifaximin adsorbed by the treated subject. In one embodiment, provided herein is a method of modulating the therapeutic action of rifaximin by selecting an individual suffering from liver failure and further providing prevention or treatment for liver failure.

Thus, one aspect is a method of treating traveler diarrhea (TD) in an individual. In this method, rifaximin is administered to a subject with a disease that can be treated by rifaximin. Inform the subject that systemic plasma exposure to rifaximin is increased in individuals with hepatic insufficiency compared to individuals without hepatic insufficiency. This information increases the level of safety of administering rifaximin to the subject. Examples of diseases that can be treated by rifaximin include traveler diarrhea and hepatic encephalopathy.

As used herein, “informing” or “advising” means referring to or providing published or oral material. For example, the active agent may be provided in conjunction with published data to the user; Oral presentation of information, for example by presentation at a seminar, conference, or other educational presentation, by a conversation between a representative of the pharmaceutical scale and a healthcare practitioner, or by a conversation between a healthcare practitioner and a patient; Or explain information intended for the purpose of understanding to the user. Examples of medical practitioners include doctors, nurses and nurse practitioners.

One aspect of the present invention includes providing information to patients and prescribers who have been treated with rifaximin useful for minimizing the safety concerns of rifaximin. In this embodiment, the information describes that systemic plasma exposure to rifaximin is increased in individuals with hepatic insufficiency compared to individuals without hepatic insufficiency. In one embodiment, the information is provided for the label. In another embodiment, the information is provided about an information sheet presented to the patient when a prescription for rifaximin is formulated.

In addition, the method also distributes a prescribing rifaximin dose to a pharmacy, and educational material including information on what the patient needs to know and what the patient should do to avoid any adverse effects of rifaximin while receiving the dose. Distributing the educational material to a pharmacy including a pharmacist may include the steps.

The method may also include the step or steps of providing a reference to the pharmacist to advise the patient what the patient needs to know and what the patient should do to safely take their rifaximin administration. The method may further comprise the step of requiring acknowledgment of educational material and criteria from the pharmacist, and further acknowledgment of receipt of educational material by the patient from the pharmacist.

Another aspect is a method of using rifaximin to treat a patient's condition. This embodiment provides a patient with rifaximin, and systemic plasma exposure to rifaximin is increased in individuals with hepatic insufficiency, and administration of rifaximin to patients with hepatic insufficiency is associated with plasma concentration, safety of rifaximin. Or informing the patient or healthcare practitioner that it may affect efficacy.

Another aspect includes a method of treating an individual with an indication that can be treated by rifaximin. The method includes administering rifaximin to the subject and advising the subject that systemic plasma exposure to rifaximin is increased in individuals with hepatic insufficiency compared to individuals without hepatic insufficiency.

How to treat

Provided herein are methods for determining rifaximin doses for treating, preventing or alleviating intestinal related diseases, particularly traveler's diarrhea, for example in individuals further suffering from liver failure due to hepatic encephalopathy. Bowel-related diseases include liver failure, cirrhosis, polycystic liver disease, irritable bowel syndrome, diarrhea, pathogen-associated diarrhea, and Clostridium difficile ) related diarrhea, traveler's diarrhea, small intestine bacterial overgrowth, Crohn's disease, chronic pancreatitis, pancreatic insufficiency, enteritis, colitis, hepatic encephalopathy (or other disease that increases ammonia levels) or cystitis.

The term “hepatic insufficiency” as used herein includes diseases and disorders in which the individual has a defective functional action of the liver. Clinically, individuals with hepatic insufficiency have reduced hepatic function, for example, a statistically significant decrease in hepatic potential. Liver failure often leads to liver damage. One exemplary disease that demonstrates liver failure is hepatic encephalopathy.

As used herein, the term "hepatic encephalopathy" refers to reversible neuropsychiatric abnormalities in the setting of chronic or acute liver injury. If the individual has liver damage, toxic substances that are normally removed by the liver accumulate in the blood, thereby impairing brain function. These toxic substances are often nitrogenous substances, most notably ammonia. Once in brain tissue, the compound causes changes in neurotransmission that affect consciousness and behavior. Four progressive stages of injury associated with HE, defined using West Haven criteria (or Conn scores), ranging from stage 0 (lack of detectable change in personality) to stage 4 (coma, cerebral posture, pupil dilation) Is present. Common symptoms of hepatic encephalopathy may include impaired cognition, flotation progression (immobilization), coma (eg hepatic coma), reduced levels of consciousness including brain edema, and possibly death. Hepatic encephalopathy is commonly referred to in the literature as hepatic coma or portal encephalopathy.

As used herein, the term "traveler's diarrhea" refers to gastrointestinal diseases common among travelers. Most cases are caused by bacterial, viral or protozoan infections. The main source of infection is the intake of food or water contaminated with stools. The length of treatment for a particular bowel disease depends in part on the disease. For example, HE can be treated daily for the remainder of an individual's life, and traveler's diarrhea requires only 12 to about 72 hours of treatment, while Crohn's disease requires about 2 to 3 months of treatment. You can do Administration of rifaximin will also vary depending on the disease state.

Identification of individuals in need of prophylactic treatment for intestinal diseases is within the abilities and knowledge of those skilled in the art. Certain methods of identification of individuals at risk of developing intestinal disease that can be treated by the present method may be used in the medical field, such as family history, travel history and expected travel plans, risk factors associated with the development of the disease state in the individual. Evaluate the presence of Clinical practitioners in the art can readily identify participating individuals by, for example, clinical trials, physical trials, and the use of medical history / family history / travelling history.

Methods for assessing the amount of liver failure in a subject can include the use of any of the provided scoring systems, eg, MELD scores, Child-Pugh scores, or Conn scores.

In another aspect, a method of treating an individual suffering from or susceptible to intestinal disease comprises treating the individual by administering a therapeutically effective amount of rifaximin to a subject in need thereof. Include. Rifaximin is administered upon identification of an individual suffering from or susceptible to intestinal disease. Rifaximin can be administered, for example, after diagnosis, after the HE state, in the course of the HE state, after the diagnosis of minimal HE, or when the critical flicker frequency reaches a level that indicates the HE state. As discussed herein, a physician may choose to alter the administration of rifaximin administered to a subject for the treatment of intestinal disease if the subject also has liver failure. Therapeutic efficacy can be measured, for example, as a reduction in bacterial overgrowth. Efficacy can also be in reducing one or more of the symptoms associated with bowel disease, stabilizing the symptoms, or stopping the symptoms associated with bowel disease, such as vomiting, bloating, diarrhea, subsequent severity of the HE condition, or a subsequent HE condition. Can be measured in terms of one or more increases in time, cognitive ability, and the like.

One embodiment is a method of treating or preventing hepatic encephalopathy (HE) by administering to a subject a therapeutically effective amount of rifaximin.

Aspects of the invention relate to the discovery of potent rifaximin for the treatment and prevention of hepatic encephalopathy. Aspects relate to the use of rifaximin to prevent the onset of HE symptoms and to extend the time for the first breakthrough HE episode. In one embodiment, the time for the first breakthrough HE episode increases the Conn score to a rating ≧ 2 (eg, 0 or 1 to ≧ 2) or of each class for an individual with a baseline Conn score of 0. It was measured by increasing the Conn and fixation postcapability scores. In another embodiment, the time for breakthrough HE episodes, along with the Kaplan-Meier measure of cumulative ratio of subjects optionally increased on Days 28, 56, 84, 112, 140, and 168, is determined by the Conn score (mentality). Status)) or time for any increase from baseline in the fixed posture grade.

Another embodiment was the mean change from baseline in blood ammonia concentration over time, or the mean change from baseline in critical flicker frequency values over time. Additional aspects include mean daily lactulose consumption over time, shift from baseline in Conn scores over time; Or by movement from baseline in the fixed posture grade over time. Unless otherwise specified, a shift in value is a change in value from a reference value.

Other measures of efficacy of treatment described herein include, but are not limited to, mean change from baseline in Chronic Liver Disease Questionnaire (CLDQ) scores over time; Mean change from baseline in the Epworth Sleepiness Scale score over time; And the daytime sleepiness rating scale included the ratio of individuals with a score> 10. Assessment of the severity of persistent hepatic encephalopathy can also be based on, for example, the Conn score.

In another embodiment, rifaximin may be administered to an individual suffering from hepatic encephalopathy (HE), susceptible to hepatic encephalopathy, or having a drive from hepatic encephalopathy for about 24 to 24 months. In the treatment of HE, rifaximin can be administered to a subject, for example, 12 months and longer for the entire life of the subject. In one embodiment, rifaximin is administered daily until death of the subject.

In one embodiment, the present invention is directed to a method of reducing the risk of an individual with an unexpected condition by administering rifaximin to an individual. In one embodiment, for individuals with a final HE episode 90 days prior to or greater than the start of treatment, the risk of injury was reduced by 58%. In another embodiment, the risk of developing injury is reduced by about 30 to 70%. In another embodiment, the risk has been reduced by about 40-70%.

In one embodiment, for individuals with a last HE greater than 90 days prior to rifaximin, the risk of developing the injury is reduced by about 60%. In another embodiment, the risk of developing injury is reduced by about 2 to 80%.

In another embodiment, for individuals with two or fewer HE episodes six months prior to initiation of treatment, the risk of breakthrough HE episodes was reduced by about 56%. In one embodiment, the risk of breakthrough HE episodes is reduced by about 20-70%.

In another embodiment, for individuals with more than two HE episodes 6 months prior to initiation of treatment, the risk of breakthrough HE episodes has been reduced by about 63%. In another embodiment, the risk has been reduced by about 30-80%.

As used herein, the term "terminal elimination rate constant" refers to a primary rate constant indicating rifaximin removal from the body of an individual. This is the overall elimination rate constant indicating the elimination of rifaximin by all elimination processes including excretion and metabolism.

As used herein, the term "plasma concentration" refers to the concentration of rifaximin in the plasma of an individual. The plasma concentration of rifaximin can be measured using reverse phase high performance liquid chromatography by, for example, tandem quadrupole mass spectrometry detection (LS / MS / MS) as shown in the Examples. . The maximum plasma concentration at steady state is referred to herein as C _max and the minimum plasma concentration is referred to as C _min .

As used herein, the term "clearance rate" refers to the volume of biological fluid from which drug metabolites have been completely removed as measured in unit time. Removal occurs as a result of metabolic processes in the kidneys, liver, saliva, sweat, intestines, heart, brain and other areas.

Alanine aminotransferase, as used herein, also referred to as ALT, refers to a test performed to identify liver damage or liver destruction. Enzyme, ALT levels are measured to determine if liver damage or disease is present individually. Low levels of ALT are commonly found in the blood. However, if the liver is damaged or diseased, ALT is released into the bloodstream. ALT levels can be measured by methods known to those skilled in the art.

Pharmaceutical preparations

Embodiments Also provided are pharmaceutical compositions comprising an effective amount of rifaximin and a pharmaceutically acceptable carrier described herein. In a further embodiment, the effective amount is effective to treat bacterial infections such as small intestinal bacterial hyperplasia, Crohn's disease, hepatic encephalopathy, antibiotic-associated colitis and / or diverticulary disorders in individuals who also suffer from liver failure.

Examples of the use of rifaximin to treat traveler's diarrhea are described in 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, MD, Sack DA, MD, Riopel L, Ph.D., Zhi-Dong J, Ph.D., Strurchler M, MD, Ericsson CD, MD, Lowe B, M. Phil., Waiyaki P, Ph.D., White M, Ph.D., DuPont HL, MD 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. The dose can be selected, for example, based on the desired amount of systemic absorption, rate of clearance, plasma concentration, and the like. Embodiments of the pharmaceutical composition further include excipients, for example one or more of diluents, binders, lubricants, disintegrants, colorants, flavors or sweeteners. 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 packets. For example, the composition may be formulated for topical use, eg, ointments, pomades, creams, gels, and lotions. In one embodiment, rifaximin can be used in a pharmaceutically acceptable formulation, eg, at least 12 hours, 24 hours, 36 hours, 48 hours, 1 week, after administration of the pharmaceutically acceptable formulation to the subject, The subject is administered using a pharmaceutically acceptable formulation that provides sustained release of rifaximin to the subject for 2, 3 or 4 weeks.

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, eg For example, a trench (aqueous or non-aqueous solution or suspension), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example by subcutaneous, intramuscular or intravenous injection, for example as a sterile solution or suspension; (3) topical administration, for example, as a cream, ointment or spray applied to the skin; (4) intravaginal or rectal administration, for example as a pessary, cream or foam; Or (5), for example, an aqueous aerosol, liposome formulation or aerosol as solid particles containing the compound.

The phrase “pharmaceutically acceptable” is intended for use in contact with tissues of humans and animals within the scope of sound medical judgment, without undue toxicity, irritation, allergic reactions or other problems or complications, which are reasonable at a reasonable benefit / risk ratio. Means a rifaximin composition and / or dosage form containing suitable rifaximin.

The phrase "pharmaceutically acceptable carrier" refers to liquid or solid fillers, diluents, excipients, solvents, which are involved in the transport or transport of the chemical from one organ or part of the body to another organ or part of the body. Or a pharmaceutically acceptable material, composition or vehicle, such as encapsulating material. Each carrier is preferably "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the subject. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars (eg, lactose, glucose and sucrose); (2) starch (eg, corn starch and potato starch); (3) cellulose and its derivatives (eg sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate); (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients (eg, cocoa butter and suppository waxes); (9) oils (eg, peanut oil, cottonseed oil, safflower seed oil, sesame oil, olive oil, corn oil and soybean oil); (10) glycols (eg propylene glycol); (11) polyols (eg, glycerin, sorbitol, mannitol and polyethylene glycol); (12) esters (eg, ethyl oleate and ethyl laurate); (13) agar; (14) buffers (eg, magnesium hydroxide and aluminum hydroxide); (15) alginic acid; (16) water without pyrogen; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions and (21) other nontoxic miscible materials used in pharmaceutical formulations.

In solid dosage forms of rifaximin for oral administration (capsules, tablets, pills, dragees, powders and granules, etc.), the active ingredient typically contains one or more pharmaceutically acceptable carriers such as sodium citrate, Mix with dicalcium phosphate and / or any of the following: (1) fillers or extenders (eg, starch, lactose, sucrose, glucose, mannitol and / or silicic acid); (2) binders (eg, carboxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia); (3) humectants (eg glycerol); (4) disintegrants (eg, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate); (5) solution retardants (eg, paraffin); (6) absorption accelerators (eg, quaternary ammonium compounds); (7) wetting agents (eg, acetyl alcohol and glycerol monostearate); (8) absorbents (eg kaolin and bentonite clay); (9) lubricants (eg, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof); (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical composition may also comprise a buffer. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose as well as high molecular weight polyethylene glycols and the like.

Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may include binders (e.g. gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (e.g. sodium starch glycolate or crosslinked sodium carboxymethyl cellulose), surface-active agents or It can be prepared using a dispersant. Molded tablets may be prepared by molding in a suitable device a mixture of the powdered active ingredient moistened with an inert liquid diluent.

Tablets and other solid dosage forms (eg dragees, capsules, pills and granules) of the pharmaceutical compositions described herein may optionally be coated, such as enteric coatings and other coatings well known in the pharmaceutical-formulation art. And shellacs. They can also be used to control the sustained release or controlled release of the active ingredient therein in various ratios, for example, to provide the desired release profile, other polymeric materials, liposomes and / or microspheres. It may be formulated to provide release. These can be sterilized by incorporating a sterilizing agent, for example, in the form of a sterile solid composition which can be sterilized by filtration through a bacteria-retaining filter or dissolved in sterile water or some other sterile injectable medium immediately before use. have. These compositions may also optionally contain an opacifying agent, which may be a composition which releases the active ingredient (s) alone or preferentially in a delayed manner to a specific site of the gastrointestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be present in micro-capsule form, optionally with one or more of the aforementioned 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, liquid dosage forms are inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers (eg, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl). Alcohols, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseeds, peanuts, corn, embryos, olives, castors and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan Fatty acid esters, and mixtures thereof).

In addition to inert diluents, oral compositions may include auxiliaries such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, flavoring agents and preservatives.

In addition to rifaximin, the suspension may be, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxyde, bentonite, agar and tragacanth, and mixtures thereof It may contain a suspending agent such as.

Pharmaceutical compositions for rectal or vaginal administration can be presented as suppositories, which comprise one or more suitable non-irritating excipients or carriers, including rifaximin, for example, cocoa butter, polyethylene glycols, suppository waxes or salicylates. It can be prepared by mixing, which is solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity to release the active agent.

Compositions suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers known in the art as suitable.

Dosage forms for topical or transdermal administration of rifaximin include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. Rifaximin may be mixed with pharmaceutically acceptable carriers and preservatives, buffers or propellants that may be necessary under sterile conditions.

Ointments, pastes, creams and gels, in addition to rifaximin, include excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanths, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc and oxidation Zinc, or mixtures thereof.

In addition to rifaximin, the powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these materials. Sprays may also contain conventional propellants such as chlorofluoro hydrocarbons and volatile unsubstituted hydrocarbons (eg butane and propane).

Rifaximin can also be administered by aerosol. This is accomplished by making solid particles containing aqueous aerosols, liposome preparations or compounds. Non-aqueous (eg fluorocarbon propellant) suspensions may be used. Ultrasonic nebulizers are preferred because the nebulizers can minimize the exposure of the agent to the shear, leading to degradation of the compound.

Injectable depot forms are made by forming microencapsulated substrates of rifaximin in biodegradable polymers (eg, polylactide-polyglycolide). Depending on the ratio of drug to polymer and the nature of the particular polymer used, 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 that are compatible with body tissues.

When rifaximin is administered to humans and animals as a medicament, it contains from 0.1 to 99.5% (more preferably from 0.5 to 90%) of the active ingredient, either by itself or together with, for example, a pharmaceutically acceptable carrier. It can be presented as a pharmaceutical composition.

Regardless of the route of administration, selected rifaximins that can be used in the pharmaceutical compositions provided herein are formulated into pharmaceutically acceptable dosage forms by methods known to those skilled in the art.

The actual dosage level and time course of administration of the active ingredient in the pharmaceutical composition can be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response to the particular subject, composition, and mode of administration, without toxicity to the subject. have. Exemplary dose ranges are 25 to 3000 mg / day.

The preferred dose of rifaximin is the maximum that an individual can tolerate without causing serious side effects. Preferably, rifaximin is administered at a concentration of about 1 to about 200 mg / kg body weight, about 10 to about 100 mg or about 40 to about 80 mg / kg body weight. The intermediate ranges for the above recited values are also to be part of this invention.

In an exemplary embodiment, the subject is administered rifaximin one, two, three or four times daily. Exemplary administrations are rifaximin 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 550 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg Oral administration of 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg or 2000 mg. The intermediate ranges for the above recited values are also to be part of this invention. In certain exemplary embodiments, the subject is administered 600 mg / day of rifaximin. In a further particular embodiment, the subject is administered three 200 mg / day tablets.

In combination therapy treatment, rifaximin and other drug (s) are administered to the mammal (eg, human, male or female) by conventional methods. The formulations may be administered in a single dosage form or in separate dosage forms. Effective amounts of other therapeutic agents are well known to those skilled in the art. However, determining the optimum effective amount range of other therapeutic agents is widely within the skill of the skilled person. In one embodiment where another therapeutic agent is administered to the animal, the effective amount of rifaximin is less than its effective amount when no other therapeutic agent is administered. In other embodiments, the effective amount of a conventional formulation is less than its effective amount when rifaximin is not administered. In this way, undesirable side effects associated with high doses of each agent can be minimized. Other potential advantages (including but not limited to improved dosing regimens and / or reduced drug costs) will be apparent to those skilled in the art.

In various embodiments, the therapy (eg, a prophylactic or therapeutic agent) is administered at intervals of less than 5 minutes, at intervals of less than 30 minutes, at intervals of 1 hour, at intervals of about 1 hour, and at intervals of about 1 to about 2 hours. At about 2 to about 3 hours, at about 3 to about 4 hours, at about 4 to about 5 hours, at about 5 to about 6 hours, at about 6 to about 7 hours, about 7 to about At intervals of about 8 hours, at intervals of about 8 to about 9 hours, at intervals of about 9 to about 10 hours, at intervals of about 10 to about 11 hours, at intervals of about 11 to about 12 hours, at intervals of about 12 to 18 hours, At 18 to 24 hour intervals, at 24 to 36 hour intervals, at 36 to 48 hour intervals, at 48 to 52 hour intervals, at 52 to 60 hour intervals, at 60 to 72 hour intervals, at 72 to 84 hour intervals, Administered at intervals of 84 to 96 hours, or at intervals of 96 to 120 hours. In a preferred embodiment, two or more therapies are administered within a visit of the same individual.

In certain embodiments, one or more compounds and one or more other therapies (eg, prophylactic or therapeutic agents) are administered clinically. Cycling therapy may be followed by administration of a first therapy (eg, a first prophylactic or therapeutic agent) for a period of time, followed by administration of a second therapy (eg, a second prophylactic or therapeutic agent) for a period of time. Then, optionally for a period of time, administering a third therapy (eg, a prophylactic or therapeutic agent), and reducing the generation of resistance to such sequential administration, eg, one of the therapies, and one of the therapies Repeating the cycle to avoid or reduce the side effects of and / or to improve the efficacy of the therapies.

In certain embodiments, administration of the same compound may be repeated, wherein the administration is at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 It can be separated by months or at least six months. In other embodiments, administration of the same therapy (eg, a prophylactic or therapeutic agent) other than rifaximin may be repeated and the administration is at least 1 day, 2 days, 3 days, 5 days, 10 days, It can be separated by 15 days, 30 days, 45 days, 2 months, 75 days, 3 months or at least 6 months.

Certain instructions may require longer treatment times. For example, treatment for traveler's diarrhea can last only about 12 to about 72 hours, while treatment for Crohn's disease can be about 1 day to about 3 months. Treatment for hepatic encephalopathy can be, for example, for the remainder of the individual's lifespan. Treatment for IBS can be intermittent for weeks or months at a time or for the remainder of the subject's life.

Manufacturing products ( article of manufacture )

Another embodiment is a medicament suitable for oral or topical administration of rifaximin, for example with printed labeling instructions that provide a discussion of when a particular dosage form should be administered with food and when consumed on an empty stomach. An article of manufacture comprising a container for holding a pharmaceutical composition. The administration can be modified for administration to a subject suffering from liver failure, or can include labeling for administration to a subject suffering from liver failure. Exemplary dosage forms and methods of administration are described below. The composition is present in a suitable container capable of maintaining and dispensing the dosage form, which does not interact significantly with the composition and may exist in a physical relationship with proper labeling. The labeling instructions will be consistent with the method of treatment as previously described. The labeling may be combined with the container in a manner that maintains both physical accessibility by way of non-limiting examples, which may be contained in a packaging (e.g., box or plastic shrink wrap), or may be used for labeling instructions or other methods of bonding or maintaining. It can be combined with the instructions coupled to the container itself by the pool to ensure.

Another aspect is an article of manufacture comprising a container containing a pharmaceutical composition comprising rifaximin, wherein the container preferably maintains the rifaximin composition in unit dosage form and wherein the pharmaceutical composition is in the presence and absence of food. When ingested under combined with printed labeling instructions that advise different absorptions.

In another aspect, provided herein is an article of manufacture or kit comprising rifaximin or a pharmaceutical composition thereof, packaged with instructions for administration to a subject with liver failure. In one embodiment, the instructions indicate to the prescribing physician, pharmacist, or individual that the individual with hepatic encephalopathy absorbs more rifaximin systemically than the individual with a normal, eg, fully functional liver system. Inform. In one embodiment, the instructions advise the prescribing physician that they must determine if the subject has hepatic insufficiency before prescribing rifaximin to the subject to treat intestinal disease. In one embodiment, the instructions advise the prescribing physician if they should take into account changes in administration or dosing regimen when prescribing rifaximin to individuals with hepatic encephalopathy. In addition, the instructions may provide prescription information for individuals with hepatic insufficiency. In another embodiment, the instructions inform the subject and / or the healthcare provider that there is a difference in plasma exposure to rifaximin between the HE subject and the subject with normal liver function.

Packaging compositions are also provided and may include a therapeutically effective amount of rifaximin. Rifaximin and a pharmaceutically acceptable carrier or diluent, wherein the composition is formulated to treat an individual suffering from or susceptible to intestinal disease, and to treat an individual suffering from or susceptible to intestinal disease Packed with instructions.

Kits, such as kits for treating intestinal disease in a subject, are also provided herein. The kit may, for example, contain instructions for use in treating rifaximin and an individual also suffering from liver failure for intestinal disease. Instructions for use may contain prescription information, administration information, storage information, and the like.

Packaging compositions are also provided and may include a therapeutically effective amount of rifaximin and a pharmaceutically acceptable carrier or diluent, wherein the composition is formulated to treat an individual suffering from or susceptible to enteric disease. And are packaged with instructions for treating an individual suffering from or susceptible to enteric disease.

Example

Aspects of the invention are based, in part, on the description that rifaximin is absorbed differently in individuals with other clinical conditions, such as hepatic encephalopathy. It should be understood that the present invention should not be considered limited to the embodiments described now, but rather that the invention should be considered to include all equivalent changes and some and all applications provided herein within the skill of one of ordinary skill in the art. do.

Example  One

For objects with impaired liver function Rifaximin  Clinical Study of Dosing

To determine the effect of impaired liver function on rifaximin efficacy, tests are performed on individuals with hepatic encephalopathy (HE), also known as hepatic coma or portal encephalopathy, and are severe and rare associated with advanced liver disease, It is a complex and potentially reversible neuropsychological syndrome. Nitrogen substances, most notably ammonia, gain access to systemic circulation as a result of reduced liver function or portal systemic short circuits. Once in brain tissue, the compound causes changes in neurotransmission that affect consciousness and behavior. There are four progressive stages of damage associated with HE defined by using the West Haven criterion (or Conn score), which ranges from stage 0 (lack of detectable change in nature) to stage 4 (coma, cerebral posture, pupil dilation). exist.

Management of patients with chronic HE includes 1) providing sustained protection, 2) identifying and eliminating factors involved, 3) reducing nitrogen loading from the intestines, and 4) evaluating the need for long-term treatment. Nitrogen loading from the intestines is typically reduced using non-absorbable disaccharides (lactulose) and / or antibodies. Lactulose is considered the best treatment in the United States, but is not currently approved for the treatment or prevention of HE. Rifaximin is an attractive therapy for the treatment of patients with HE because of its described effects and due to the disadvantages of systemic antibiotics and nonabsorbable disaccharides. Disadvantages of chronic systemic antibiotic therapy include nephrotoxicity and ditoxicity, and disadvantages of lactulose therapy include dehydration, excessive sweetness and GI side effects due to diarrhea (factors involved in HE).

In this example, rifaximin is administered to an outpatient set at 550 mg BID (for a total daily dose of 1100 mg of rifaximin). Subjects receive 550 mg of rifaximin BID for at least seven consecutive days prior to the day of pharmacokinetic sampling.

To ensure steady state plasma concentrations, blood sampling for pharmacokinetic analysis is performed after rifaximin 550 mg BID administration for at least seven consecutive days. Blood samples for pharmacokinetic analysis are collected one day after 100% compliance with a rifaximin 550 mg BID dosing regimen for at least seven consecutive days. Multiple samples for pharmacokinetic analysis were subjected to 12 hours (e.g., 1 hour, 2 hours, 4 hours, 6 hours, 8 hours before and after administration) to allow steady state characterization of the plasma rifaximin concentration-time profile. , 10 hours and 12 hours later). Subjects are fasted overnight (approximately 10 hours of no food) prior to administration of rifaximin, and the study drug is administered 1 hour after the standardized light meal (followed by the planned 1 hour plasma collection).

The pharmacokinetic parameters of rifaximin in plasma are calculated using noncompartmental methods (eg, standard model-independence approach).

Pharmacokinetic sample collection is performed on day 1 after 100% compliance with a rifaximin 550 mg BID administration regimen for at least 7 consecutive days. A total of eight blood samples were collected over 12 hours (eg 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 12 hours before and after dosing) and 12-hour dosing intervals. Allow steady-state characterization of individual plasma rifaximin concentration-time profiles for.

Plasma concentrations of rifaximin are measured using reverse phase high performance liquid chromatography by tandem quadrupole mass spectrometry detection (LS / MS / MS) using an accepted analytical method. The lower limit of quantification (LOQ), the deviation of the calibration standard from the theoretical value, and the precision are established using standard methods.

The pharmacokinetic parameters of rifaximin in the plasma is calculated using ^WinNonlin? Enterprise (Version 5.2).

Pharmacokinetic parameters are calculated using noncompartmental methods (eg, standard model-independence approach). The following steady-state pharmacokinetic parameters for rifaximin in plasma are calculated using the actual concentration-time profile for each individual:

If the proper data is possible, it is determined by other parameters, such as the apparent oral clearance (CL / F) and the end or disposed half-life (t _1/2). In addition to the planned analysis, the AUC (AUC _{0 -t} ) from time 0 (pre-administration) to the last measurable concentration is also calculated.

Individual plasma concentrations and pharmacokinetic parameters of rifaximin can be calculated using Child-Pugh scores (A and B) by descriptive statistics (eg, N, mean, SD, CV%, median, minimum, maximum, geometric mean). For the entire pharmacokinetic population and by the severity of liver injury.

Demographics and other baseline characteristics are summarized for individuals by hepatic injury severity using descriptive statistics using Child-Pugh scores (A and B) and model terminal liver disease (MELD) scores. Baseline characteristics include albumin, alkaline phosphate, alanine aminotransferase (ALT), aspartate aminotransferase (AST), international baseline (INR), serum creatine and serum total bilirubin, wherein the baseline is of rifaximin. It is defined as the last possible assessment before the first administration.

Rifaximin pharmacokinetic parameters AUC _τ and C _max in individuals with Child-Pugh scores A and B (eg mild to moderate liver injury) are compared using ANOVA model analysis.

ANOVA pairs are used to assess the concentration values of rifaximin measured before and after 12 hours of administration to assess possible differences in steady state rifaximin concentrations.

A total of 25 individuals are included in the pharmacokinetic evaluable population and evaluated for safety.

18 of 25 individuals (72.0%) have mild liver damage in baseline (eg Child-Pugh score A). The remaining seven individuals (28.0%) had moderate liver damage on a sms basis (eg Child-Pugh Score B).

Rifaximin pharmacokinetic parameters are compared with results from separate studies on healthy individuals with normal liver function.

Individual demographics and baseline characteristics

Table 1 summarizes the demographics for all enrolled individuals. A total of 25 individuals were enrolled in the study, with 17 individuals (68.0%) male and 8 individuals (32.0%) female. The average age of the participants was 58 years (range 45-68 years). Twenty-two individuals (88.0%) are white and the other three (12.0%) are black. Seven out of 25 individuals (28.0%) are Latin American.

Eighteen individuals have a Child-Pugh classification A and seven individuals have a Child-Pugh classification B. 15 individuals had a baseline MELD score of <11 and 10 individuals had a baseline MELD score of 11-18 (inclusive). Most individuals who participated had a Conn score of 0 (22/25; 88.0%) in the criteria for pharmacokinetic sub-studies, and 3 of 25 (12.0%) had a Conn score of 1 in the criteria.

Overall, demographic characteristics are comparable for Child-Pugh A and Child-Pugh B individuals. Baseline demographics are also generally similar for individuals with a baseline MELD score of <11 and for individuals with a baseline MELD score of 11-18 (inclusive). The higher ratio of individuals with a MELD score of 11 to 18 is Latin American (50.0% vs. 13.3%) compared to individuals with a MELD score of ≦ 10.

Reference laboratory findings are consistent with liver function impaired in the individual. The results of the baseline liver function test were higher among individuals categorized as Child-Pugh B as compared to individuals categorized as Child-Pugh A and among those with 11 to 18 MELD scores compared to individuals with a MELD score of <11. Indicates large liver damage. In particular, Child-Pugh B individuals and individuals with a MELD score of 11 to 18 have noticeably higher baseline values for alkaline phosphatase, AST, and direct and total bilirubin at baseline.

On the day of pharmacokinetic harvesting, most subjects receive two rifaximin doses at approximately 12 hour intervals. The shortest interval between doses for an individual is 10 hours; The longest interval for the subject is 13.55 hours. The second rifaximin dose is administered before food (13 individuals) or after food (12 individuals), regardless of dinner.

On the day of pharmacokinetic sampling, the morning rifaximin dose is administered overnight followed by at least 10 hours of fasting. All subjects are fed a light meal at 1 hour pharmacokinetic plasma sampling, followed by 1 hour after administration. The next rifaximin dose is taken immediately after the 12 hour pharmacokinetic plasma sampling, with the exception of one.

The average plasma concentration of rifaximin peaked one hour after drug administration and then slowly decreased over 12 hours (FIG. 1). Rifaximin plasma concentrations are above the limit of quantification (LOQ) of the assay over the entire 12-hour sampling interval in all subjects. A total of five individuals showed a double peak plasma concentration profile.

Rifaximin Pharmacokinetic Parameters at Steady State in Subjects with Liver Injury Classifications of Child-Pugh A and Child-Pugh B

Table 2 summarizes the pharmacokinetic parameters of rifaximin following treatment for at least 7 days in individuals with impaired hepatic function for the overall pharmacokinetic population, by Child-Pugh score. In a separate study, columns containing measured values for healthy individuals are provided to facilitate the comparison.

Child - Pugh  A (minor damage) Child - Pugh  Comparison between individuals with B (medium damage) and <11 (minor damage) vs. 11 to 18 (medium damage) MELD  Comparison between individuals with scores

The mean AUC _τ and C _max values (161 ng * h / mL and 25.1 ng / mL, respectively) in individuals with Child-Pugh score B were observed in individuals with Child-Pugh score A (118 ng * h / mL and 19.5 ng, respectively). / mL) approximately 36% and 29% higher. Rifaximin clearance rates in individuals with a Child-Pugh B score are approximately 29% longer than those observed in individuals with a Child-Pugh A score (10.5h vs. 8.12h). The pharmacokinetics of rifaximin are characterized by the coefficient of variability (CV%) for AUC _τ and C _max ranging from approximately 50 to 60%. This corresponds to the previously observed variation in healthy individuals, eg CV% of 45-60%.

Rifaximin pharmacokinetic parameters AUC _τ and C _max are compared using an ANOVA model in individuals with Child-Pugh scores A and B (respectively, mild and moderate liver damage, respectively). If AUC _τ cannot be calculated, the corresponding AUC _{0- t} value is used for inference statistics.

The results of the one-way ANOVA analysis are summarized in Table 3. The ratio of the AUC _τ geometric LSM of Child-Pugh Score B to Child-Pugh Score A is 151.2%, and the 90% confidence interval is 98.8% to 231.5% (p = 0.1092). The ratio of the C _max geometric LSM of Child-Pugh Score B to Child-Pugh Score A is 149.9%, and the 90% confidence interval is 98.8% to 227.5% (p = 0.1096). The confidence interval for the ratio of LSM is the AUC _τ and C _max in both populations. Very large variation between parameters of the object is presented.

Covariate analysis includes biochemical markers of impaired liver function such as increased albumin, total bilirubin and rifaximin systemic exposure (AUC _tau and C _max ) with increased international baseline values and reduced oral clearance (CL / F) Indicates a correlation.

Rifaximin's pharmacokinetics are evaluated in individuals with impaired liver function. After receiving the same dosing regimen (eg, 550 mg BID), the rifaximin systemic exposure value (AUC _tau ) at steady state in subjects Child-Pugh A and B was approximately 9.6, respectively, as observed in healthy subjects at steady state. Fold and 13.1 times higher.

Systemic exposures are compared using different methods to assess liver function MELD scores. The ratio of geometric LSM and 90% CI to AUC _tau and C _max is measured for individuals with a MELD score of <11 (n = 15) to a MELD score of 11-18 (n = 10). The results of this analysis (see Table 4) showed that when MELD scores were used to assess liver function, systemic exposure was statistically significantly higher in individuals with moderate hepatic impairment compared to mild hepatic impairment (p <0.05). ). The ratio of AUC _τ to MELD score of <11 to 11 to 18 is 168.22% with 90% CI of 110.5 to 256.2% (p = 0.0451); The ratio of C _max is 178.12% with 90% CI of 116.7 to 271.8% (p = 0.0283). The correlation between the MELD score and the Child-Pugh category in the A-subjects of 25 subjects in the sub-studies is small (correlation coefficient: p = 0.399).

Rifaximin is rapidly absorbed and observed 1 hour after administration in most individuals with high plasma concentrations. A total of three individuals in the Child-Pugh A group had delayed rifaximin uptake and maximum plasma concentrations were observed 6-10 hours after administration.

Compared to individuals with normal liver function

Results from conventional studies are compared with historical data from individuals with normal liver function. The arithmetic mean (± SD) pharmacokinetic parameters of rifaximin 550 mg multi-dose BID in healthy individuals are shown in Table 5.

Rifaximin exposure values (118 and 161 ng * h / mL, respectively) in subjects with Child-Pugh scores A and B were observed in healthy subjects at oral doses of 550 mg twice daily (12.3 ng * h / mL). Approximately 9.6 times and 13.1 times higher than except the t _1/2, and the variation between individuals in the pharmacokinetics of a healthy individual is generally similar to that measured in the liver is damaged objects.

Comparison of predose concentrations for 12 hours after dosing in pharmacokinetic substudies

ANOVA pair results for pre-dose concentration assessments at 0 and 12 hours are shown in Table 6.

These results indicate that the 12 hour concentration value after rifaximin administration was reduced by 37.8% compared to the concentration before morning administration (p <0.0001). Administration with meals is reported to increase the level of rifaximin uptake by approximately 2-3 times. Morning dosing is under fasting.

Covariate  Analysis method

Multivariate linear regression models were developed to assess the effects of various covariates on rifaximin AUC _τ , C _max and CL / F. The following covariates are tested in the model: Child-Pugh scores and laboratory test results (albumin, alkaline phosphatase, ALT, AST, creatinine clearance, serum creatinine, INR and total bilirubin). Covariates selected for analysis are known measures of liver and kidney function. Visual diagnosis is performed to detect potential trends between covariates of interest and AUC _τ , C _max and CL / F.

The results are shown in Tables 7-9 below.

Covariate assays correlate with biochemical markers of impaired liver function such as increased albumin, total bilirubin, and increased rifaximin systemic exposure (AUC _τ and C _max ) with increased INR values. Decreases CL / F).

Models with the highest R ² include albumin, total bilirubin, INR and ALT (R ² = 53.6%, Cp = 4.4101).

Based on model analysis, the parsimonious model decides to include only albumin, total bilirubin and INR. The final model for AUC _τ is shown in Table 7.

The model with three parameters with the highest R ² includes total bilirubin, INR and ALT (R ² = 39.1%, Cp = 3.7193). In a subset of models with four parameters; Models with the highest R ² include albumin, total bilirubin, INR and ALT (R ² = 46.9%, Cp = 3.0598). If R ² is presented higher for a model with four parameters; The conservation model is determined to include four parameters: albumin, total bilirubin, INR and ALT. The final model is shown in Table 8.

In a subset of models with four parameters; Models with the highest R ² include albumin, total bilirubin, INR and ALT (R ² = 54.9%, Cp = 3.4103). The results of this model are shown in Table 9.

Example  2

To evaluate the efficacy, tolerance and safety of rifaximin in patients with grade I, II or III hepatic encephalopathy Randomization , Double-blind, dose discovery study

Pharmacokinetic studies are performed in individuals who are HE in a dose-finding study. A total of 54 individuals (32 men, 22 women, ages 32-82 years) were included in the study and 200 mg, 400 mg, corresponding to the daily doses of 600 mg, 1200 mg and 2400 mg, respectively, for 7 consecutive days. Or 800 mg rifaximin TID (200 mg tablet). Rifaximin plasma and urine concentrations are determined by LC-MS / MS (LLOQ = 0.5 ng / mL).

Urine recovery of rifaximin is provided in Table 10.

There is no relationship between the dose administered and the amount of rifaximin recovered from urine. In urine collected within 24 hours after the last (third) 200 mg, 400 mg and 800 mg dose on day 7 of the last dose, the mean (SD) amount of rifaximin recovered from urine was 0.06% (± 0.66%) of the dose. ) To 0.1% (± 0.093%), and these values are consistent with rifaximin (eg, 0.030% ± 0.020% dose) recovered after a 400 mg radiolabelled dose alone.

Mean maximal rifaximin plasma concentrations of 2.7 ng / mL, 10.5 ng / mL and 13.5 ng / mL are measured 3 hours after the first single dose of 200 mg, 400 mg and 800 mg rifaximin, respectively.

Example  3

Rifaximin  absorption

The study is performed on liver damaged individuals. The mean AUC _tau and C _max values for subjects with Child-Pugh scores B (161 ng * h / mL and 25.1 ng / mL, respectively) were calculated for subjects with Child-Pugh scores A (118 ng * h / mL and 19.5 ng / mL, respectively). Approximately 36% and 29% higher than observed. Child-Pugh B removal of rifaximin in the score of the object t _1/2 is approximately 29% longer than would be observed for the Child-Pugh score of object A (10.5 Time for 8.12 hours). Rifaximin pharmacokinetic parameters have a coefficient of variation between individuals (CV%) for AUC _{0 - tau} and C _max in the range of approximately 50-60% in both subpopulations. This is consistent with the rate of variation previously observed in healthy individuals, for example 45-60% CV.

Rifaximin is rapidly absorbed and in most of the individuals a maximum plasma concentration is observed 1 hour after administration. A total of three individuals in the Child-Pugh A group had delayed rifaximin uptake and maximal plasma concentrations were observed between 6 and 10 hours after administration. Some individuals exhibit a flat or double-peak plasma concentration profile of rifaximin. Gastrointestinal motility and bile secretion abnormalities in individuals with cirrhosis and HE may potentially explain the delayed / sustained rifaximin uptake observed in this study.

The results of the multiple linear regression model correlate with biochemical markers of liver function such as increased albumin, total bilirubin and rifaximin systemic exposure (AUC _τ and C _max ) with increased international baseline, Decreases CL / F). A positive correlation between reference alanine aminotransferase and C _max is also observed.

In a separate study, pharmacokinetic parameters are studied. This population includes 18 individuals with minor liver damage (Child-Pugh A) (72%) and 7 individuals with moderate liver injury (Child-Pugh B). Healthy individuals study included 28 individuals.

Rifaximin exposure values (AUC _tau ) (118 and 161 ng / h / mL, respectively) in individuals with Child-Pugh Score A and Child-Pugh Score B were observed in healthy individuals following oral administration of 550 mg twice daily ( 12.3 ng h / mL), which is approximately 9.6 and 13.1 times higher, respectively. except the t _1/2, and the variation between individuals of a healthy individual pharmacokinetics are similar to those measured in the liver usually damaged objects.

Example  4

Phase 3 research

A step 3 randomized, double-blind, placebo-regulated multi-center study (Study A) is performed to assess the efficacy and safety of rifaximin in patients who are typically differential from HE already described. The study consists of a screening period (4 days), an observation period (3 days), a baseline visit and a treatment period (6 months). After measuring eligibility, the patient has a baseline evaluation period before randomization. This period is 7 days in duration and is used to measure the patient's eligibility, provide appropriate instructions for the caregiver, and establish baseline mental state and neuromuscular function before entering the double-blind period. Patients are randomized to administer rifaximin 550 mg tablet BID or corresponding placebo tablet BID for 6 months. Subjects have the option to use lactulose as the accompanying drug, with 91% of subjects taking lactulose during the course of the study. Subjects have mental status (Conn scores) and neuromuscular functionalization (immobilized posture) to measure the incidence of breakthrough overt HE episodes by researchers and practitioners, and from the subject's diary, with each direct study visit, telephone interview, and assistant report. You will receive a significant assessment of. Subjects are discontinued from the study during breakthrough overt HE episodes. After participating in the study, the subject has the option to enroll in an open-label, treatment-extending study (Study B).

Rifaximin  Volume

The dosing regimen (550 mg BID) used in Study A is based on past clinical experience with rifaximin in patients with HE and other populations. In several previous studies, rifaximin is safe and effective for individuals with HE at a dose of 1200 mg (2 × 200 mg tablet TID) per day with or without concomitant lactulose. In a six month study of rifaximin against neomycin, rifaximin 1200 mg / day and neomycin (3 g / day) had comparable efficacy in patients with HE. In a three month study of rifaximin for laccitol, individuals receiving rifaximin at 1200 mg (2 × 200 mg tablets, TID) daily showed significant improvement in the end of HE.

In dose-range studies in individuals with active symptoms of HE, there is a dose-dependent trend in improving the PSE index up to 1200 mg (2 × 200 mg tablet TID). Similar results are observed for 1200 mg and 2400 mg doses (4 × 200 mg tablet TID) (Table 11). In the dose-response analysis, the Jonckheere-Terpstra test showed a tendency to improve the PSE index for the dose group (p = 0.0586).

Study population

For Study A, male or female subjects aged 18 and older are eligible for the study if they meet the following inclusion criteria:

○ Conn score 0 or 1

History within 6 months (ie, subjects are documented) with ≧ 2 episodes of overt HE, associated with chronic liver disease (eg cirrhosis or portal hypertension) with a severity documented prior to screening with a Conn score ≧ 2. With proven recurrent, overt HE). At least one previous episode is verified from the medical record. Hepatic encephalopathy episodes that primarily contribute to GI bleeding, drugs (eg drugs, neurostabilizers, sedatives), kidney failure requiring dialysis or CNS damage (eg, subdural hematoma) are not counted as previous, Qualify the episode.

○ MELD score ≤ 25

○ Screening (if any)> TIPS placement or calibration 3 months ago and

○ Whether a close family member or other person continues to manage the subject and facilitates the subject during the study.

Subjects are excluded from the study if the following criteria apply:

○ expected to have liver transplant within 1 month of screening

Evidence of alcohol within 14 days of screening, stabilizer intake or drug dependence within 7 days

○ HIV determined by medical history

○ active SBP or daily prophylactic antibiotic treatment

○ GI bleeding requiring hospitalization and transfusion within months of screening

○ presence of bowel obstruction or inflammatory bowel disease

○ Renal failure (serum Cr> 2.0 mg / dL)

○ Anemia (HgB <8gm / dL)

○ Hypoglycemia or electrolyte abnormalities (Na + <125 mEq / L, Ca ++> 10 mg / dL, K + <2.5 mEq / L)

○ Necessity of Prohibited Concurrent Dosing

End of efficacy efficacy endpoints ) Justice

The main terminal in Study A is the time for the first breakthrough overt HE episode. Breakthrough overt HE episodes are an increase in Conn score from grade ≥ 2 (ie, from 0 or 1 to ≥ 2), or an increase in Grade 1 Conn and Inability to Posture, respectively, for individuals with zero Conn scores to enter the study. It is defined as The time for breakthrough overt HE episodes is the duration from the first dose of study drug for the first breakthrough overt HE episode.

The main secondary stages are set out below:

1. Time for first HE-related hospitalization.

2. Time of increase from baseline in Conn score (mental state rating).

3. Time of increase from baseline in fixed posture ratings.

4. Mean change from baseline in fatigue domain rating for LCDQ at the end of treatment.

5. Mean change from baseline in venous ammonia concentration at the end of treatment.

The details of treatment groups for Study A are set forth in Tables 12-13 below.

Reference characteristics

HE severity (Conn score and inability to fix posture for recent episodes of overt HE) And ITT population, such as time since the last HE episode Hepatic encephalopathy baseline characteristics are summarized in Table 4. Liver disease characteristics and other characteristics (eg, the severity of the disease (MELD score), time since the first diagnosis of advanced liver disease and the etiology of liver disease) of individuals that are the reference in the ITT population are shown in Tables 15, 16, and 17 It is summarized in Baseline characteristics are generally comparable across treatment groups.

Study b design

Study B is an ongoing Phase 3, multi-center, open-label, treatment-extension study to assess the long-term safety of rifaximin 550 mg BID in individuals with a history of recurrent, episode overt HE. All eligible subjects have a history of overt HE episodes with severity demonstrated by documentation of Conn score ≧ 2 at registration, ≦ 2 at enrollment within 12 months prior to screening, and have participated in Study A or are new individuals. Treatment with rifaximin 550 mg tablet BID is planned for at least 24 months or until controlled approval. Concurrent therapy with lactulose is optional.

Although Study B was primarily designed to assess the long-term safety of rifaximin 550 mg, the Conn score and the assessment of the added efficacy of the non-fixed posture rating are collected during the study. In Study B, breakthrough overt HE increased the Conn score to Grade ≥ 2, increased the Conn and Ability Rating rating of Grade 1 for individuals with a Conn score of 0 respectively, and individuals with a Conn Score of 2 at the start of the study. Is defined as the increase in Conn score to ≧ 3.

Study C, Study D and Study E Design

Study C is a double-blind, dose-range study in individuals with grades 1 to 3 HE enrolled in five institutions in the UK. Subjects are randomized to rifaximin at a daily dose of 600 mg (200 mg TID), 1200 mg (400 mg TID) or 2400 mg (800 mg TID) for 7 days. Planned registration is 54 individuals (18 per group).

Study D is a double-blind, double-dummy of rifaximin 1200 mg / day and laccitol 60 g / day for up to 10 days of treatment in hyperammonemia hepatic cirrhosis individuals with grades 1 to 3 HE registered in 16 institutions in Spain. (double-dummy), comparative, phase 3 study. Planned registration is 120 individuals (60 per group).

Study E compares 14 days of rifaximin 400 mg TID to placebo in cirrhosis individuals with mild to moderate hepatic encephalopathy that are not resistant to the GI side effects of lactulose or laccitol.Step 3, International, Multi-center, Randomized, Double-blind, placebo-controlled, parallel-group study. The study was conducted in the United States, Poland, Hungary and the United Kingdom. Planned registration is 112 individuals (56 per group).

Terminal Primary Efficacy ( primary efficacy endpoint ) Justice

Mental status (Conn score) and neuromuscular function (fixed posture rating) are assessed in Study C, Study D, and Study E using the same criteria as described above for Study A and Study B.

Venous ammonia levels, NCT scores, and EEG results are graded with increasing severity.

Study C : For Study C The end of primary efficacy is the PSE index at the end of the study. The PSE index is a component grade, including grades for mental state (Conn score), inability to fix posture, venous ammonia levels, NCT and EEG.

At the end of the study with rifaximin 600 mg, 1200 mg and 2400 mg daily treatment groups, the difference in PSE index is assessed by analysis of covariates.

Study D : The four primary efficacy stages are defined as follows:

1. Improvement of mental state (Conn score)

2. PSE Index

3. Decrease Intravenous Ammonia Levels

4. Reduction of PSE Index

Study E : The primary efficacy late stage is at least 1 level after completion of treatment compared to baseline (eg, a change from Conn score 2 to Conn score 1 or 0). Overall response, defined as the ratio of individuals exhibiting improvement in mental state (Conn score) Speed.

Demographic and Baseline Characteristics

In Study C, mean ages were 55.2, 52.3 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 laccitol groups, respectively. In Study E, mean ages were 53.6 and 53.3 years in the rifaximin and placebo groups, respectively.

Demographic characteristics are generally similar across study groups in Study C, Study D, and Study E.

Table 8 shows a summary of the baseline characteristics for Study C, Study D, and Study E. Subjects in Study D have more severe HE symptoms than subjects in Study E, as measured by mental state / Conn score, inability to fix posture, and PSE index. In addition, the disease severity is greater in D than in C. For example, the population ratio of mental state / Conn scores of 2 or more in the baseline is 70% (rifaximin) and 60.3% (laxitol) in D, 14.6% (rifaximin) and 4.4% in E, and 600 in C. 16.7%, 31.6% and 23.5% in the mg, 1200 mg and 2400 mg groups. The time since diagnosis of the HE state (ie HE duration) is substantially longer in Study D than in Study E and Study C (see Table 8).

Patient placement

At the 120-day safety update, 280 individuals enrolled at 60 study sites. A total of 152 (54.3%) of these individuals were extended from the introductory study (Study A), and 128 (45.7%) were new individuals. A total of 187 (66.8%) are still in the study. 93 subjects (33.2%) discontinued treatment initially, the main reasons being death, liver transplantation, individual request and adverse effects.

Reference characteristics

Baseline characteristics are generally similar between study A and study B individuals. Demographics were presented and baseline characteristics were presented for the new rifaximin population in Study B.

Differences in baseline characteristics between Study A and Study B are associated with differences in entry criteria. Subjects have ≧ 1 verifiable HE episodes within 12 months before screening for Study B for ≧ 2 HE episodes within 6 months before screening for Study A. Consistent with these differences, when compared to Study A, the subjects in Study B have a longer duration of presently proven drive from HE and a lower ratio of individuals with two or three verifiable HE episodes before the start of the study.

outbreak Manifestation HE Subgroups against time for

Rifaximin treatment reduces the risk of experiencing breakthrough overt HE episodes through all subgroups examined.

The hazard ratio (end of primary efficacy), 95% CI and p-value for the risk of experiencing breakthrough overt HE in the rifaximin group for placebo from the Cox proportional hazard model is shown in FIG. 2. A risk ratio of less than one indicates that the results are beneficial for rifaximin, and more than one is favorable for placebo.

Times for the first breakthrough overt HE episode results from the Child-Pugh classification at baseline are shown in Table 9. Child-Pugh subgrades, total grades and classifications are obtained after the study. Rifaximin treatment results in a significant reduction in the risk of experiencing breakthrough overt HE episodes when compared to placebo through the Child-Pugh A, B or C groups. Statistically significant rifaximin treatment effects in reducing the risk of experiencing breakthrough overt HE are observed in the Child-Pugh A (5-6), B (7-9) and C (10-15) classifications.

Study A Secondary Efficacy Analysis

Rifaximin treatment results in a 50% reduction in the risk of HE-related hospitalization during the 6 month treatment period (i.e. hospitalization occurs directly from HE or HE conditions that occur during the hospitalization process), compared to placebo (risk ratio = 0.500, 95% CI: 0.287-0.873, p = 0.0129). Hepatic encephalopathy-related hospitalization has been reported in 19 of 140 individuals and 36 of 159 individuals in the rifaximin and placebo groups, respectively. After normalization for exposure, the HE-related hospitalization rate is 51% lower in the rifaximin group (0.38 outbreaks / PEY, rifaximin versus 0.78 outbreaks / PEY, placebo).

Individuals of the rifaximin group, compared with placebo, had a 56% reduction in the risk of HE-cause hospitalization (ie, hospitalization only directly induced from HE) during the 6 month treatment period (risk ratio = 0.438, 95% CI: 0.238 to 0.807, p = 0.0064). HE-cause hospitalization was reported in 15 of 140 individuals and 33 of 159 individuals in the rifaximin and placebo groups, respectively. HE-cause admission rates are 0.30 outbreaks in the rifaximin group / PEY versus 0.72 outbreaks in the placebo group / PEY.

At the end of study A's treatment CLDQ  Change from baseline in fatigue domain rating

Health-related characteristics of life assessments are carried out through the use of the Permitted Chronic Liver Disease Questionnaire (CLDQ) for individuals with chronic liver disease.

Typically, the CLDQ analysis is performed by comparing the change from baseline to final evaluation of CLDQ and domain grade between two treatment groups. However, this study using a simple change from baseline analysis has the following limitations. First, the questionnaire measures the characteristics of the individual's living conditions over two weeks before completing the questionnaire. By comparing the results from two weeks before the last assessment to two weeks before the baseline (change from baseline analysis), no change over the entire course of the study is captured in the analysis. Second, most individuals in the study also have comorbid conditions associated with cirrhosis, which can potentially distort the outcome, depending on the timing of complications and at or near the initial or final assessment. Finally, individuals who have experienced an overt HE outbreak episode are withdrawn from the study according to the protocol and have completed the final CLDQ assessment at the end of the study visit, which often occurs after resolution of the HE occurrence. Thus, for these individuals, the CLDQ results could be similar to the reference level. To account for these limitations, an AUC analysis using A T _wa (adjusted AUC for study exposure time in the study) is performed, which allows inclusion of CLDQ results over the full participation time of the subject, particularly in studies prior to breakthrough HE episodes. Because.

When the CLDQ results are analyzed using T _wa , individuals in the rifaximin group have significantly less fatigue and significantly greater overall quality of life than individuals in the placebo group. The CLDQ results favoring the rifaximin group were also evaluated for the overall CLDQ domain score (p = 0.0093) and for abdominal symptoms (p = 0.0090), systemic symptoms (p = 0.0160), activity (p = 0.0022), emotional function (p = 0.0065) and worry (p = 0.0436), respectively, for different component domains of CLDQ.

The CLDQ results were shown to predict breakthrough overt HE episodes as defined by late stage 1 (FIG. 4). There is a significant difference in the frequency distribution of T _wa (AUC normalized by exposure time) for all domains of CLDQ between individuals with breakthrough overt HE and those without breakthrough overt HE. The mean T _wa for each domain and overall correlates with the presence or absence of breakthrough overt HE episodes.

Long term efficacy (study A and study B)

Although Study B was designed primarily to assess the long-term safety of rifaximin 550 mg, the Conn score and the additive efficacy assessment of the non-fixed grade were collected at each visit and overt HE breakthrough. Kaplan Meier analysis of time for the first breakthrough overt HE episode shows consistent, durable and repeatable protective effects of rifaximin compared to placebo as shown in Study A.

Breakthrough in Study B Manifestation HE Time for-Consistency with Study A Results

Kaplan-Meier measures of time for the first breakthrough overt HE episode are similar between the rifaximin group in study A (rifaximin PEY = 50) and new rifaximin individuals in study B (rifaximin PEY = 80) (relative risk). For the difference of p = 0.800). In addition, similar ratios of individuals breakthrough overt HE episodes in the rifaximin group of study A (22%, 140 of the 140 [rifaximin groups]) and the new rifaximin group of study B (20.5%, 42 of 210). Has The rate of breakthrough overt HE episodes, adjusted for exposure, is 0.62 occurrences / PEY in the rifaximin group from Study A, compared to 0.5 occurrences / PEY for new rifaximin individuals in Study B.

Of study B Rifaximin  As a cure Crossed  Breakthrough in Placebo Subject of Study A Manifestation HE  Time for episode

Placebo treated individuals from Study A that were crossed into Study B follow the open-label study process (n = 82). A comparison of Kaplan Meier measurements of time for the first breakthrough overt HE episode between the placebo experience in Study A and the first 6 months of rifaximin treatment in Study B is shown in FIG. 5. For rifaximin treatment to placebo treatment, the incidence of breakthrough overt HE episodes is 0.2112 (95% CI: 0.1006 to 0.4432, p <0.0001 for group differences in relative risk). This result represents a 79% reduction in the risk of experiencing breakthrough overt HE during rifaximin treatment in Study B compared to their prior placebo experience in Study A. Breakthrough overt HE experienced 39 of 82 in the placebo treatment in Study A and 14 of 82 during the 6 months of rifaximin treatment in Study B. The rate of breakthrough HE episodes was 1.5 occurrences / PEY during the placebo experience in Study A and 0.4 occurrences / PEY during the rifaximin experience in Study B.

Collectively, these results indicate that placebo crossover individuals in Study B experienced a similar protective effect on breakthrough HE episodes compared to Rifaximin-treated individuals in Study A and the continuing rifaximin group in Study B.

In the short course of treatment PSE  Indices

Improvements (ie reductions) in the PSE index are observed in all treatment groups at the end of treatment from baseline in Study C, a dose-range study. At the end of treatment, the mean change from baseline in the PSE index is -6.4%, -10.3% and -10.7% in the 600 mg, 1200 mg and 2400 mg daily dose groups, respectively. In Study D, which compared daily Rifaximin 1200 mg for laccitol, there was a significant decrease in the PSE index in the Rifaximin group as compared to the Laxitol group (p = 0.0103). Also in Study D, the PSE potency index shows a significant improvement in the rifaximin group as compared to the laccitol group (p = 0.0083). Changes in the PSE index are similar between rifaximin and placebo groups in Study E.

6 shows the PSE index results at the end of baseline and studies C, D and E. FIG.

In the short course of treatment Conn  Improvement of score

In Study C (dose-range studies), there is evidence of statistical trends indicating a greater proportion of individuals with improved mental status (Conn scores) in the 1200 mg group compared to the 600 mg group (proportional odds model). p = 0.099) using the odds model). In addition, at the 2400 mg daily dose, higher ratio individuals had an improvement in Conn score compared to the 600 mg daily dose (31.3% vs. 26.7% had a Conn score change of −1 or −2).

Improvement in mental state (Conn score) was not significantly different between rifaximin and laccitol groups in Study D, but at the end of Study D Primary Efficacy; Reduction of the PSE index, improvement of the PSE efficacy index, and reduction of venous ammonia levels indicate a significant useful effect of rifaximin. Significant absence of rifaximin in improvement of Conn score in Study D is due to short-term study drug treatment (day 10).

In Study E, the lack of rifaximin effect on improvement of Conn score can be attributed to short-term treatment (15 days) and mild HE symptoms in this study. Subjects in Study E have mild HE symptoms, as measured by mental state / Conn score, fixed posture disability rating, and PSE index, as compared to Subjects in Study D or Study C.

Fixed postoperative disability rating in the course of short-term treatment, NCT  Results and global response

The percentage of subjects that improved in the fixed postural disability rating was increased by higher rifaximin doses in study C with medication. In study D (rifaximin vs laccitol), the ratio of individuals improved in the fixed postural disability rating was similar between groups. In the rifaximin vs placebo study, Study E, a greater frequency of individuals had an improvement in the fixation posture rating in the rifaximin group as compared to the laccitol group (39.1% vs. 9.3%; p for the intergroup differences favored rifaximin = 0.0097).

Changes in NCT scores are generally similar across groups in each of the three studies.

The overall global response to treatment is assessed in Study D. The percentage of individuals (Conn scores of standardized venous ammonia and mental state / 0) that were considered treated at the end of the study were higher in the rifaximin group (53.1% vs. 39.2%) compared to the laxitol group.

Summary of Results for Short-Term Treatment Study C, Study D, and Study E

In Study C, a dose-dependent trend was observed in improving the PSE index (p = 0.056) and mental state / Conn scores, and the results from this study showed the effect of a 1200 mg rifaximin daily dose (400 mg TID). . These data, along with results from published studies of rifaximin 1200 mg / day in the treatment of HE, provide the basis for dose selection for the Phase 3 studies, Study A and Study B.

In Study D, there is a significant group-to-group difference in changes in the PSE index and venous ammonia levels (all of which are late stages) favoring the rifaximin group as compared to laccitol; Higher ratios of rifaximin individuals are considered treated at the end of treatment (standardized venous ammonia and Conn score of mental state / 0).

In Study E, significantly larger ratios of rifaximin individuals showed improvement in the fixation postcapability rating compared to placebo subjects; As a result of the end stage 1, the ratio of improved individuals in the Conn score is not significantly different between groups. Subjects in Study E have mild HE symptoms when compared to subjects in Study D.

Quote by reference

The contents of all documents, patents, pending patent applications, and published patents cited throughout this application are hereby specifically incorporated by reference.

Equivalent

One skilled in the art can recognize or ascertain many equivalents to the specific embodiments provided herein using only routine experimentation. Such equivalents are intended to be included in the following claims.

Claims (59)

Select an object that contains hepatic insufficiency,
A method of increasing rifaximin systemic exposure (AUCtau) in an individual following oral administration, comprising orally administering rifaximin to the individual comprising liver failure,
Wherein the systemic exposure to rifaximin is increased in individuals with hepatic insufficiency, as compared to individuals without hepatic insufficiency. The method of claim 1, wherein the liver dysfunction of the subject comprises a model end stage liver disease (MELD) score of less than 11 for the subject. The method of claim 1, wherein the liver dysfunction of the subject comprises a model terminal liver disease (MELD) score of 11 to 18 for the subject. The method of claim 1, wherein the liver dysfunction of the subject comprises Child-Pugh A diagnosis for the subject. The method of claim 1, wherein the liver dysfunction of the subject comprises Child-Pugh B diagnosis for the subject. The method of claim 1, wherein the systemic exposure to rifaximin in the individual suffering from liver failure comprises at least 5 times higher exposure than in an individual without liver failure. The method of claim 1, wherein the systemic exposure to rifaximin in the individual suffering from liver failure comprises at least 9.6 times higher exposure than in an individual without liver failure. The method of claim 1, wherein the rifaximin systemic exposure in an individual suffering from liver failure comprises at least 13.1 times higher exposure than in an individual without liver failure. The method of claim 1, wherein the rifaximin systemic exposure in an individual with liver failure comprises from about 5 to about 13.1 times higher exposure than in an individual without liver failure. The method of claim 1, wherein the individual suffering from liver failure comprises an individual suffering from hepatic encephalopathy. The method of claim 1, further comprising administering rifaximin with food. The method of claim 11, wherein the rifaximin systemic exposure in an individual suffering from liver failure comprises at least 10 times higher exposure than in an individual not comprising liver failure. The method of claim 11, wherein the rifaximin systemic exposure in an individual suffering from liver failure comprises at least two times higher exposure than in an individual that does not comprise liver failure. The method of claim 11, wherein the rifaximin systemic exposure in an individual suffering from liver failure comprises about 2 to about 10 times higher exposure than in an individual not comprising liver failure. The method of claim 1, further comprising selecting an individual susceptible to or suffering from traveler's diarrhea. The method of claim 15, further comprising informing the subject that the rate of elimination of rifaximin is reduced in the population of individuals with hepatic insufficiency relative to the population of individuals without hepatic insufficiency. Select an object that contains hepatic insufficiency,
A method of increasing rifaximin plasma concentration (C _max ) in an individual following oral administration, comprising orally administering rifaximin to the individual comprising liver failure,
Wherein the plasma concentration of rifaximin is increased in individuals with hepatic insufficiency compared to individuals without hepatic insufficiency. The method of claim 17, wherein the subject, including hepatic insufficiency, has increased alanine aminotransferase (ALT). The method of claim 17, wherein the rifaximin plasma concentration in a subject suffering from or susceptible to liver failure comprises at least two times higher exposure than in a subject not comprising liver failure. The method of claim 17, further comprising administering rifaximin with food, wherein the time to reach maximum plasma concentration is delayed. The method of claim 17, further comprising selecting an individual susceptible to traveler's diarrhea or having traveler's diarrhea. The method of claim 21, further comprising informing the individual that the rate of elimination of rifaximin is reduced in the population of individuals with hepatic insufficiency relative to the population of individuals without hepatic insufficiency. Select an object that contains hepatic insufficiency,
A method of reducing the rate of rifaximin removal in an individual following oral administration comprising orally administering rifaximin to the subject with liver failure,
Wherein the rate of elimination of rifaximin is reduced in individuals with hepatic insufficiency as compared to individuals without hepatic insufficiency. The method of claim 23, wherein the rifaximin removal rate is reduced by at least 25% in individuals with hepatic insufficiency compared to individuals without hepatic insufficiency. The method of claim 23, wherein the liver dysfunction of the subject comprises a Child-Pugh A score. The method of claim 23, wherein the liver dysfunction of the subject comprises a Child-Pugh B score. The method of claim 23, wherein the decreasing rate of removal further comprises an increase in the bioavailability of rifaximin in the subject with hepatic insufficiency. The method of claim 23, wherein the individual comprising hepatic insufficiency comprises the individual comprising at least one sign, symptom or episode of hepatic encephalopathy. The method of claim 23, wherein the subject comprising hepatic insufficiency comprises at least one portal systemic shunt. The method of claim 23, further comprising selecting an individual susceptible to or suffering from traveler's diarrhea. 31. The method of claim 30, further comprising informing the individual that the rate of elimination of rifaximin is reduced in the population of individuals with hepatic insufficiency relative to the population of individuals without hepatic insufficiency. Selecting an individual containing hepatic encephalopathy,
A method of determining a therapeutically effective amount of rifaximin for an individual comprising determining a therapeutically effective amount in view of said individual with hepatic encephalopathy. 33. The method of claim 32, wherein the individual has traveler's diarrhea. The method of claim 32, wherein an increased dose is presented to the subject as compared to the subject without hepatic encephalopathy. The method of claim 32, wherein a reduced dose is presented to the subject as compared to the subject without hepatic encephalopathy. 33. The method of claim 32,
The rate of elimination of rifaximin is reduced in the population of individuals with hepatic insufficiency compared to the population of individuals without hepatic insufficiency,
Systemic exposure to rifaximin is increased in a population of individuals with hepatic insufficiency compared to a population of individuals without liver insufficiency,
The plasma concentration of rifaximin is increased in the population of individuals with liver dysfunction compared to the population of individuals without liver dysfunction,
Informing the subject of one or more of which the clearance rate of rifaximin is reduced in the population of individuals with hepatic insufficiency relative to the population of individuals without hepatic insufficiency. Select an object that contains hepatic insufficiency,
Associate one or more of increased systemic exposure to rifaximin, increased plasma concentrations of rifaximin, or reduced clearance of rifaximin with liver failure,
Determining a therapeutically effective amount by considering at least one of increased systemic exposure to rifaximin, increased plasma concentrations of rifaximin, or reduced clearance of rifaximin in a subject associated with liver failure. Method for determining the therapeutically effective amount of rifaximin for Korean. The method of claim 37, wherein the liver dysfunction of the subject comprises Child-Pugh A diagnosis for the subject. The method of claim 37, wherein the liver dysfunction of the subject comprises Child-Pugh B diagnosis for the subject. The method of claim 37, wherein the liver dysfunction of the subject comprises a model terminal liver disease (MELD) score of less than 11 for the subject. The method of claim 37, wherein the liver dysfunction of the subject comprises a model terminal liver disease (MELD) score of 11 to 18 for the subject. The method of claim 37, wherein the liver dysfunction of the subject comprises increased ALT for the subject. The method of claim 37, wherein the liver dysfunction of the subject comprises at least one contextual paragraph in the subject. The method of claim 37, wherein the liver dysfunction of the subject comprises at least one episode of hepatic encephalopathy. 38. The method of claim 37, further comprising selecting an individual susceptible to or suffering from traveler's diarrhea. The method of claim 45,
The rate of elimination of rifaximin is reduced in the population of individuals with hepatic insufficiency compared to the population of individuals without hepatic insufficiency,
Systemic exposure to rifaximin is increased in a population of individuals with hepatic insufficiency compared to a population of individuals without liver insufficiency,
The plasma concentration of rifaximin is increased in the population of individuals with liver dysfunction compared to the population of individuals without liver dysfunction,
Informing the subject of at least one of the clearance rates of rifaximin are reduced in the population of individuals with hepatic insufficiency compared to the population of individuals without hepatic insufficiency. Select objects that suffer from traveler diarrhea (TD) or are susceptible to traveler diarrhea,
Instructing the subject to orally administer rifaximin,
The rate of elimination of rifaximin is reduced in the population of individuals with hepatic insufficiency compared to the population of individuals without hepatic insufficiency,
Systemic exposure to rifaximin is increased in a population of individuals with liver failure, compared to a population of individuals without liver failure,
The plasma concentration of rifaximin is increased in the population of individuals with hepatic insufficiency compared to the population of individuals without liver insufficiency,
A method for treating traveler's diarrhea comprising informing the subject of one or more of which the clearance rate of rifaximin is reduced in the population of individuals with hepatic insufficiency compared to the population of individuals without liver insufficiency. The method of claim 47, wherein the liver dysfunction of the subject comprises a model terminal liver disease (MELD) score of less than 11 for the subject. The method of claim 47, wherein the liver dysfunction of the subject comprises a model terminal liver disease (MELD) score of 11 to 18 for the subject. 48. The method of claim 47, wherein the liver dysfunction of the subject comprises Child-Pugh A diagnosis for the subject. The method of claim 47, wherein the liver dysfunction of the subject comprises Child-Pugh B diagnosis for the subject. The method of claim 47, wherein the individual with hepatic insufficiency comprises an individual with hepatic encephalopathy. 48. The method of claim 47, further comprising identifying a subject with liver failure. The method of claim 53, wherein the subject is tested for liver failure. 48. The method of claim 47, further comprising varying the amount of rifaximin administered based on the subject with liver failure as compared to the subject without liver failure. 48. The method of claim 47, further comprising changing the dosing regimen of rifaximin based on the subject with hepatic insufficiency compared to the subject without hepatic insufficiency. 48. The method of claim 47, further comprising informing the subject that the systemic exposure or plasma concentration of rifaximin is changed by food. A kit comprising rifaximin or a pharmaceutical composition thereof and instructions for administration to a subject with liver failure. 59. The kit of claim 58, comprising instructions for administering rifaximin to a subject with hepatic encephalopathy.

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