CN102625701A - Modulation of systemic exposure to rifaximin - Google Patents

Modulation of systemic exposure to rifaximin Download PDF

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CN102625701A
CN102625701A CN2010800370901A CN201080037090A CN102625701A CN 102625701 A CN102625701 A CN 102625701A CN 2010800370901 A CN2010800370901 A CN 2010800370901A CN 201080037090 A CN201080037090 A CN 201080037090A CN 102625701 A CN102625701 A CN 102625701A
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experimenter
rifaximin
hepatic insufficiency
hepatic
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W·福布斯
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Salix Pharmaceuticals Inc
Salix Pharmaceuticals Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Abstract

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

Description

Adjusting to the exposure of rifaximin system
Related application
The rights and interests of U.S. Provisional Application 61/187,251 that the application requires to submit on June 15th, 2009 and the U.S. Provisional Application 61/297,696 submitted on January 22nd, 2010.The entirety of each application all is attached among this paper by reference.
Background of invention
Rifaximin (rifaximin) (INN; Referring to Merck index (The Merck Index), XIII version, 8304) be a kind of antibiotic that belongs to rifamycinoid antibiotics, for example pyridine-imidazole and rifamycin.It is reported that rifaximin is characterised in that because of its physicochemical characteristics has negligible system absorbs (Descombe J.J. etc.; Pharmacokinetic study of rifaximin after oral administration in healthy volunteers.Int J Clin Pharmacol Res 14(2), 51-56, (1994)).
Rifaximin is described among italian patent IT1154655 and the EP0161534, and it is all through being attached among this paper for all purposes with its integral body by reference.EP0161534 disclose with rifamycin-O as raw material prepare rifaximin method (Merck index, XIII version., 8301).
Summary of the invention
This paper provides following discovery: compare with the normal experimenter of liver system, rifaximin shows different drug kinetics in hepatic insufficiency (hepatic insufficiency) experimenter.Therefore; On the one hand; This paper provides the method that the system that after orally give, increases rifaximin among the experimenter exposes (AUCtau); It realizes that through selecting the hepatic insufficiency experimenter and giving said experimenter with the rifaximin oral administration wherein compare with the experimenter who does not suffer from hepatic insufficiency, the system of rifaximin exposes in said hepatic insufficiency experimenter increases.
In related embodiment, the experimenter who suffers from hepatic insufficiency has whole hepatopathy model in latter stage (MELD) for the experimenter less than 11 scoring.In another related embodiment, the experimenter who suffers from hepatic insufficiency has the scoring of whole hepatopathy model in latter stage (MELD) 11-18 for the experimenter.
In another embodiment, the experimenter who suffers from hepatic insufficiency has Child-Pugh A scoring.In another embodiment, the experimenter who suffers from hepatic insufficiency has Child-Pugh B scoring.
In another embodiment, the system of rifaximin exposes to comprise it being at least 5 times the exposure of not suffering from the hepatic insufficiency experimenter among the hepatic insufficiency experimenter.In another embodiment, the system of rifaximin exposes to comprise it being at least 9.6 times the exposure of not suffering from the hepatic insufficiency experimenter among the hepatic insufficiency experimenter.In another embodiment, the system of rifaximin exposes to comprise it being at least 13.1 times the exposure of not suffering from the hepatic insufficiency experimenter among the said hepatic insufficiency experimenter.In another embodiment, the system of rifaximin exposes to comprise it being about 5 times of extremely about 13.1 times exposures of not suffering from the hepatic insufficiency experimenter among the said hepatic insufficiency experimenter.
In a concrete embodiment, said hepatic insufficiency experimenter suffers from hepatic encephalopathy.
In another embodiment, the method that this paper provided also comprises with food and gives rifaximin.
In one embodiment, food postpones to reach the time of maximal plasma concentration.
In another embodiment, the method that this paper provided also comprises the experimenter who selects to be prone to suffer from or suffer from traveler's diarrhea.
In another related embodiment, the method that this paper provided also comprises informs the experimenter: compare with the population of subjects of not suffering from hepatic insufficiency, the elimination factor of rifaximin reduces in the hepatic insufficiency population of subjects.
On the other hand, this paper increases rifaximin PC (C after being provided at orally give in the experimenter Max) method; It is realized through selecting to suffer from the experimenter of hepatic insufficiency and give the hepatic insufficiency experimenter with the rifaximin oral administration; Wherein compare with the experimenter who does not suffer from hepatic insufficiency, the PC of rifaximin increases in said hepatic insufficiency experimenter.
In one embodiment, the hepatic insufficiency experimenter has the alanine aminotransferase (ALT) of rising.
In one embodiment, the said PC of suffering from rifaximin among the hepatic insufficiency experimenter comprises it being at least 2 times the exposure of not suffering from the hepatic insufficiency experimenter.
In another embodiment, the method that this paper provided also comprises with food and gives rifaximin, thereby postpones to reach the time of maximal plasma concentration.
In another embodiment, said method also comprises the experimenter who selects to be prone to suffer from or suffer from traveler's diarrhea.
In another related embodiment, the method that this paper provided also comprises informs said experimenter: compare with the population of subjects of not suffering from hepatic insufficiency, the elimination factor of rifaximin reduces in the hepatic insufficiency population of subjects.
On the other hand; This paper is provided at orally give reduces the rifaximin elimination factor afterwards in the experimenter method; It carries out through selecting to suffer from the experimenter of hepatic insufficiency and give the hepatic insufficiency experimenter with the rifaximin oral administration; Wherein compare with the experimenter who does not suffer from hepatic insufficiency, the elimination factor of rifaximin reduces among the hepatic insufficiency experimenter.
In one embodiment, the elimination factor of rifaximin reduces at least 25% than the experimenter who does not suffer from hepatic insufficiency among the hepatic insufficiency experimenter.
In another embodiment, the hepatic insufficiency experimenter has Child-Pugh A scoring.In another embodiment, the hepatic insufficiency experimenter has Child-Pugh B scoring.
In another embodiment, reduce elimination factor also is included in increases rifaximin among the hepatic insufficiency experimenter bioavailability.
In another embodiment, the experimenter who suffers from hepatic insufficiency is at least a symptom, symptom or at least once outbreak with hepatic encephalopathy, or the experimenter of at least one body shunting (portal systemic shunt).In another embodiment, said experimenter is prone to suffer from or suffer from traveler's diarrhea.
In another related embodiment, the method that this paper provided also comprises informs the experimenter: compare with the population of subjects of not suffering from hepatic insufficiency, the elimination factor of rifaximin reduces in the hepatic insufficiency population of subjects.
On the other hand, this paper provides the method for confirming the treatment effective dose of rifaximin to the experimenter, and it is suffered from the experimenter of hepatic encephalopathy and the said experimenter who suffers from hepatic encephalopathy is confirmed that the treatment effective dose realizes through selection.
In one embodiment, said experimenter suffers from or the easy traveler's diarrhea of suffering from.
In another embodiment, compare, give the experimenter the dosage that increases with the dosage that gives not suffer from or be difficult for suffering from the experimenter of hepatic encephalopathy.
In another embodiment, compare, give the experimenter the dosage that reduces with the dosage that gives not suffer from or be difficult for suffering from the experimenter of hepatic encephalopathy.
In another embodiment, method also comprises and informs that said experimenter is with the next item down or multinomial: compare with the population of subjects of not suffering from hepatic insufficiency, the elimination factor of rifaximin reduces in the hepatic insufficiency population of subjects; Compare with the population of subjects of not suffering from hepatic insufficiency, the system of rifaximin exposes in the hepatic insufficiency population of subjects increases; Compare with the population of subjects of not suffering from hepatic insufficiency, the PC of rifaximin increases in the hepatic insufficiency population of subjects; And/or compare with the population of subjects of not suffering from hepatic insufficiency, the clearance rate of rifaximin reduces in the hepatic insufficiency population of subjects.
On the other hand, this paper provides the method for confirming the treatment effective dose of rifaximin among the experimenter through the experimenter who selects to suffer from or be prone to suffer from hepatic insufficiency, and it comprises:
With hepatic insufficiency with following at least one relevant: the system of rifaximin exposes to be increased, the PC of rifaximin increases or the clearance rate reduction of rifaximin and
Through considering with the next item down or multinomial definite treatment effective dose: the system of suffering from rifaximin among the experimenter of hepatic insufficiency exposes to be increased, the PC of rifaximin increases or the clearance rate of rifaximin reduces.
In another embodiment, the experimenter who suffers from hepatic insufficiency has Child-Pugh A scoring.In another embodiment, the experimenter who suffers from hepatic insufficiency has Child-Pugh B scoring.
In related embodiment, experimenter's whole hepatopathy model in latter stage (MELD) is marked less than 11.In another related embodiment, suffer from or whole hepatopathy model in latter stage (MELD) scoring of be prone to suffering from the experimenter of hepatic insufficiency is 11-18.
On the other hand, the experimenter has the ALT level of rising.
On the other hand, the experimenter has at least one body shunting.In another embodiment, existing at least hepatic encephalopathy outbreak of experimenter.In another embodiment, experimenter's pro-has at least hepatic encephalopathy outbreak in 6 months.In another embodiment, experimenter's pro-has the outbreak of at least twice hepatic encephalopathy in 6 months.
In another embodiment, method also comprises the experimenter who selects to be prone to suffer from or suffer from traveler's diarrhea.
On the other hand, this paper provides the method for confirming for the treatment effective dose of experimenter's rifaximin, and it comprises:
Selection suffers from or is prone to suffer from the experimenter of hepatic insufficiency,
With hepatic insufficiency with following at least one relevant: the system of rifaximin exposes to be increased, the PC of rifaximin increases or the clearance rate reduction of rifaximin and
Confirm the treatment effective dose through at least one below considering: the system of suffering from rifaximin among the experimenter of hepatic insufficiency exposes to be increased, the PC of rifaximin increases or the clearance rate of rifaximin reduces.
On the other hand; This paper provides the method for treatment traveler's diarrhea (TD); It is through selecting to suffer from or be prone to suffer from the experimenter of TD; Instruct experimenter's oral administration to give rifaximin, and inform that the experimenter is with the next item down or multinomial the realization: compare with the population of subjects of not suffering from hepatic insufficiency, the elimination factor of rifaximin reduces in the hepatic insufficiency population of subjects; Compare with the population of subjects of not suffering from hepatic insufficiency, the system of rifaximin exposes in the hepatic insufficiency population of subjects increases; Compare with the population of subjects of not suffering from hepatic insufficiency, the PC of rifaximin increases in the hepatic insufficiency population of subjects; And/or compare with the population of subjects of not suffering from hepatic insufficiency, the clearance rate of rifaximin reduces in the hepatic insufficiency population of subjects.
In another embodiment, the experimenter who suffers from hepatic insufficiency has Child-Pugh A scoring.In another embodiment, the experimenter who suffers from hepatic insufficiency has Child-Pugh B scoring.
In related embodiment, experimenter's whole hepatopathy model in latter stage (MELD) is marked less than 11.In another related embodiment, the scoring of hepatic insufficiency experimenter's whole hepatopathy model in latter stage (MELD) is 11-18.
In related embodiment, hepatic insufficiency comprises hepatic encephalopathy.
In another embodiment, method also comprises and differentiates the experimenter suffer from hepatic insufficiency.In related embodiment, method also comprises the hepatic insufficiency that detects the experimenter.
In another embodiment, method also comprises according to hepatic insufficiency experimenter and the administered dose that relatively changes rifaximin of not suffering from the experimenter of hepatic insufficiency.
In another embodiment, method also comprises according to the hepatic insufficiency experimenter and does not suffer from the experimenter's of hepatic insufficiency the dosage regimen that relatively changes rifaximin.
In another embodiment, method comprises that also the system of informing experimenter's rifaximin exposes and/or the PC of rifaximin changes with food.
On the other hand, this paper provides medicine box, and it comprises rifaximin or its pharmaceutical composition, and the operation instructions that are used for hepatic insufficiency experimenter administration.In one embodiment, medicine box comprises the operation instructions that are used for rifaximin is given the hepatic encephalopathy experimenter.
Hereinafter discloses other embodiment and aspect.
The accompanying drawing summary
Fig. 1 is the diagram that shows the meansigma methods+SD of rifaximin PC on the lineal scale-time distribution.
Fig. 2 shows each inferior group to time of breakthrough obvious HE outbreak (first breakthrough overt HE episode) first.
Fig. 3 shows the overall and individual domain T of the CLDQ of treatment group (ITT colony) WaThe result.
Fig. 4 shows the overall and individual domain T of the CLDQ of breakthrough obvious HE state WaThe result.
Fig. 5 shows the comparison of the breakthrough first relatively obvious HE outbreak of the Kaplan-Meier estimated value of time.Be presented at and treat the placebo experience contrast rifaximin experience that reaches 6 months among the placebo intersection experimenter.
Fig. 6 is presented in the clinical research at baseline with in the mean P SE value of treatment during latter stage.
DESCRIPTION OF THE PREFERRED
The embodiment that this paper provided relates to have been found to compare with the normal experimenter of liver function, the difference of system's exposure of rifaximin in the hepatic insufficiency patient, PC and whole last elimination factor constant.In addition, the present invention relates to find that food is to reaching the effect of rifaximin maximal plasma concentration in the experimenter.
The main pathogeny of HE relates to the nitrogen substance that is derived from intestinal and brain function is had adverse effect.Think that what have the greatest impact in these chemical compounds is ammonia, it is for proteopeptic by-product and in liver, detoxified usually.Yet, in the liver cirrhosis dependency of the blood level and the mental status inaccurate, partly be because blood brain barrier increases the permeability of ammonia among the HE patient.Also the someone proposes other toxin that is derived from intestinal that causes HE.
The no HE patient suitable with the age compares, and in chronic hepatitis patients, the generation of hepatic encephalopathy is low relevant with quality of life.Obviously the HE outbreak makes us weak, can have no omen ground and occur, and the patient can not be taken care of oneself, and often cause hospitalization.The symptom of HE patient experience comprises fatigue, drowsiness in the daytime and loss of consciousness (Conn scoring 1); With the daily function of remarkable interference and reduce confusion of consciousness and the disorientation (Conn scoring 2) of self-care ability.Usually, the shortage of this self-care ability cause nutrition improper with can not adhere to treatment and can further upgrade to more serious symptoms, for example drowsiness increase, comprehensively disorientation and numb (stupor) (Conn scoring 3) or stupor (Conn scoring 4).
The order of severity of also finding obvious HE history of attack and HE outbreak can indicate that the chronic hepatitis patients survival rate reduces.Suffering from liver cirrhosis and having among the patient of obvious HE history of attack, after experience HE outbreak, 1 year survival rate is that 42%, 3 year survival rate is 23%.In another was analyzed, in liver cirrhosis patient, 4 times of increases of generation and mortality risk of the HE outbreak of Conn scoring 2 were relevant.
These toxic chemicals are able to get into the body circulation, are the results that liver function reduces or door-body is shunted.In case entering cerebral tissue, these chemical compounds just cause influencing the change of the neurotransmission of consciousness and behavior.HE is owing to the inhibition of nitrogen-containing compound to whole central nervous system, and it causes the excitement of GABA (GABA) and the minimizing of glutamic acid neurotransmission.
Risk factor comprises azotemia (29%), tranquilizer, tranquilizer (tranquilizer), analgesic (analgesic) (24%), gastrointestinal hemorrhage (18%), excessive dietary protein (9%), metabolic alkalosis (11%), infects (3%), constipation (3%).Operation especially through jugular vein liver inside door-body shunting (TIPS) art, also can cause HE.Because of the HE due to the unknown cause only accounts for 2% case.
Initial performance is subclinical and needs diagnostic psychometric test.According to West Haven standard (or Conn scoring) is known 4 by stages damaged are continuously arranged; Its scope is from the 0th phase (lacking detectable personality changes) to the 4th phase (stupor, decerebrate posture (decerebrate posturing), platycoria), as going through of hereinafter.
HE shows as successive psychomotor dysfunction, impaired memory, response time increase, paraesthesia, poor concentration and serious form and for example goes into a coma.Can be observed the change of personality, consciousness, behavior and neuromuscular function.The neurological symptom can comprise hyperreflexia, tetanic, myoclonus and asterixis (approximate " flapping wing appearance " muscular tremor).Cognitive task (for example connecting numeral with line) can be unusual.Fetor hepaticus (breathing zone sweet taste) can appear.It is non-specific slow that electroencephalogram (EEG) spike shows, mainly active at the triphasic wave in frontal lobe district.Prothrombin time can prolong and also can't correct with vitamin K.The head computed tomography can normally or show overall atrophy.At last, can record hepatopathy symptom for example jaundice and ascites.
According to medical history, body & mind status checkout and as required clinical key element, make the diagnosis of HE to the understanding of existing hepatopathy, triggering factor and/or previous HE medical history.EEG can show that slow wave is active, even in slight case.It is distinctive that the serum ammonia level raises, but nonessential, and poor with the horizontal dependency of encephalopathy.
Control to chronic HE patient comprises: 1) providing support property nursing, 2) differentiate and get rid of risk factor, 3) alleviate the nitrogenous load and 4 from intestinal) needs of evaluate long term treatment.Use nonabsorbable disaccharidase (lactulose) and/or antibiotic can alleviate nitrogenous load usually from intestinal.
In the U.S., lactulose is considered to first-line treatment, but does not ratify to be used for treatment or prevention HE at present as yet in the U.S..Lactulose is by the intestinal bacteria metabolism of colon, and it causes feces pH to reduce, and causes the hypocatharsis effect then, finally causes defecation.Feces pH reduces makes ammonia (NH 3) ionization becomes ammonium ion (NH 4 +), it can be used for aminoacid and proteinic synthetic by antibacterial.This has reduced the serum ammonia level and has improved moral function.
Conventional therapy is intended to reduce the generation and the absorption of ammonia.The common using dosage of lactulose is 30-60g every day.Yet dosage also can progressively increase to three times-four times a day 20-40g every day, and is just half-formed to realize draining 2-3 every day.If lactulose can not oral administration or nasal feeding tube give the for example HE patient of the 3rd phase and the 4th phase, just can be used as 300cc (200g) enema,retention and give.
For acute encephalopathy, but lactulose through port or nasal feeding tube and orally give, or give through enema,retention.Usually oral dose is 30g, gives once till draining according to every 1-2 hour.At this moment, dose titration is drained 2-3 time soft stool to every day.
Lactulose is the nonprescription drugs of obtaining easily.Can obtain convenient and tasteless relatively preparation, in commerce, be commonly referred to " the lactulose powder that is used for oral solution ", for example from Bertek Pharmaceuticals, Sugarland, Tex. is called Kristalose RTM10gm and 20gm packing.The Cephulac agent of selling as aperient usually comprises Cephulac RTM, Chronulac RTM, Cholac RTMAnd Enulose RTMThese syrups can be used for substituting the lactulose powder, promptly through using enough syrups, so that the lactulose of required dosage to be provided; Common said syrup contains the 10gm lactulose of having an appointment in the 15ml syrup.
Comprise neomycin, metronidazole, vancomycin and paromomycin wide spectrum GI living antibiotics can with or do not use with lactulose.Present guilding principle is recommended oral 1-2g/ days neomycin and is periodically monitored kidney and annual monitoring audition, or 250 metronidazole.Lactulose can cause diarrhoea, causes dehydration, and this is one of risk factor of HE.In addition, the patient has limited the compliance to lactulose because of disagreeable its sweet excessively taste.In addition, side effect and the relevant administration time table of acidosis with bowl evacuation habit and flatulence (flatulence), flatulence (bloating), suffer from diarrhoea (it causes dehydration) make lactulose be difficult to life-time service.
Life-time service caused by antibiotics toxicity has limited its use in the HE treatment.Specifically, the system of neomycin, metronidazole and ampicillin absorbs the only a few case that has caused nephrotoxicity, ototoxicity, salmonella enteritis (S.enterocolitis) and/or the development of tolerant bacteria bacterial strain.In addition, neomycin only suppresses aerobic bacteria.Metronidazole is slow at hepatic insufficiency patient internal metabolism, and to ethanol interaction potentialization (disulfiram-like action), and high blood level can cause outbreak.
A kind of gastrointestinal tract specific antibiotic is exactly a rifaximin.Rifaximin is the non-aminoglycoside semisynthetic antibiotics that is derived from rifamycin-O.It is the wide spectrum oral antibiotic that the gastrointestinal enteric pathogenic bacteria is had specific non-systemic, non-absorption.With respect to former used antibiotic, find that rifaximin has advantage in the HE treatment, for example negligible system absorbs (＜0.4%) (when not considering food intake or not having gastroenteropathy) and when high dose or repeat administration, in blood plasma, does not have and accumulate.The shortage system absorbs and makes rifaximin become safety and the medicine with well tolerable property, has therefore improved patient's compliance and has reduced the relevant side effect of existing known treatment.
Rifaximin (INN; Referring to Merck index, XIII version, 8304) be a kind of antibiotic that belongs to rifamycinoid antibiotics, for example pyridine-imidazole and rifamycin.Rifaximin is for example being brought into play its broad spectrum antibiotic activity to local gastrointestinal tract antibacterial in the gastrointestinal tract, and said gastrointestinal tract antibacterial can cause infectious diarrhea, irritable bowel syndrome, small bowel bacterial overgrowth, Crohn disease (Crohn ' s disease) and/or pancreatic insufficiency.It is reported that rifaximin is characterised in that because of its physicochemical characteristics has negligible system absorbs (Descombe J.J. etc.; Pharmacokinetic study of rifaximin after oral administration in healthy volunteers.Int J Clin Pharmacol Res 14(2), 51-56, (1994)).
Rifaximin is described among italian patent IT1154655 and the EP0161534.EP patent 0161534 discloses the method (Merck index, XIII version, 8301) for preparing rifaximin with rifamycin-O as raw material.US 7,045, and 620 B1 disclose the polymorphic forms of rifaximin.Patent application that this paper mentions and patent all are attached among this paper for all purposes with its integral body by reference.
The embodiment that this paper provided also relate to comprise compositions for example the pharmaceutical preparation of rifaximin need the treatment the experimenter.
Rifaximin is the chemical compound of rifamycinoid antibiotics.Rifaximin is the chemical compound with formula I structure:
Figure BPA00001514750900111
In one embodiment, rifaximin is the molecule of absorption difference in some experimenter.In the clear this point of clinical pharmacokinetics research invading the exterior: in the normal subjects, at single with prove that repeatedly rifaximin is from gastrointestinal absorption poor (for example orally give post-absorption＜this medicine of 1%) after the oral dose.Although in urine, only detect trace parent drug and metabolite, the response rate that in feces, mainly is the rifaximin that does not change medicine is high.During repeat administration, do not have or seldom have system's drug accumulation and reach time of stable state short.Unexpectedly, every day give in the cube case that 1.5 times of higher daily doses do not cause that the rifaximin system exposes every day total amount corresponding increase; AUC after three administrations every day TotalOnly exceed about 13% than twice administration every day.
" rifaximin " used herein comprises the solvate and the polymorphic forms of this molecule, comprises for example α, β, γ, δ, ε, η, ζ and the amorphous form of rifaximin.These forms are specified in for example USSN 11/873,841; USSN 11/658,702; EP 05 004 635.2, and on May 3rd, 2005 submitted to; USPN 7,045, and 620; US 61/031,329; And G.C.Viscomi, etc., CrystEngComm, 2008,10,1074-1081 (in April, 2008).These lists of references are attached among this paper with its integral body separately by reference.
" polymorphic (polymorphism) " used herein is meant that the different crystal form appears in the unification compound in different hydration status, for example is the character of some chemical compound and complex.Therefore, polymorph (polymorph) is different solids of sharing same molecular formula, but every kind of polymorph can have different physical properties.Therefore, the unification compound can obtain various polymorphic forms, and wherein every kind of form has different with unique physical property, for example dissolubility property, melting temperature, hygroscopicity, grain shape, density, flowability, compactibility and/or x ray diffraction peaks separately.The dissolubility of every kind of polymorph has nothing in common with each other, and it is necessary that the existence of therefore differentiating the medicine polymorph provides the medicine with measurable dissolubility property.Preferably study all solid-state forms of medicine, comprise all polymorphic forms, and measure stability, dissolution (dissolution) and the flowability of every kind of polymorphic forms.In laboratory can through the X-ray diffraction spectrometry or through additive method for example infrared spectrometry distinguish the polymorphic forms of chemical compound.Generality summary for the pharmaceutical applications of polymorph and polymorph can be referring to G.M.Wall, Pharm Manuf.3,33 (1986); J.K.Haleblian and W.McCrone, J Pharm.Sci., 58,911 (1969); And J.K.Haleblian, J.Pharm.Sci., 64,1269 (1975), all these documents all are attached among this paper by reference.
Term used herein " system's exposure " is meant through administration and the experimenter is exposed rifaximin and experimenter's blood plasma is exposed rifaximin, in subject, spreads all over subsequently.Can measure system's exposure of increase through the rifaximin PC that detects the experimenter.In exemplary embodiment, the increase that system exposes is attributable to the reduction of rifaximin clearance rate.
Compare with the health volunteer, the combination of physiological and pathological factor is soluble to have the increase that rifaximin exposes among the experimenter of HE medical history.Because the door that liver cirrhosis is relevant-body shunting and portal vein hypoperfusion, the nitrogen substance (mainly being ammonia) that is derived from intestinal is accumulated the central nervous system, thereby causes the hepatic encephalopathy outbreak.Recruit under study for action have slight with the moderate liver dysfunction and there is the hepatic encephalopathy outbreak to write down the patient of medical history.Hepatic encephalopathy is by the liver cirrhosis complication due to portal hypertension, cerebral vasodilators and the hepatic insufficiency.Recent research is illustrated in high popular that spontaneous door-body is shunted in the lasting hepatic encephalopathy.
In chronic hepatopathy, the essential part of Portal circulation is perfusion functional property hepatocyte not, because exist in the liver functional shunting or liver to dissect shunting outward.As a result, the head of the medicament that oral administration gives crosses clearance rate (first pass clearance) and reduces, and the system biological availability raises.The exposure value of rifaximin is higher, maybe be in part because in the presence of door-body shunting and/or portal hypertension, presystemic metabolism (presystemic metabolism) reduces.This probability is by following true the support: although be limited (about 0.32% dosage) to the plasma exposure from the gastrointestinal rifaximin; But suppose that so little absorption portion experiences first pass metabolism (about 90.6%) in the health volunteer, in urine, drain (0.03% dosage) because only lack the unaltered rifaximin of part.In addition, because in HE experimenter, rifaximin is last t eventually 1/2On clinical statistics is learned, significantly be longer than health volunteer's (about 2 times), exposure value is higher in HE, possibly be because the System Cleaning rate of medicine reduces.
" experimenter " used herein comprises the organism of the enteropathy that can suffer from the treatment of available rifaximin or other disease or can from give rifaximin product as herein described, obtain the organism of other interests, for example people and non-human animal.Term used herein " non-human animal " comprises all vertebratess, for example mammal (for example Rodents, for example mice) and nonmammalian (for example non-human primates, for example sheep, Canis familiaris L., cattle, chicken, amphibian, reptiles etc.).
" be prone to suffer from enteropathy " used herein comprises the experimenter who is among the risk that enteropathy occurs; For example suffer from HE, immunosuppressant experimenter, be exposed to the experimenter of other bacterial infection patients, experimenter with enteropathy family history; Experimenter with the gene profile that shows disease or enteropathy risk; The experimenter of known easy trouble enteropathy, doctor, nurse, the experimenter who travels to the known outlying district of containing the antibacterial that causes traveler's diarrhea etc.
The experimenter of " suffering from hepatic insufficiency " used herein comprises suffering from the experimenter of liver function reduction clinically after diagnosing, for example, because hepatic encephalopathy, hepatitis or liver cirrhosis.Hepatic insufficiency can adopt the multiple staging that comprises whole hepatopathy model in latter stage (MELD) scoring, Child-Pugh scoring or Conn scoring any quantize.
Patient's serum bilirubin, the value of serum creatinine and the INR (INR) of prothrombin time used in the MELD scoring, so that the weighting numerical value relevant with the predicting survival rate to be provided.The scoring of 10-19 with 3 months in 27% mortality rate relevant,＜10 scoring then with 3 months in 4% mortality rate relevant.The method of measuring and analyze the MELD scoring is well known in the art.
The Child-Pugh scoring (being also referred to as the Child-Turcotte-Pugh scoring sometimes) that is used to estimate chronic hepatopathy (mainly being liver cirrhosis) prognosis is the comprehensive grading of these 5 clinical measurement values of bilirubin, serum albumin, INR, ascites and hepatic encephalopathy.Each mark is designated as the value of 1-3, and total value is used to provide the scoring that is divided into A (5-6 point), B (7-9 point) or C level (10-15 point), and it is relevant with 2 years survival rates with 1 year.The method of measuring and analyze the Child-Pugh scoring is well known in the art.
Can measure the change of the mental status through for example Conn scoring (being also referred to as West Haven scoring).Conn scoring has been widely used as the tolerance of the mental status and based on the Parsons-Smith standard by Conn improved in HE research.When the Conn standards of grading of below using, listing are estimated experimenter's state, will not will consider asterixis.
The classification that is used for the Conn marking system provides as follows.
0 grade=do not detect abnormality of personality or dystropy
1 grade=slight consciousness, the glad or anxiety of lacking; Attention span
Shorten; The addition and subtraction ability weakens
2 grades=drowsiness; Disturbance of orientation in time; Significantly personality changes; Misbehave
3 grades=drowsiness numb, stimulation is responded to partly; Mental disorder; Entirely
The face disorientation; Behavior is strange
4 grades=stupor; Can't measure the mental status
Can let the experimenter lift both arms, forearm is flat to be stretched, and wrist opens to dorsal flexion and with finger >=and 30 seconds, measure asterixis (asterixis) classification (asterixis (flapping tremor)).Asterixis can be measured with 5 continuous ranks, and the almost lasting flapping movement of for example 0 grade to 4 grades=no abnormal motion contrast shows below respectively:
0 grade=atremia;
1 grade=rarely have flapping movement;
2 grades=idol has irregular flapping wing appearance;
3 grades=frequent flapping wing appearance; With
4 grades=almost lasting flapping movement.
The fractionated effectiveness of relevant asterixis can be measured as in the asterixis classification from the time of baseline to any increase.With in the asterixis classification to the Time Calculation that increases for from give the classification of rifaximin to asterixis first, occurring the natural law that increases first from baseline.
" the prevention effective dose " of term chemical compound is meant the amount of the chemical compound that the formula that this paper provided (I) chemical compound that can effectively prevent or treat bacterial infection or HE when single or a plurality of dosage give the experimenter or this paper describe in addition.
Term " treatment effective dose " is meant when single or a plurality of dosage give the experimenter to be the amount that the experimenter effectively provides the medicament of treatment benefit.In another embodiment, the treatment benefit is to suppress bacterial infection or make the survival period of suffering from such bacterial infection patients to the expection life cycle that surpasses no said treatment.
Rifaximin is brought into play extensive antibacterial activity to causing the local gastrointestinal tract antibacterial (comprising the anaerobic bacterial strain) of infectious diarrhea in gastrointestinal tract.Having reported that rifaximin is characterised in that because of its physicochemical characteristics has negligible system absorbs (Descombe J.J. etc.; Pharmacokinetic study of rifaximin after oral administration in healthy volunteers.Int J Clin Pharmacol Res 14(2), 51-56, (1994)).
The existence of having found hepatic insufficiency has effect to the plasma exposure of rifaximin in the body.Therefore, it is used to treat the standard that enteropathy for example can be considered during the rifaximin prescription of traveler's diarrhea or IBS as health care professional (for example doctor, doctor assistant, nurse practitioner, pharmacist) opening potion.Hepatic insufficiency makes the experimenter who receives treatment learn upward significantly increase to the clinical statistics that is absorbed in of rifaximin.An embodiment disclosed herein is the method for regulating the therapeutical effect of rifaximin, promptly through selecting the hepatic insufficiency experimenter and prevention or the treatment to hepatic insufficiency further being provided.
Therefore, method that embodiment is a traveler's diarrhea (TD) among the treatment experimenter.In the method, the experimenter who rifaximin is suffered from the disease of available rifaximin treatment.Inform said experimenter, compare that the system plasma exposure of rifaximin of suffering from the experimenter of hepatic insufficiency increases with the experimenter who does not suffer from hepatic insufficiency.This information has increased the level of security that rifaximin is given the experimenter.Comprise traveler's diarrhea and hepatic encephalopathy with the medicable disease instance of rifaximin.
" informing " used herein or " sincere advice " are meant refers to or provides material publication or oral.The material of active agents and publication for example, is provided to user; Or the oral information that gives, for example show through seminar, meeting or other forms of education, through the dialogue between medicine representative of sales & marketing and medical and health work person, or through the dialogue between medical and health work person and the patient; Or to user explanation predetermined information and reach and let the purpose of its understanding.Medical and health work person's instance comprises doctor, nurse and nurse practitioner.
One aspect of the present invention comprises to doctor who prescribes and the patient who accepts the rifaximin treatment provides information, is used to make the rifaximin security concerns to minimize.In this embodiment, information has been described with the experimenter who does not suffer from hepatic insufficiency and has been compared, and system's plasma exposure of suffering from rifaximin among the experimenter of hepatic insufficiency increases.In one embodiment, information provides on label.In another embodiment, information provides on information table, when filling in the prescription of rifaximin, gives the patient with it.
In addition; Method can comprise that also the rifaximin with prescribed dose is distributed to the pharmacy and educational material is distributed to the step that the pharmacy comprises the pharmacist; Wherein said educational material comprises that relevant needs of patients knows the information that must accomplish with the patient, any untoward reaction of rifaximin when avoiding taking medicine.
In addition, method can comprise to the pharmacist provides the step to consulting patient's (about needs of patients is known and the patient must accomplish) guilding principle, so that safety clothes are used rifaximin dosage.Method can comprise that also step and doctor that the requirement doctor acknowledges receipt of educational material and guilding principle confirm that the patient receives the step of educational material.
Another embodiment is the method that rifaximin is used to treat patient's disease.Said embodiment comprises to the patient to be provided rifaximin and informs said patient or medical and health work person; System's plasma exposure of rifaximin increases and gives PC, safety or the effect that the hepatic insufficiency patient can influence rifaximin with rifaximin in suffering from the patient of hepatic insufficiency.
An embodiment comprises the experimenter's who treats the indication of suffering from available rifaximin treatment method again.This method comprises rifaximin is given said experimenter and sincerelys advise the experimenter, compares with the experimenter who does not suffer from hepatic insufficiency, and system's plasma exposure of rifaximin increases in suffering from the experimenter of hepatic insufficiency.
Therapeutic Method
This paper provides the method for confirming rifaximin dosage, is used for treating, preventing or alleviates going back intestinal relevant disease, the especially traveler's diarrhea of suffering from the experimenter of hepatic insufficiency because of for example hepatic encephalopathy.The intestinal relevant disease comprises following one or more: hepatic insufficiency, liver cirrhosis, polycystic liver disease, irritable bowel syndrome, diarrhoea, the relevant diarrhoea of microorganism, the relevant diarrhoea of clostridium difficile (Clostridium difficile), traveler's diarrhea, small bowel bacterial overgrowth, Crohn disease, chronic pancreatitis, pancreatic insufficiency, enteritis, colitis, hepatic encephalopathy (or other disease that causes ammonia level to raise) or cryptitis (pouchitis).
Term used herein " hepatic insufficiency " comprises that wherein the patient has active disease of damaged liver function and disease.Clinically, hepatic insufficiency patient's liver function reduces, and for example statistics significantly reduces.Hepatic insufficiency often causes liver failure.A kind of exemplary disease that hepatic insufficiency occurs is a hepatic encephalopathy.
Term used herein " hepatic encephalopathy " be meant chronic or the acute hepatic failure situation in reversible neuropsychiatric abnormalities.When the experimenter had hepatic injury, the toxicant of being removed by liver usually accumulated in blood, thereby the infringement brain function.These toxicants normally nitrogenous thing, the most particularly ammonia.In case the neurotransmission that entering cerebral tissue, these chemical compounds just cause influencing consciousness and behavior changes.Relevant damaged through using West Haven standard (or Conn scoring) to define 4 progressive HE by stages, its scope is from the 0th phase (lacking detectable personality changes) to the 4th phase (stupor, decerebrate posture, platycoria).The classical symptom of hepatic encephalopathy can comprise that cognitive defect, asterixis (asterixis) and level of consciousness reduction comprise stupor (for example hepatic coma), cerebral edema, and maybe be dead.Hepatic encephalopathy is commonly called hepatic coma or door-body encephalopathy in document.
Term used herein " traveler's diarrhea " is meant the gastroenteropathy that usually occurs among the traveller.Most of case is by due to antibacterial, virus or the protozoal infections.The main source of infection is the food or the water of having taken food and having received fecal pollution.The treatment length of concrete enteropathy will partly depend on disease.For example, in HE patient's the remaining years, possibly all will treat HE every day, traveler's diarrhea then only need treat 12 to about 72 hours time, and Crohn disease need be treated about 2 days to 3 months time.The dosage of rifaximin also can be different because of the difference of morbid state.
To those experimenters' of needing the prophylactic treatment enteropathy discriminating in those skilled in the art's the ability and the ken.Medical domain is understood some discrimination method to the experimenter that trouble enteropathy (its available this method treatment) risk is arranged, and for example the relevant risk factor of experimenter's family history, travelling history and expection itinerary, this morbid state development exists situation.This area clinical technology personnel can easily differentiate such candidate experimenter through using for example Clinical Laboratory, health check-up and medical history/family history/travelling history.
The hepatic insufficiency degree methods can comprise any marking system that provides more than the use among the evaluation experimenter, for example MELD scoring, Child-Pugh scoring or Conn scoring.
Again on the one hand, treatment suffers from or the easy method of suffering from the experimenter of enteropathy comprises that the experimenter that needs are arranged treats the rifaximin of effective dose, thus the treatment experimenter.In case identify the experimenter who suffers from or be prone to suffer from enteropathy, just give rifaximin.Can after for example diagnosing, after the HE incident, during the HE incident, diagnose after the slight HE, or when critical flicker frequency reaches the level of indication HE incident etc., rifaximin given.As described herein, if the experimenter also suffers from hepatic insufficiency, then the doctor can select to change the rifaximin dosage that is used to treat enteropathy that gives the experimenter.Can measure therapeutic efficiency, for example be expressed as the minimizing of bacterial overgrowth.Effect also can be measured as follows: according to the stable of the related indication minimizing of enteropathy, symptom or enteropathy is related indication stops; One or multinomial minimizing below for example: feel sick, flatulence, diarrhoea, the order of severity etc. of HE incident next time one or multinomial increase below perhaps: to time of HE incident next time, cognitive competence etc.
An embodiment is to give the method that the experimenter treated or prevented hepatic encephalopathy (HE) through the rifaximin that will treat effective dose.
Embodiment of the present invention relate to finds that rifaximin is used to treat and prevent the effect of hepatic encephalopathy.Embodiment relates to the purposes that rifaximin is used to prevent the HE paresthesia epilepsy and extends to the time of breakthrough first HE outbreak.In one embodiment; Through rank that Conn is marked increase to >=2 (for example from 0 grade or 1 grade increase to >=2 grades) or with baseline Conn scoring be those experimenters of 0 Conn scoring scoring respectively increases by 1 grade with asterixis, thereby measure the time of showing effect to breakthrough HE first.In another embodiment; Use is in the Kaplan-Meier estimated value of the experimenter's of any increase in 28,56,84,112,140 and 168 days accumulation ratio; Through time, measure to the time of breakthrough HE outbreak from Conn scoring (mental status classification) or the fractionated baseline of asterixis to any increase.
Another embodiment is the mean change that the mean change that begins from baseline in time of ammonia concentration or critical flicker frequency value begin from baseline in time.Other embodiment shows that in time the average daily consumption of lactulose that begins from Conn scoring baseline over time; Or the variation that begins from asterixis classification baseline in time.Except as otherwise noted, the variation of value is the variation that this value begins from baseline value.
Other mensuration of therapeutic efficiency as herein described comprises: the mean change that in chronic hepatopathy questionnaire survey (CLDQ) scoring, begins from baseline in time; The mean change that in the scoring of Epworth sleep scale, begins from baseline in time; Ratio with the experimenter of Epworth sleep scale scoring＞10.Evaluation to the order of severity of persistence hepatic encephalopathy also can be based on for example Conn scoring.
In another embodiment, can rifaximin be suffered from or be prone to suffer from the experimenter that hepatic encephalopathy (HE) or hepatic encephalopathy are alleviated, about 24 thoughtful 24 months persistent period.In treatment HE, can give the experimenter with rifaximin and reach more than 12 months, for example experimenter's whole life.In one embodiment, give rifaximin every day, till experimenter's death.
In one embodiment, the present invention relates to reduce the method that breakthrough event risk takes place the experimenter through rifaximin being given the experimenter.In one embodiment, for the preceding experimenter more than 90 days of begin treatment, (failure occurrence) risk takes place and reduces by 58% in decline for last HE outbreak.In another embodiment, the decline occurrence risk reduces about 30-70%.In another embodiment, said risk reduces about 40% to 70%.
In one embodiment, for last HE outbreak surpassed 90 days experimenter before giving rifaximin for, the decline occurrence risk reduced about 60%.In another embodiment, the decline occurrence risk reduces about 2%-80%.
In another embodiment, for the experimenter who has twice following HE outbreak at begin treatment in preceding 6 months, the risk of breakthrough HE outbreak reduces about 56%.In one embodiment, the risk of breakthrough HE outbreak reduces about 20%-70%.
In another embodiment, for having in preceding 6 months at begin treatment greater than for the experimenter of twice HE outbreak, the risk of breakthrough HE outbreak reduces about 63%.In another embodiment, risk reduces about 30%-80%.
Term used herein " eventually last elimination rate constant " is meant describes the first order rate constant that rifaximin is eliminated in the subject.This is to describe total elimination rate constant of removing rifaximin through all elimination processes that comprise drainage and metabolism.
Term used herein " PC " is meant the rifaximin concentration in experimenter's blood plasma.Can use the reversed phase high-performance liquid chromatography given among the embodiment for example and the four-electrode spectrum of connecting to detect (LC/MS/MS), measure the PC of rifaximin.The maximal plasma concentration of stable state is called Cmax in this article, and minimum plasma concentration is called Cmin.
Term used herein " clearance rate " is meant that the biofluid of in the unit interval, measuring removes the volume of drug metabolite fully.That eliminate is the result of the metabolic process in kidney, liver, saliva, perspiration, intestinal, the heart, brain and other position.
Alanine aminotransferase used herein is also referred to as ALT, is meant the test of carrying out in order to differentiate hepatic injury or liver failure.Measure the level of this enzyme ALT, to confirm whether individuality has hepatic injury or disease.In blood, find to have low-level ALT usually.But when hepatic injury or pathological changes, ALT is discharged in the blood flow.Can known by one of skill in the art method measure the ALT level.
Medication preparation
Embodiment also provides the rifaximin described herein that comprises effective dose and the pharmaceutical composition of pharmaceutically acceptable carrier.In fork one embodiment, effective dose can effectively be treated bacterial infection in the patient who also suffers from hepatic insufficiency, for example relevant colitis and/or the diverticulum disease of small bowel bacterial overgrowth, Crohn disease, hepatic encephalopathy, antibiotic.
For example the purposes of rifaximin in the treatment traveler's diarrhea can be referring to 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.ClinicalGastroenterology and Hepatology.2004; 2:135-138; With Steffen R, M.D., Sack DA, M.D., Riopel L; Ph.D., Zhi-Dong J, Ph.D., Sturchler M, M.D.; Ericsson CD, M.D., Lowe B, M.Phil., Waiyaki P; Ph.D., White M, Ph.D., DuPont HL; M.D.TherapyofTravelers ' Diarrhea With Rifaximin on Various Continents.The American Journal of Gastroenterology.2003 May, the 98th volume, the 5th phase, all these all is attached among this paper by reference.Embodiment also provides the pharmaceutical composition that comprises rifaximin and pharmaceutically acceptable carrier.For example can select dosage based on system's absorption of aequum, elimination factor, PC etc.The embodiment of pharmaceutical composition also comprises excipient, for example, and one or more diluent, binding agent, lubricant, disintegrating agent, coloring agent, correctives or sweeting agent.Can prepare a kind of compositions, the selected coating that is used for packing or not pill, lozenge, magnificent husband's thin slice, pill and the powder of coated tablet, hard and soft gelatin capsule agent, sugar coating.For example, but compositions formulated supplies local usefulness, for example ointment, hair cream agent (pomade), ointment, gel and lotion.In embodiments; Use pharmaceutically acceptable preparation; Give the experimenter with rifaximin; Said formulation example is as after giving said experimenter with said pharmaceutically acceptable preparation, can continue to send at least 12 hours, 24 hours, 36 hours, 48 hours, 1 week, 2 weeks, 3 week or 4 weeks to what the experimenter provided rifaximin.
In certain embodiments, these pharmaceutical compositions are applicable to part or orally give experimenter.In other embodiments; As will be detailed later; The pharmaceutical composition that this paper provided can be through special preparation; Be used for solid-state or liquid form administration, comprise being applicable to following those: (1) oral administration, for example filled medicament (drench) (aqueous or non-aqueous solution agent or suspensoid), tablet, bolus, powder, granule, paste; (2) parenteral is for example through subcutaneous, intramuscular or intravenous injection, for example sterile solution agent or suspensoid; (3) topical application for example is administered to ointment, ointment or the spray of skin; (4) interior or internal rectum, for example vaginal suppository, ointment or foam of transvaginal; Or (5) aerosol, for example contain aqueous aerosol, Liposomal formulation or the solid granulates of said chemical compound.
Phrase " pharmaceutically acceptable " is meant such the rifaximin compositions and/or the dosage form that contain rifaximin: it is applicable to the humans and animals tissue in rational medicine judgement scope and contacts, and does not have excessive toxicity, zest, allergy or other problem or complication and be complementary with rational interests/risk ratio.Phrase " pharmaceutically acceptable carrier " comprises another organ or pharmaceutically acceptable material, compositions or the solvent of another part, for example liquid state or solid-state filler, diluent, excipient, solvent or the encapsulating material that body was carried or be transported to participation with said chemical substance from a certain organ or certain part of body.Every kind of carrier is " acceptable " preferably, and the meaning is compatible and harmless to the experimenter with other composition of preparation.Some instances that can be used as the material of pharmaceutically acceptable carrier comprise: (1) saccharide, for example lactose, dextrose plus saccharose; (2) starch based, for example corn starch and potato starch; (3) cellulose and derivant thereof, for example sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdery tragakanta; (5) Fructus Hordei Germinatus; (6) gelatin; (7) Pulvis Talci; (8) excipient, for example cocoa butter and suppository are used wax; (9) oils, for example Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum sesami, olive oil, Semen Maydis oil and soybean oil; (10) glycols, for example propylene glycol; (11) polyhydric alcohol, for example glycerin, sorbitol, mannitol and Polyethylene Glycol; (12) esters, for example ethyl oleate and ethyl laurate; (13) agar; (14) buffer agent, for example magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) apirogen water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; (21) be used for other nontoxic compatible material of pharmaceutical preparation.
Be used for oral rifaximin solid dosage forms (capsule, tablet, pill, lozenge, powder, granule etc.); Usually can the pharmaceutically acceptable carrier of active component and one or more be mixed; Said carrier is sodium citrate or dicalcium phosphate for example; And/or following any composition: (1) filler or supplement (extender), for example starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binding agent, for example carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and/or arabic gum; (3) wetting agent, for example glycerol; (4) disintegrating agent, for example agar, calcium carbonate, potato starch or tapioca, alginic acid, some silicate and sodium carbonate; (5) solution blocker, for example paraffin; (6) absorb accelerator, for example quaternary ammonium compound; (7) wetting agent, for example spermol (acetyl alcohol) and glyceryl monostearate; (8) absorbent, for example Kaolin and Bentonite; (9) lubricant, for example Pulvis Talci, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and composition thereof; (10) coloring agent.With regard to capsule, tablet and pill, pharmaceutical composition also can comprise buffer agent.Also can use the excipient of lactose for example or toffee, and high molecular weight polyethylene glycol etc., the solid-state composition of similar type is filled the filler in the gelatine capsule agent as soft with hard.
Tablet can be suppressed or molded preparations with one or more auxiliary agents through optional.Compressed tablets can use following reagent to prepare: binding agent (for example gelatin or hydroxypropyl emthylcellulose), lubricant, inert diluent, antiseptic, disintegrating agent (for example sodium starch glycollate or cross-linking sodium carboxymethyl cellulose), surfactant or dispersant.Molded tablet can be through processing with the powdered activated mixture of ingredients pressing mold of inertia liquid diluent moistening in suitable machine.
The tablet of pharmaceutical composition described herein and other solid dosage formss, for example lozenge, capsule, pill and granule can be chosen indentation wantonly or with coating and shell, and for example other coating of knowing of enteric coating and pharmaceutical field prepares.Also can use hydroxypropyl emthylcellulose, other polymeric matrix, liposome and/or microsphere that the different proportion of required release characteristics for example can be provided to prepare them, make the active component wherein can slow or in check release.Also can sterilize, for example filter, or through at the biocide that faces with the aseptic solid-state composition form of preceding adding, it dissolves in sterilized water, or some other aseptic injections are used medium through the filter of holding back antibacterial to them.These compositionss also can be chosen wantonly and contain opacifier and can be only to discharge at a certain position of gastrointestinal or the compositions of preferential release of active ingredients, optionally discharge with delayed mode.The instance of spendable implant compositions comprises polymeric material and wax.Active component also can be microencapsulation form, if suitable, together with one or more above-mentioned excipient.
The liquid dosage form that is used for the orally give rifaximin comprises pharmaceutically acceptable Emulsion, microemulsion, solution, suspensoid, syrup and elixir.Except active component; Liquid dosage form also can contain this area inert diluent commonly used; For example water or other solvent, solubilizing agent and emulsifying agent; For example ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 butylene glycol, oils (particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, germ oil, olive oil, Oleum Ricini and Oleum sesami), glycerol, oxolane alcohol, Polyethylene Glycol and fatty acid esters of sorbitan and composition thereof.
Except inert diluent, Orally administered composition also can comprise adjuvant, for example wetting agent, emulsifying agent and suspending agent, sweeting agent, correctives, coloring agent, spice and antiseptic.
Suspensoid also can contain suspending agent except rifaximin, for example ethoxylation isooctadecanol, polyoxyethylene sorbitol and Isosorbide Dinitrate, microcrystalline Cellulose, inclined to one side aluminium hydroxide, Bentonite, agar and tragakanta and composition thereof.
The pharmaceutical composition that is used for rectum or vagina administration can be suppository form; Said suppository can be through (comprising that for example cocoa butter, Polyethylene Glycol, suppository are with wax or salicylate with rifaximin and one or more suitable nonirritant excipients or carrier; And it at room temperature is solid-state and be liquid under body temperature, therefore in rectum or vaginal canal, can melt and release bioactive agent) mix and prepare.
Be applicable to that the compositions that vagina gives also comprises vaginal suppository, cotton balls (tampon), ointment, gel, paste, foam or spray agent, it contains suitable carrier known in the art.
The dosage form that is used for part or transdermal administration rifaximin comprises powder, spray, ointment, paste, ointment, lotion, gel, solution, patch and inhalant.Can be under aseptic condition rifaximin and pharmaceutically acceptable carrier and any antiseptic, buffer agent or the propellant that possibly need be mixed.
Ointment, paste, ointment and gel also can contain excipient except rifaximin, for example animals and plants fat, oil, wax, paraffin, starch, tragakanta, cellulose derivative, Polyethylene Glycol, silicone, Bentonite, silicic acid, Pulvis Talci and zinc oxide or its mixture.
Powder and spray also contain excipient, the for example mixture of lactose, Pulvis Talci, silicic acid, aluminium hydroxide, calcium silicates and polyamide powder or these materials except containing rifaximin.Spray also can contain conventional propellant, and for example CFC and volatility do not replace hydrocarbon, for example butane and propane.
Rifaximin also alternately gives through aerosol.This can realize through aqueous aerosol, Liposomal formulation or solid granulates that preparation contains said chemical compound.Can use non-aqueous (for example fluorocarbon propellant) suspensoid.Preferred velocity of sound aerosol apparatus (Sonic nebulizer) because they can reduce to minimum with the shearing of reagent, can cause degradation and shear.
Injection depot formulation (depot) form can through biodegradable polymer for example polylactide-the gather microcapsule substrate that forms rifaximin in the Acetic acid, hydroxy-, bimol. cyclic ester prepare.According to the character of medicine and polymer ratio and used concrete polymer, may command drug release rate.The instance of other biodegradable polymer comprises and gathers (ortho esters) and gather (acid anhydride).The depot formulation injection preparation also can prepare through medicine being wrapped in liposome compatible with body tissue or the microemulsion.
When rifaximin gives humans and animals as medicine, can give separately or give as pharmaceutical composition, said compositions contains for example active component and the pharmaceutically acceptable carrier of 0.1-99.5% (more preferably 0.5-90%).
Regardless of route of administration, known method by one of skill in the art, the selected rifaximin that will be used for the pharmaceutical composition that this paper provides is mixed with pharmaceutically acceptable dosage form.
The actual dose level of active component can be different with giving time course in the pharmaceutical composition; Make for concrete experimenter, compositions and mode of administration; Can obtain the amount of the active component that effectively reaches required therapeutic response, and nontoxic to the experimenter.Exemplary dosage range is 25-3000mg every day.
The preferred dose of rifaximin is the maximum that the experimenter can stand and not produce serious side effects.The concentration that preferably gives rifaximin is that about 1mg is to about 200mg/kg body weight, the about 80mg/kg body weight of the about 100mg/kg of about 10-or about 40mg-.Scope in above-mentioned numerical value also is a part of the present invention.
In exemplary embodiment, give experimenter's rifaximin every day 1,2,3 or 4 times.Exemplary dosage comprises 100,200,300,400,500,550,600,700,800,900,1000,1100,1200,1300,1400,1500,1600,1700,1800,1900 or the rifaximin oral dose of 2000mg.Scope in above-mentioned numerical value also is a part of the present invention.In concrete exemplary, give experimenter 600mg rifaximin every day.In another concrete embodiment, give every day the experimenter 3 200mg tablets.
In therapeutic alliance, give mammal (for example people, sex) through conventional method with rifaximin and other medicament.The dosage form of can single dosage form or separating gives medicament.The effective dose of other healing potion is well known to those skilled in the art.Yet the best effective dose scope of confirming other healing potion is in technical staff's limit of power.In an embodiment that another healing potion is given animal, the effective dose of rifaximin is less than at the rifaximin effective dose that does not give under other healing potion situation.In another embodiment, the effective dose of conventional dose is less than at the effective dose that does not give conventional dose under the rifaximin situation.Like this, just can the undesirable side effect that the high dose of every kind of medicine is relevant reduce to minimum.Other potential advantages (including but not limited to the medicine cost of improved dosage regimen and/or reduction) will be conspicuous to those skilled in the art.
In various embodiments, treatment (for example preventing medicament or healing potion) gives by following interval: every at a distance from less than 5 minutes, every at a distance from less than 30 minutes, every at a distance from 1 hour; Every at a distance from about 1 hour, every, every, every at a distance from about 3 hours to about 4 hours at a distance from about 2 hours to about 3 hours at a distance from about 1 to about 2 hours; Every at a distance from about 4 hours to about 5 hours, every, every, every at a distance from about 7 hours to about 8 hours at a distance from about 6 hours to about 7 hours at a distance from about 5 hours to about 6 hours; Every at a distance from about 8 hours to about 9 hours, every, every, every at a distance from about 11 hours to about 12 hours at a distance from about 10 hours to about 11 hours at a distance from about 9 hours to about 10 hours; Every at a distance from about 12 hours to 18 hours, every, every, every at a distance from 36 hours to 48 hours at a distance from 24 hours to 36 hours at a distance from 18 hours to 24 hours; Every at a distance from 48 hours to 52 hours, every, every at a distance from 60 hours to 72 hours at a distance from 52 hours to 60 hours; Every at a distance from 72 hours to 84 hours, every at a distance from 84 hours to 96 hours, or every at a distance from 96 hours to 120 hours.In preferred embodiments,, same experimenter gives treatment more than twice in going to a doctor.
In certain embodiments, periodically give one or more chemical compounds and one or more other treatments (for example preventing medicament or healing potion).Periodically treatment comprises that giving first treatment (for example first prevention medicament or the healing potion) reaches a period of time; Give second treatment (for example second prevention medicament or the healing potion) again and reach a period of time, give the 3rd treatment (for example preventing medicament or healing potion) again and reach a period of time or the like, repeat so sequential giving then; Cycle for example; To reduce the resistance that one of treatment is produced, avoid or reduce the side effect of one of treatment, and/or improve therapeutic efficiency.
In certain embodiments, can repeat to give same chemical compound and the interval that gives can be at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months or at least 6 months.In other embodiments, can repeat to give same treatment (for example preventing medicament or healing potion) but not rifaximin and to give can be at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months or at least 6 months at interval.
Some indication possibly need longer treatment time.For example, can only continue about 12 hours to about 72 hours, and can be about 1 day to about 3 months the treatment of Crohn disease to the treatment of traveler's diarrhea.Therapy for hepatic encephalopathy is for example experimenter's the remaining years.Treatment to IBS can be interrupted, and once carries out several weeks or several months, or is experimenter's the remaining years.
Manufacture (Article of Manufacture)
Another embodiment comprises manufacture; It comprises the container of the operation instructions that the pharmaceutical composition that is applicable to oral or topical administration rifaximin and printing decals for example are housed, and said operation instructions provide particular dosage form should be when to give with when the explanation should (medicine) being taken before meal used with food.Can revise dosage to give the hepatic insufficiency patient, comprise that perhaps label is to give the hepatic insufficiency patient.Exemplary dosage form and dosage regimen are described below.Compositions will be packed in any suitable containers, and it can hold and distribute dosage form and can not take place significantly to interact and also have physics to get in touch with suitable decals with compositions.The operation instructions of decals will be consistent with Therapeutic Method mentioned above.Can be by any way with label attached on the container; Make the two keep physics approaching; As limiting examples; Can pack they boths into packaging material for example in chest or the plastic shrinkage packing, the perhaps available bonding or method of clamping of glue that the operation instructions that paste fog or other that for example can not make is attached to operation instructions on the container.
Be manufacture on the other hand; It comprises the container that the pharmaceutical composition that comprises rifaximin is housed; Wherein said container preferably is equipped with the rifaximin compositions of unit dosage forms and has the operation instructions of printing decals; Said operation instructions inform when pharmaceutical composition with or when not taking with food, it absorbs different.
On the other hand, this paper provides manufacture or medicine box, and said manufacture or medicine box comprise rifaximin or its pharmaceutical composition, and packaging together with the operation instructions that are used to give the hepatic insufficiency patient.In one embodiment, operation instructions are informed doctor, pharmacist or the experimenter who prescribes, and compare with the experimenter of normal (for example having function liver system completely), and hepatic encephalopathy patient absorbs more substantial rifaximin through system.In one embodiment, the doctor that operation instructions sincere advice is prescribed, they just should confirm opening the rifaximin prescription to the experimenter with before treating enteropathy whether said experimenter suffers from hepatic insufficiency.In one embodiment, the doctor that operation instructions sincere advice is prescribed, when opening the rifaximin prescription for the hepatic encephalopathy patient, they should consider to change dosage or dosage regimen.In addition, operation instructions can be the hepatic insufficiency patient prescription information are provided.In another embodiment, operation instructions will be informed experimenter and/or health care supplier, and the plasma exposure of rifaximin there are differences among the normally functioning experimenter of HE patient's regulating liver-QI.
Also packaged composition can be provided, it can comprise the rifaximin of treating effective dose.Rifaximin and pharmaceutically acceptable carrier or diluent are wherein prepared said compositions and are used to treat the experimenter who suffers from or be prone to suffer from enteropathy, and suffer from treatment or to be prone to suffer from experimenter's the operation instructions of enteropathy packaging together.
This paper also provides medicine box, for example is used for treating the medicine box of experimenter's enteropathy.The operation instructions that medicine box can contain rifaximin for example and when treatment also suffers from patient's the enteropathy of hepatic insufficiency, use.The operation instructions that use can contain prescription information, dosage information, storage information etc.
Packaged composition also is provided; It can comprise rifaximin and the pharmaceutically acceptable carrier or the diluent of treating effective dose; Wherein prepare said compositions and be used to treat the experimenter who suffers from or be prone to suffer from enteropathy, and suffer from treatment or to be prone to suffer from experimenter's the operation instructions of enteropathy packaging together.
Embodiment
Embodiment of the present invention are based in part on following demonstration: have other clinical disease for example among the experimenter of hepatic encephalopathy the absorption of rifaximin different.Should be understood that the present invention is not limited to present described embodiment; On the contrary, the present invention should be regarded as comprising that any and whole application and all interior equivalences of those of ordinary skill technical scope that this paper provides change.
Embodiment 1
Rifaximin is given liver function damage experimenter's clinical research
For measuring of the effect of impaired liver function, the patient who suffers from hepatic encephalopathy (HE) is made an experiment to the rifaximin effect.HE is also referred to as hepatic coma or door-body encephalopathy, is relevant serious, rare and complicated, the neural psychosyndrome that possibly reverse of hepatopathy in a kind of late period.Nitrogen substance is ammonia the most significantly, is able to get into the body circulation, is the result that liver function reduces or door-body is shunted.In case entering cerebral tissue, these chemical compounds just cause influencing the change of the neurotransmission of consciousness and behavior.Relevant damaged through using West Haven standard (or Conn scoring) to define 4 progressive HE by stages, its scope is from the 0th phase (lacking detectable personality changes) to the 4th phase (stupor, decerebrate posture, platycoria).
Control to chronic HE patient comprises: 1) providing support property nursing, 2) differentiate and get rid of risk factor, 3) alleviate the nitrogenous load and 4 from intestinal) needs of evaluate long term treatment.Use nonabsorbable disaccharidase (lactulose) and/or antibiotic can alleviate nitrogenous load usually from intestinal.Although in the U.S., lactulose is considered to first-line treatment, does not ratify to be used for treatment or prevention HE at present as yet.Rifaximin is attractive treatment for HE patient's treatment, because it has verified effectiveness, also because systemic antibiotic and nonabsorbable disaccharidase have defective.The defective of chronic systemic antibiotic therapy comprises nephrotoxicity and ototoxicity, and the defective of lactulose treatment comprises because of diarrhoea is dewatered (risk factor of HE), sweet excessively taste and GI side effect.
In this embodiment, give the out-patient with rifaximin, dosage setting is 550mgBID (twice of every day) (total consumption per day is the 1100mg rifaximin).BID gives the experimenter with the 550mg rifaximin, continuous at least 7 days, carries out the pharmacokinetics sampling then.
For guaranteeing Cpss, the blood sampling that is used for pharmacokinetic analysis gave to carry out after the rifaximin 550mg BID at continuous at least 7 days.Collection in independent a day after continuous at least 7 days 100% comply with rifaximin 550mg BID dosage regimen is used for the blood sample of pharmacokinetic analysis.Gathered a plurality of samples that are used for pharmacokinetic analysis at 12 hours in (for example 1,2,4,6,8,10 and 12 hour before the administration and after the administration), characterize the concentration-time overview of blood plasma rifaximin to allow stable state.Before giving rifaximin, experimenter's overnight fasting (not taking food in about 10 hours), (after 1 hour sampled plasma of plan) 1 hour gives the light food of standard after studying medicine then.
Use noncompartmental method (for example master pattern-independent solution) to calculate the pharmacokinetic parameter of rifaximin in the blood plasma.
Pharmacokinetics sampling occurs in independent one day that comply with in continuous at least 7 days 100% after the rifaximin 550mgBID dosage regimen.Gathered 8 parts of blood samples altogether at 12 hours in (for example 1,2,4,6,8,10 and 12 hour before the administration and after the administration), to allow to characterize the rifaximin PC-time overview of 12 hours individualities in the dosing interval.
The use reversed phase high-performance liquid chromatography uses the series connection four-electrode spectrum to detect (LC/MS/MS), the analysis programme of use experience card, the PC of mensuration rifaximin.Set up deviation and the precision that quantizes lower limit (LOQ), calibration criterion and theoretical value with standard method.
Use
Figure BPA00001514750900301
Enterprise (5.2 version) to calculate the pharmacokinetic parameter of rifaximin in the blood plasma.
Use noncompartmental method (for example master pattern-independent solution) to calculate pharmacokinetic parameter.Use actual concentrations-time overview of each experimenter, calculate the following stable state pharmacokinetic parameter of rifaximin in the blood plasma:
Figure BPA00001514750900302
If can obtain enough data, can estimate for example apparent oral clearance of other parameter (CL/F) and t1/2 or dispose half-life (t 1/2).Except the analysis of plan, also can obtain from the AUC (AUC of 0 o'clock (before the administration) concentration measured to the end 0-t).
For overall pharmacokinetics colony; Individual rifaximin PC and pharmacokinetic parameter have been summarized; And, use Child-Pugh scoring (A and B) and descriptive statistics (for example N, meansigma methods, SD, CV%, intermediate value, minima, maximum, geometrical mean) through the hepatic injury order of severity.
Through the hepatic injury order of severity, use Child-Pugh scoring (A and B) and whole hepatopathy model in latter stage (MELD) scoring and descriptive statistics, summarized experimenter's Demographics and other baseline characteristic.Baseline characteristic comprises albumin, alkali phosphatase (alkaline phosphate), alanine aminotransferase (ALT), aspartate aminotransferase (AST), INR (INR), serum creatinine and serum total bilirubin, and wherein baseline is defined as and gives the rifaximin evaluation that can get at last before first.
Come the rifaximin pharmacokinetic parameter AUC among the experimenter of comparison Child-Pugh scoring A and B (for example slightly and moderate hepatic injury) with variance analysis (ANOVA) model τAnd C Max
Pairing ANOVA be used to estimate before administration with administration after the rifaximin concentration value measured in 12 hours, to estimate the possible difference of stable state rifaximin concentration.
25 experimenters are included in pharmacokinetics and can estimate in the colony and evaluate safety property altogether.
In 25 experimenters, there are 18 people (72.0%) to have slight hepatic injury (for example Child-Pugh scoring A) at baseline.All the other 7 experimenters (28.0%) have moderate hepatic injury (for example Child-Pugh scoring B) at baseline.
Result with the independent research that liver function normal healthy experimenter is carried out compares with the pharmacokinetic parameter of rifaximin.
Experimenter's demography and baseline characteristic
Table 1 has been summarized all and has been participated in experimenter's demography.Have 25 experimenters and participate in this research; 17 experimenters (68.0%) are the male, and 8 experimenters (32.0%) are the women.Participate in 58 years old mean age (scope 45-68 year) of experimenter.22 experimenters (88.0%) are white men, and all the other 3 experimenters (12.0%) are Black people.There are 7 people (28.0%) to belong to Spain group (ethnicity) among 25 experimenters.
18 experimenters' Child-Pugh is categorized as A, and 7 experimenters' Child-Pugh is categorized as B.＜11,10 experimenters' of baseline MELD scoring of 15 experimenters baseline MELD scoring (comprises this two values) between 11 to 18.Most of baseline Conn scoring of participating in the experimenter is 0 (22/25; 88.0%), is used for the son research of pharmacokinetics; Among 25 experimenters 3 people's (12.0%) baseline Conn scoring being arranged is 1.
The experimenter of table 1. experimenter Demographics and baseline characteristic-all participations
Figure BPA00001514750900311
Abbreviation: MELD=hepatopathy model in whole latter stage.
Generally, the experimenter's of Child-Pugh A and Child-Pugh B Demographics is comparable.Baseline MELD scoring is also similar usually for＜11 experimenter and baseline MELD scoring baseline demography of the experimenter of (and comprising this two values) between 11-18.Compare with the experimenter of MELD scoring≤10, the more a high proportion of experimenter of MELD scoring between 11-18 is Spaniard's (50.0% contrast 13.3%).
The baseline laboratory is found consistent with experimenter's liver dysfunction.The baseline liver functional test is the result show, the experimenter who is categorized as Child-Pugh B is bigger than the hepatic injury that is categorized as Child-Pugh A experimenter, and the experimenter of MELD scoring between 11-18 is bigger than the experimenter's of MELD scoring＜11 hepatic injury.Specifically, Child-Pugh B experimenter and MELD scoring has significantly higher baseline value for the experimenter's of 11-18 alkali phosphatase, AST and baseline bilirubin direct and STB.
In the previous day that pharmacokinetics is collected, most subjects is accepted 2 doses of rifaximins, about 12 hours at interval.For any experimenter, the weak point between the administration is 10 hours at interval; For any experimenter, the length between the administration is 13.55 hours at interval.Do not consider dinner, can be before the meal (13 experimenters) or after the meal (12 experimenters) give the 2nd dose of rifaximin.
On the same day in the pharmacokinetics sampling, after at least 10 hours overnight fast, give rifaximin in the morning.After all experimenters put in 1 h drug kinetics blood plasma sampling time, light food of feed in 1 hour after administration.Behind 12 h drug kinetics blood plasma sampling times point, give rifaximin for the second time immediately, except that 1 people.
The mean plasma concentration of rifaximin reached peak value in 1 hour after administration, (Fig. 1) then slowly descended in 12 hours.In whole 12 hour sampling interval, the rifaximin PC all exceeds the quantification limit (LOQ) of mensuration in all experimenters.Have 5 experimenter's showed double peaks plasma concentration profile.
In the hepatic injury patient who is categorized as Child-Pugh A and Child-Pugh B, the stable state pharmacokinetic parameter of rifaximin.
Table 2 has been summarized the pharmacokinetic parameter of the rifaximin of liver dysfunction patient after treating at least 7 days through Child-Pugh scoring and for whole pharmacokinetics colony.The column that is included in the numerical value of in the independent research health volunteer being measured is provided, so that compare.
The meansigma methods of table 2. rifaximin drug plasma kinetic parameter in the hepatic injury patient (± SD)
Figure BPA00001514750900331
a?n＝17
b?n＝6
c?n＝23
The d intermediate value (Min, Max)
E harmonic-mean (false SD)
f?n＝14
g?n＝5
h?n＝19
Child-Pugh A (minor injury) experimenter contrast between Child-Pugh B (Moderate lesion) experimenter and the experimenter of MELD scoring＜11 (minor injuries) contrast 11-18 (Moderate lesion) between comparison
Average A UC with Child-Pugh scoring A experimenter τAnd C MaxValue (being respectively 118ng*h/mL and 19.5ng/mL) is compared, the experimenter's of Child-Pugh scoring B average A UC τAnd C MaxValue (being respectively 161ng*h/mL and 25.1ng/mL) exceeds about 36% and 29%.With viewed comparing among the experimenter of Child-Pugh A scoring, the experimenter's of Child-Pugh B scoring rifaximin elimination factor prolongs about 29% (10.5h contrasts 8.12h).For AUC τAnd C Max, the rifaximin pharmacokinetic characteristic is that the coefficient of variation between the experimenter (CV%) scope is about 50-60%.This and previous observed variability consistent (for example CV% is 45% to 60%) in the health volunteer.
The rifaximin pharmacokinetic parameter AUC that compares Child-Pugh scoring A and B (being respectively slight and moderate hepatic injury) experimenter with the ANOVA model τAnd C MaxCan't obtain AUC τSituation under, can be with corresponding AUC 0-tValue is used for inferential statistics.
The result that unidirectional ANOVA analyzes is summarized in table 3.The AUC of Child-Pugh scoring B and Child-Pugh scoring A τThe ratio of how much LSM is 151.2%, and wherein 90% confidence interval is 98.8% to 231.5% (p=0.1092).The C of Child-Pugh scoring B and Child-Pugh scoring A MaxThe ratio of how much LSM is 149.9%, and wherein 90% confidence interval is 98.8% to 227.5% (p=0.1096).In view of AUC between experimenter in two colonies τAnd C MaxThe variability of parameter, the confidence interval of the ratio of LSM is very big.
Table 3. hepatic injury scoring (Child-Pugh A contrast Child-Pugh B) is to the effect of the main pharmacokinetic parameter of rifaximin
Figure BPA00001514750900351
The covariant analysis shows, the biochemical marker of the impaired liver function for example rising of albumin, STB and INR numerical value and the system of rifaximin exposes (AUC TauAnd C Max) increase and reduce relevant with oral clearance (CL/F).
In the experimenter of liver function damage, estimate the pharmacokinetics of rifaximin.Accepting identical dosage regimen (for example 550mg BID) afterwards, among the experimenter of Child-Pugh A and B when stable state the exposure value (AUC of system of rifaximin Tau) be among the health volunteer when stable state about 9.6 times to 13.1 times of observed value.
Use distinct methods to come comparison system to expose, to estimate liver function, the MELD scoring.Measure the MELD scoring and be＜11 experimenter (n=15) and ratio and the AUC of MELD scoring for how much LSM of the experimenter of 11-18 (n=10) τAnd C Max90%CI.The result of this analysis (seeing table 4) shows, when the MELD scoring is used to estimate liver function, compares with slight hepatic injury experimenter, and the system among the moderate hepatic injury experimenter is exposed to significantly raise on the statistics (p＜0.05).The AUC of MELD scoring＜11 and scoring 11-18 τRatio be 168.22%, 90%CI is 110.5% to 256.2% (p=0.0451); C MaxThe ratio of ratio is 178.12%, and 90%CI is 116.7% to 271.8% (p=0.0283).Participate among the sub experimenter who studies the little (correlation coefficient: p=0.399) of dependency between MELD scoring and the Child-Pugh classification at 25.
Table 4. hepatic injury scoring (MELD scoring＜11 contrast scoring 11-18) is to the effect of the main pharmacokinetic parameter of rifaximin
Figure BPA00001514750900352
Figure BPA00001514750900361
Rifaximin is by fast Absorption, in most experimenters, all observes peak plasma concentrations after the administration in 1 hour.The rifaximin that in Child-Pugh A group, has 3 experimenters absorbs and is postponed, and between 6-10 after the administration hour, observes peak plasma concentrations.
Comparison with the liver function normal subjects
Present result of study and liver function normal subjects's historical data is compared.The arithmetic mean of instantaneous value of rifaximin 550mg multiple dose BID in the health volunteer (± SD) pharmacokinetic parameter is seen table 5.
After every day twice orally give 550mg, rifaximin exposure value (AUC in the experimenter of Child-Pugh scoring A and B τ, be respectively 118 and 161ng*h/mL) be respectively observed about 9.6 times and 13.1 times of health volunteer (12.3ng*h/mL).Remove t 1/2Outside, the variability in health volunteer's the pharmacokinetics between the experimenter is similar to the variability of in the hepatic injury experimenter, measuring usually.
(± SD) the pharmacokinetic parameter of the arithmetic mean of instantaneous value of rifaximin 550mg multiple dose BID among table 5. health volunteer
aIntermediate value (Min, Max), bHarmonic-mean (false SD)
The scholar studies the same day in pharmacokinetics, relatively before the administration with administration after 12 hours concentration
The pairing ANOVA result who is used to estimate after preceding 0 o'clock of administration and the administration 12 hours concentration sees table 6.
These results show, after the administration 12 hours rifaximin concentration value than the administration in morning before concentration reduced by 37.8% (p＜0.0001).It is reported, make the rifaximin degree of absorption be increased to about 2-3 doubly simultaneously with food.Under fasted conditions, give the dosage in morning.
Table 6. matching side difference analysis (AN0VA) estimate before administration with administration after 12 hours rifaximin concentration change (In-Transformed Concentration).
Figure BPA00001514750900381
Covariant is analyzed
Develop a kind of multiple linear regression model, to estimate various covariants to rifaximin AUC τ, C MaxInfluence with CL/F.Test following covariant: Child-Pugh scoring and laboratory detection result (albumin, alkali phosphatase, ALT, AST, creatinine clearance, serum creatinine, INR and STB) in this model.The selected covariant that is used to analyze is known hepatic and renal function index.Estimate diagnosis, to detect target covariant and AUC τ, C MaxAnd the potential trend between the CL/F.
The result 7-9 that sees the following form.
The covariant analysis shows, in this research, the biochemical marker of the impaired liver function for example rising of albumin, STB and INR value and the system of rifaximin exposes (AUC TauAnd C Max) increase and reduce relevant with oral clearance (CL/F).
The highest R 2Model comprises albumin, STB, INR and ALT (R 2=53.6%, Cp=4.4101).
According to model analysis, confirm that brief model (parsimonious model) will include only albumin, STB and INR.AUC τFinal mask see table 7.
Table 7. rifaximin AUC τAnd the relation between the covariant-brief model
Figure BPA00001514750900391
Has the highest R 23 parameter models comprise STB, INR and ALT (R 2=39.1%, Cp=3.7193).In 4 parameter model subclass, has the highest R 2Model comprise albumin, STB, INR and ALT (R 2=46.9%, Cp=3.0598).R in view of 4 parameter models 2Higher, confirm that brief model will comprise 4 parameters: albumin, STB, INR and ALT.Final mask is seen table 8.
Table 8. rifaximin C MaxAnd the relation between the covariant-brief model
Figure BPA00001514750900392
In 4 parameter model subclass, has the highest R 2Model comprise albumin, STB, INR and ALT (R 2=54.9%, Cp=3.4103).This model result is seen table 9.
The CL/F of table 9. rifaximin and the relation between the covariant-brief model
Figure BPA00001514750900393
Figure BPA00001514750900401
Embodiment 2:
In I level, II level or III level hepatic encephalopathy patient, estimate rifaximin effect, toleration and safety at random, double blinding, dosage find research
Find in HE experimenter, to carry out pharmacokinetic study in the research at dosage.Comprise 54 experimenters (32 male, 22 women, age 32-82 year) in this research altogether, let and accepted to be equivalent to respectively 600,1200 and 200,400 or 800mg rifaximin every day three times (200mg tablet) of 2400mg daily dose in its continuous 7 days respectively.Measure the PC and the urine concentration (LLOQ=0.5ng/mL) of rifaximin through LC-MS/MS.
The urine of rifaximin reclaims sees table 10.
Table 10: the urine yield of rifaximin during 24 hours collection intervals after the last administration
Figure BPA00001514750900411
Give that it doesn't matter between the urine yield of dosage and rifaximin.In the twenty-four-hour urine liquid of after giving last (the 3rd time) 200,400 and 800mg dosage the last day (the 7th day) of administration, collecting; Average (SD) weight range of the rifaximin that in urine, is recovered to be 0.06% (± 0.66%) to 0.1% (± 0.093%), and these values are consistent with the rifaximin (for example 0.030% ± 0.020% dosage) that is recovered to after single gives the radiolabeled dosage of 400mg.
After giving single 200,400 and 800mg rifaximin dosage first 3 hours, measure average maximum rifaximin PC and be respectively 2.7,10.5 and 13.5ng/mL.
Embodiment 3
Rifaximin absorbs
In the experimenter of liver damage, study.With observed average A UC among the experimenter of Child-Pugh scoring A TauAnd C MaxValue (being respectively 118ngh/mL and 19.5ng/mL) is compared, the experimenter's of Child-Pugh scoring B average A UC TauAnd C MaxValue (being respectively 161ngh/mL and 25.1ng/mL) exceeds about 36% and 29%.With observed comparing among the Child-Pugh A scoring experimenter, Child-Pugh B scoring experimenter's rifaximin is eliminated t1/2 and is prolonged about 29% (10.5h contrasts 8.12h).For the AUC in two subgroups 0-tauAnd C Max, coefficient of variation percentage rate (CV%) scope is about 50% to 60% between the experimenter of rifaximin pharmacokinetic parameter.This with before in the health volunteer observed variability consistent, for example CV% is 45% to 60%.
Rifaximin is by fast Absorption, in most experimenters, all observes peak plasma concentrations after the administration in 1 hour.The rifaximin that in Child-Pugh A group, has 3 experimenters absorbs and is postponed, and between 6-10 after the administration hour, observes peak plasma concentrations.Some experimenters show the straight or bimodal plasma concentration profile of rifaximin.In liver cirrhosis and HE experimenter, gastrointestinal movement and abnormal bile secretion might explain that the rifaximin of observed delay/prolongation in this research absorbs.
A plurality of linear regression model (LRM) results show that the biochemical marker of liver function is the rising of albumin, STB and INR for example, with the exposure (AUC of system of rifaximin TauAnd C Max) increase and reduce relevant with oral clearance (CL/F).Baseline alanine aminotransferase and C have also been observed MaxBetween positive correlation.
In an independent research, studied pharmacokinetic parameter.This colony comprises 18 slight hepatic injury (Child-Pugh A) experimenters (72%) and 7 moderate hepatic injury (Child-Pugh B) experimenter.Health volunteer's research comprises 28 experimenters.
After every day twice orally give 550mg, rifaximin exposure value (AUC in the experimenter of Child-Pugh scoring A and B Tau, be respectively 118 and 161ngh/mL) be observed about 9.6-and 13.1 times among the health volunteer (12.3ng*h/mL).Remove t 1/2Outside, the variability in health volunteer's the pharmacokinetics between the experimenter is similar to the variability of in the hepatic injury patient, measuring usually.
Embodiment 4
The research of 3 phases
Among the patient of formerly suffer from HE, at present having alleviated, carry out 3 phases at random, the multicenter study (research A) of double blinding, placebo, to estimate the effect and the safety of rifaximin.This research comprises screening phase (4 days), observation period (3 days), baseline visit and treatment phase (6 months).When confirm qualified after, the patient experienced baseline and estimates the phase before randomization.This phase continues 7 days, is used for confirming patient's qualification, suitable guidance is provided for nursing staff (caregiver), and definite baseline mental status and neuromuscular function, gets into the double blinding stage then.The placebo tablet BID that lets the patient accept rifaximin 550-mg tablet BID at random or be complementary reaches 6 months.The experimenter can select for use lactulose as the while administered agents, and during research was carried out, two groups had 91% experimenter and take lactulose.By research worker and Field Force in each individual research visit, in telephone interview, report that the nursing staff neutralization is from subject diary; The experimenter is carried out the deep evaluation of the mental status (Conn scoring) and neuromuscular function (asterixis classification), be used for confirming the generation of breakthrough obvious HE outbreak.In breakthrough obvious HE outbreak, end the experimenter is studied.After participating in this research, the experimenter can select to participate in research open label, that treatment enlarges (research B).
The dosage of rifaximin
Used dosage regimen (550mg BID) was used the clinical experience of rifaximin among the research A in HE patient and other population of subjects based on the past.In some previous researchs, dosage is the rifaximin of 1200mg/ days (2 * 200mg tablet every day three times), uses simultaneously or without lactulose, be safety in HE patient with effectively.In the research of 6 months rifaximins contrast neomycin, rifaximin 1200mg/ days and neomycin (3g/ days) have comparable effect in HE patient.3-month rifaximin contrast lactitol (lactitol) research in, accept rifaximin 1200mg/ days the experimenter of (2 * 200mg tablet every day three times) demonstrates remarkable improvement in the HE terminal point.
In dosage-scope research of in experimenter, carrying out, in the improvement of PSE index, there is dose dependent trend to reach 1200mg (2 * 200mg tablet every day three times) with the active symptom of HE.Also observe similar results (table 11) for 1200mg and 2400mg dosage (4 * 200mg tablet every day three times).In dose-response was analyzed, the Jonckheere-Terpstra test demonstrated the improved trend of PSE index (p=0.0586) in dose groups.
The change that table 11. begins from baseline in the PSE index (ITT colony)
Figure BPA00001514750900441
Research colony
For research A, if age whole standards below the sex experimenter more than 18 years old satisfies, then they are qualified as far as this research:
Zero Conn scoring 0 or 1
Zero before screening, the medical history in 6 months >=2 time obvious HE outbreak, and it is relevant with chronic hepatopathy (for example liver cirrhosis or portal hypertension), and the order of severity of record is equivalent to Conn scoring >=2 (that is, the experimenter has the obvious HE of recurrent of record).At least 1 previous outbreak has case history to confirm.Mainly hemorrhage, medicine (for example anesthetics, tranquilizer (tranquilizer), tranquilizer), the renal failure that needs dialysis or CNS because of GI damage hepatic encephalopathy outbreak that subdural hematoma for example causes statistics be the qualified outbreak of previous HE.
Zero MELD scoring≤25,
Zero before screening (if existence), TIPS place or correct＞3 months with
Zero during studying, and has intimate family or other people lasting careful treatment also can visit the experimenter.
If the experimenter satisfies one of following standard, just they are excluded from research:
Zero in 1 month of screening expection to accept liver transplantation
Zero in 14 days of screening, drink, in 7 days with tranquilizer or the drug dependence evidence is arranged
Zero medical history defines HIV
Zero has TB to infect history or TB treatment of infection history
Zero active SBP or PA treatment every day
Zero screening≤individual month in, need the hemorrhage and blood transfusion of the GI of hospitalization
Zero exists intestinal obstruction or suffers from inflammatory bowel
Zero renal insufficiency (change of serum C r＞2.0mg/dL)
Zero anemia (HgB＜8gm/dL)
Zero hypovolemia or electrolyte unusual (Na+＜125mEq/L, Ca++＞10mg/dL, K+＜2.5mEq/L
Zero need forbid medication simultaneously
The definition of effect terminal point
The main terminal point (primary endpoint) of research A is to time of breakthrough obvious HE outbreak first.The progression that breakthrough obvious HE outbreak is defined as the Conn scoring increases to >=2 (promptly from 0 or 1 to >=2) in the time of maybe will getting into this research the Conn scoring be that those experimenters of 0 Conn marks and asterixis is marked and respectively increased by 1 grade.Time to breakthrough obvious HE outbreak is from studying the persistent period of the extremely breakthrough first obvious HE outbreak of medicine first.
The second crucial terminal point is listed below:
1. to time of the relevant hospitalization of HE first.
In Conn scoring (mental status classification) from time of baseline to any increase.
In the asterixis classification from baseline to time of any increase.
4. when treatment finishes, the mean change that in the tired territory scoring (fatigue domain score) of CLDQ, begins from baseline.
5. when treatment finishes, the mean change that in vein ammonia concentration, begins from baseline.
The details of treatment group of the research A 12-13 that sees the following form.
The Demographics of table 12. treatment group (ITT colony)
Figure BPA00001514750900451
Figure BPA00001514750900461
Demography among table 13. research A and the B
Figure BPA00001514750900462
Figure BPA00001514750900471
Baseline characteristic
The hepatic encephalopathy baseline characteristic HE order of severity of HE outbreak in the recent period obviously (Conn scoring and asterixis classification) and be summarized in table 4 for example in the ITT colony from the time that last HE shows effect.In the ITT colony experimenter's baseline hepatopathy characteristic and further feature for example disease severity (MELD scoring), be summarized in table 15,16 and 17 from time and the hepatopathy etiology of making a definite diagnosis the hepatopathy in late period first.Usually the baseline characteristic between each treatment group is comparable.
The hepatic encephalopathy baseline characteristic of table 14. treatment group (ITT colony)
Figure BPA00001514750900472
Figure BPA00001514750900481
Figure BPA00001514750900491
The lactulose of one glass=15mL of a 10g/15mL.
The baseline hepatopathy characteristic and the further feature of table 15. treatment group (ITT colony)
Figure BPA00001514750900492
Figure BPA00001514750900501
Liver cirrhosis etiology among the table 16. research A
Figure BPA00001514750900502
*For these 13 experimenters, the liver cirrhosis etiology is ethanol and hepatitis B.
Medical history among table 17. research A or the research B
Figure BPA00001514750900503
Figure BPA00001514750900511
Research B design
Research B is the research of ongoing 3 phases, multicenter, open label, treatment expansion, is used for the experimenter in the obvious HE medical history with recurrence, outbreak, estimates the long-term safety of rifaximin 550mg BID.All qualified experimenters have obvious HE history of attack, and the order of severity of record is: Conn scoring>=2 in 12 months before screening, the Conn scoring is≤2 when recruiting, and has participated in studying A, or new experimenter.Plan to ratify with rifaximin 550mg tablet BID treatment at least 24 months or up to rules.The optional lactulose treatment of using simultaneously.
Although research B is designed for the long-term safety of estimating rifaximin 550mg, also extra collection Conn scoring and the fractionated effect evaluation of asterixis during studying.In research B; The progression that breakthrough obvious HE is defined as Conn scoring increases to >=and 2; When getting into this research the Conn scoring be those experimenters of 0 Conn scoring with asterixis scoring respectively increase by 1 grade and will get into this research the time Conn mark be those experimenters of 2 Conn mark be increased to >=3.
The design of research C, D and E
Research C is double blinding, the dosage-scope research that in the 1-3 level HE experimenter that recruit at 5 centers of Britain, carries out.Let the experimenter accept the daily dose of rifaximin 600mg (200mg every day three times), 1200mg (400mg every day three times) or 2400mg (800mg every day three times) at random, reach 7 days.54 experimenters (18 people/group) are recruited in plan.
Research D is double blinding, two mute, comparable 3 phases research, in Hispanic 16 centers hyperammonemia (hyperammonemic) that recruit, 1-3 level HE, liver cirrhosis experimenter, reaches 10 days with rifaximin 1200mg/ days with treatment in lactitol 60g/ days.120 experimenters (60 people/group) are recruited in plan.
Research E be 3 phases, internationalization, multicenter, at random, the parallel-group research of double blinding, placebo; Have slightly to the moderate hepatic encephalopathy and do not tolerating among the liver cirrhosis experimenter of GI side effect of lactulose or lactitol, relatively rifaximin 400mg every days of 14 days three times and placebo.This research is carried out in the U.S., Poland, Hungary and Britain.112 experimenters (56 people/group) are recruited in plan.
Main effect terminal point definition
In research C, D and E, use the above-mentioned identical standard that is used to study A and B, estimate the mental status (Conn scoring) and neuromuscular function (asterixis classification).
According to the order of severity that increases, with vein ammonia level, NCT scoring and EEG classification as a result.
Research C: the main effect terminal point of research C is the PSE index when research finishes.The PSE index is a composition scoring, and it comprises the scoring that is used for the mental status (Conn scoring), asterixis, vein ammonia level, NCT and EEG.
In each treatment group of every day rifaximin 600mg, 1200mg and 2400mg, through the covariant analysis, the exponential difference of PSE when evaluation study finishes.
D:4 main effect terminal point of research is defined as:
1. the mental status (Conn scoring) is improved
2.PSE index.
3. the vein ammonia level reduces
4.PSE index reduces.
Research E: main effect terminal point is the general reaction rate, is defined as after accomplishing treatment, with baseline, on the mental status (Conn scoring), shows the experimenter's of at least 1 level of improvement (for example becoming Conn scoring 1 or 0 from Conn scoring 2) ratio.
Demography and baseline characteristic
In research C, the mean age of 600mg group, 1200mg group and 2400mg group was respectively 55.2 years old, 52.3 years old and 55.3 years old.In research D, the mean age of rifaximin group and lactitol group was respectively 61.6 years old and 62.9 years old.In research E, the mean age of rifaximin group and placebo group was respectively 53.6 years old and 53.3 years old.
Demographics in research C, D and E between each treatment group is similar usually.
The general introduction of the baseline characteristic of table 8 expression research C, D and E.Like what measured through the mental status/Conn scoring, asterixis classification and PSE index, the experimenter is more serious than experimenter's among the research E HE symptom among the research D.In addition, compare with C, disease severity is bigger among the D.For example; In D; The experimenter's of the baseline mental status/Conn scoring >=2 ratio is 70% (rifaximin) and 60.3% (lactitol), and E is 14.6% (rifaximin) and 4.4%, and 600mg group, 1200mg group and 2400mg group are respectively 16.7%, 31.6% and 23.5% among the C.The time (being the HE persistent period) that self diagnosis HE disease rises among the research D is basically all than research E and longer (the seeing table 8) of studying C.
Table 18 research C, D and E: the general introduction of baseline characteristic (ITT colony)
Figure BPA00001514750900541
Disposal to the patient
In security update in 120 days, 280 experimenters have been recruited in 60 research places.Have 152 (54.3%) among these experimenters from the research of introducing (lead-in study) (research A), 128 (45.7%) are new experimenters.Have 187 experimenters (66.8%) still under study for action.93 experimenters (33.2%) just end treatment in early days, and main cause is death, liver transplantation, the requirement of answering the experimenter and adverse events.
Baseline characteristic
Among the research A experimenter with study B in baseline characteristic between the experimenter totally similar.To new rifaximin experimenter among the research B, provide Demographics and baseline characteristic.
Baseline characteristic difference between the experimenter of the experimenter of research A and research B relates to the difference of entering standard.For research B, the experimenter has in preceding 12 months in screening >=1 attested HE outbreak, and for research A, and the experimenter has in preceding 6 months in screening >=2 times HE outbreak.Consistent with these differences is, when with research A relatively the time, before getting into research, the experimenter of research B has confirmed that in the recent period the persistent period that HE alleviates is longer, and it is lower to have experimenter's ratio of 2 times or 3 times certified HE outbreaks.
Subfraction for to time of breakthrough obvious HE is analysed
In all inferior groups of being checked, the rifaximin treatment has all reduced the risk that experiences breakthrough obvious HE outbreak.
Compare with placebo group, the rifaximin group experiences the p-value of risk ratio (main effect terminal point), 95%CI and the Cox proportional hazard model of breakthrough obvious HE risk and sees Fig. 2.Risk shows that than less than 1 the result supports rifaximin, then supports placebo greater than 1.
Divide apoplexy due to endogenous wind at Child-Pugh, at the baseline place, the result of the time of extremely breakthrough first obvious HE outbreak sees table 9.Obtain the sub-scoring of Child-Pugh, overall score and classification in the research in the past.At Child-Pugh A, B or C apoplexy due to endogenous wind, to compare with placebo, the risk that the rifaximin treatment causes experiencing breakthrough obvious HE outbreak significantly reduces.Divide apoplexy due to endogenous wind all to observe the rifaximin treatment at Child-Pugh A (5-6), B (7-9) and C (10-15) and reducing the remarkable therapeutic effect of statistics in the risk that experiences breakthrough obvious HE outbreak.
Table 19 research A-is through the breakthrough obvious HE outbreak of Child-Pugh classification
The source: table 2-is through the analysis (December was submitted to FDA on the 18th in 2009) of Child-Pugh classification; Abbreviation: twice of BID=every day; The CI=confidence interval.
A is according to the risk ratio of the timing of analyzing to breakthrough HE, and 95%CI uses for handling effectively and through the stratified Cox proportional hazard model of analysis area.The P-value is to measure through the stratified Log Rank check of analysis area.
Research A second efficiency analysis
During treatment in 6 months; Compare with placebo; Rifaximin treatment make HE be correlated with hospitalization (promptly directly because of taking place during hospitalization due to the HE or the hospitalization due to the HE incident) risk reduction by 50% (risk ratio=0.500,95%CI:0.287-0.873, p=0.0129).It is reported that the relevant hospitalization of hepatic encephalopathy of rifaximin and placebo group is respectively 36 among among 140 experimenters 19 and 159 experimenters.After exposing standardization, the relevant hospitalization rate of the HE of rifaximin group reduces by 51%, and (rifaximin is 0.38 incident/PEY, and the contrast placebo is 0.78 incident/PEY).
During treatment in 6 months, compare with placebo, the risk of hospitalization due to rifaximin group experimenter's the HE (promptly directly only because of the hospitalization due to the HE) reduce by 56% (risk compares=0.438,95%CI:0.238-0.807, p=0.0064).It is reported that hospitalization due to the HE of rifaximin and placebo group is respectively 33 among among 140 experimenters 15 and 159 experimenters.The hospitalization rate is 0.30 incident/PEY due to the HE of rifaximin group, and placebo group is 0.72 incident/PEY.
When the treatment of research A finishes, in CLDQ tired territory scoring, begin from baseline Change
Chronic hepatopathy questionnaire survey (CLDQ) through the use experience card carries out the health-related quality of life evaluation to chronic hepatitis patients.
Traditionally, through relatively beginning the variation that last overall to CLDQ and that mark in the territory is estimated from baseline between the two treatment groups, carry out CLDQ and analyze.Yet, in this research, use simple change from baseline analysis, have following limitation.At first, this questionnaire survey is measured is experimenter's quality of life state in 2 weeks before accomplishing questionnaire survey.Through result's (from variation of baseline analysis) in 2 weeks before result in comparison last preceding 2 weeks of evaluation and the baseline, the variation that in analysis, can not obtain whole flow of research.Secondly, the most of experimenters in the research also have the relevant same disease (comorbidity) of liver cirrhosis that may distort the result, and this depends on the time of complication, and whether it occurs in (or closing on) first or last when estimating.At last, the experimenter who experiences the breakthrough outbreak of obvious HE is excluded from study according to scheme, and visit completion last CLDQ evaluation between tailend in research, it often occurs in after the elimination of HE incident.Therefore, for these experimenters, the CLDQ the possibility of result is similar to baseline values.In order to solve these limitations, use T Wa(for the AUC that adjusts of open-assembly time of research) carried out AUC and analyzed, because it allows CLDQ result to contain the complete time that the experimenter participates in studying, especially before breakthrough HE outbreak.
When using T WaAnalyze CLDQ as a result the time, the experimenter compares with placebo group, and rifaximin group experimenter's feeling of fatigue significantly reduces, and overall quality of life significantly improves.For overall CLDQ territory scoring (p=0.0093); And for CLDQ other forms each (the comprising abdominal symptoms (p=0.0090), systemic symptom (p=0.0160), active (p=0.0022), emotive function (p=0.0065) and anxiety (p=0.0436)) in territory, also all observe the CLDQ result of support rifaximin group.
CLDQ result has shown measurable breakthrough obvious HE outbreak, as (Fig. 4) that main terminal point limited.Experimenter with do not have between the experimenter of breakthrough obvious HE, for all territories of CLDQ, T with breakthrough obvious HE WaAll there is significant difference in the frequency distribution of (the standardized AUC through open-assembly time).For each territory and in general, average T WaWhether breakthrough obvious HE outbreak is relevant with existing.
Long-term efficacy (research A and research B)
Although research B is designed for the long-term safety of estimating rifaximin 550mg, also collect Conn scoring and the fractionated extra effect evaluation of asterixis in each visit with in obviously HE breaks through.A is said as research, compare with placebo, to the Kaplan-Meier analytical proof of time of breakthrough obvious HE outbreak first concordance, persistency and the repeatability of rifaximin protection effect.
In research B, to breakthrough obvious HE time-with the concordance of studying A result
The rifaximin group (rifaximin PEY=50) of research A with study between the rifaximin experimenter (rifaximin PEY=80) new among the B; The Kaplan-Meier estimated value of the time of extremely breakthrough first obvious HE outbreak is similar (for the difference of relative risk, p=0.800).In addition, in the new rifaximin group (20.5%, 43/210) of the rifaximin group (22%, 31/140 [rifaximin group]) of studying A and research B, the experimenter of similar ratio has breakthrough obvious HE outbreak.Exposure is adjusted, and is 0.62 incident/PEY at the breakthrough obvious HE AR of rifaximin group of research A, and Comparatively speaking, new rifaximin experimenter then is 0.5 incident/PEY among the research B.
Intersect and to the placebo subjects of studying the research A of rifaximin treatment among the B, extremely dash forward The time of the obvious HE outbreak of broken property
During open label research, follow the trail of to intersect to study among the B from research A with placebo treatment experimenter (n=82).In research A among placebo experience and the research B during preceding 6 months of the rifaximin treatment between, relatively see Fig. 5 for the Kaplan-Meier estimated value of the time of showing effect to breakthrough obvious HE first.For placebo treatment, the sickness rate of the breakthrough obvious HE outbreak of rifaximin treatment is 0.2112 (95%CI:0.1006-0.4432, p＜0.0001 is for the group difference of relative risk).This result representes before to compare in the placebo experience of research among the A with them, among the research B during the rifaximin treatment risk of the breakthrough obvious HE of experience reduce by 79%.There are 14 people of 82 philtrums to experience breakthrough obvious HE during 6 monthly interest good fortune former times Mingzhi treatments in research B, 39 people of 82 philtrums are then arranged during the placebo treatment in research A.Breakthrough HE AR among the research A during the placebo treatment is 1.5 incidents/PEY, then is 0.4 incident/PEY during the rifaximin treatment among the research B.
In a word, these results prove, with in the experimenter of rifaximin treatment and research B, continuing the rifaximin group and compare among the research A, placebo intersects the experimenter and experienced the similar protective effect that shows effect to breakthrough HE among the research B.
PSE index during the short term therapy
In dosage-scope research (research C), finish to treatment from baseline, observe all in all treatment groups that PSE is exponential to improve (promptly reducing).When treatment finished, the PSE index was respectively-6.4% ,-10.3% and-10.7% from the mean change that baseline begins in 600mg, 1200mg and the 2400mg rifaximin daily dose group.In the research D that rifaximin 1200mg/ days are compared with lactitol, to compare with the lactitol group, the PSE index of rifaximin group significantly reduces (p=0.0103).Still in research D, compare with the lactitol group, the PSE effect index of rifaximin group demonstrates remarkable improvement the (p=0.0083).Between rifaximin and the placebo group, the PSE index variation is similar among the research E.
The PSE index result of Fig. 6 explanation when baseline finishes with research C, D and E.
During short term therapy, the improvement of Conn scoring
In research C (dosage-scope research), there is tangible statistics trend to show, compare experimenter's ratio higher (p=0.099 is through usage ratio advantage model) that the mental status (Conn scoring) is improved in the 1200mg group with the 600mg group.In addition, compare with the 600mg daily dose, under the 2400mg daily dose, experimenter's Conn scoring improves (the Conn scoring of 31.3% contrast 26.7% is changed to-1 or-2) more at high proportion.
In research D, the improvement of the mental status between rifaximin group and the lactitol group (Conn scoring) does not have significant difference; Yet research D has 3 main effect terminal points: the PSE index reduces, and PSE effect index improves and the vein ammonia level reduces; The remarkable advantageous effect that shows rifaximin.Rifaximin does not have remarkable effect to the improvement of Conn scoring among the research D, possibly be because the persistent period short (10 days) of research Drug therapy.
In research E, rifaximin does not have effect to the improvement of Conn scoring, possibly be because the persistent period of treatment weak point (15 days) and in the slight HE symptom of baseline in this research.As measured through the mental status/Conn scoring, asterixis classification and PSE index, compare with the experimenter of research D or research C, the experimenter of research E has slight HE symptom.
Asterixis classification, NCT result and general reaction during the short term therapy
In research C, during continuing medication, experimenter's ratio that the asterixis classification is improved increases with rifaximin dosage.In research D (rifaximin contrast lactitol), the experimenter that the asterixis classification is improved between each group is in similar proportion.In the research (research E) of rifaximin contrast placebo, compare higher (39.1% contrast 9.3% of experimenter's frequency that the asterixis classification is improved in the rifaximin group with the lactitol group; P=0.0097, group difference is supported rifaximin).
In each of this 3 researchs, the NCT scoring between each group changes similar.
In research D, estimate overall overall situation reaction to treatment.Compare the experimenter's percentage ratio that when research finishes, is considered to cure in the rifaximin group (standardization of vein ammonia and the mental status/Conn scoring is 0) higher (53.1% contrast 39.2%) with the lactitol group.
Result's general introduction of short term therapy research C, D and E
In research C, observe the dosage-dependency trend of PSE index (p=0.056) and the mental status/Conn scoring improvement, and this result of study shows the effectiveness of 1200mg rifaximin daily dose (400mg every day three times).These data with from the rifaximin 1200mg/ days announcement results of study in treatment HE, provide the theoretical basis that is used for 3 phases research A and the selection of research B dosage.
In research D, when comparing with lactitol, there is significant group difference in the variation of PSE exponential sum vein ammonia level (the two all is main terminal point), and this supports the rifaximin group; And, treatment have more a high proportion of rifaximin experimenter to be considered to cure (standardization of vein ammonia and the mental status/Conn scoring is 0) when finishing.
In research E, when comparing with placebo subjects, significantly more a high proportion of rifaximin experimenter's asterixis classification is improved; Yet, the result of main terminal point, experimenter's ratio that the Conn scoring is improved does not have significant difference between group.Compare with the experimenter of research D, the experimenter of research E has slight HE symptom.
Combination by reference
The full content of the patent application of all lists of references that the application quoted, patent, pending trial and the patent of having announced all is attached among this paper by reference.
Be equal to embodiment
Only use normal experiment, those skilled in the art will recognize that, maybe can confirm, many embodiments that the specific embodiments that is provided with described herein and this paper is equal to.The embodiment that is equal to like this is intended to by accompanying claims included.

Claims (59)

1. the system that after orally give, increases rifaximin among the experimenter exposes the method for (AUCtau), and said method comprises:
Select the hepatic insufficiency experimenter; With
Give said hepatic insufficiency experimenter with the rifaximin oral administration, wherein compare with the experimenter who does not suffer from hepatic insufficiency, the system of rifaximin exposes among the said hepatic insufficiency experimenter increases.
2. the process of claim 1 wherein that the hepatic insufficiency among the experimenter comprises that whole hepatopathy model in latter stage (MELD) scoring is less than 11 for the experimenter.
3. the process of claim 1 wherein that the hepatic insufficiency among the experimenter comprises that final hepatopathy model (MELD) scoring is 11-18 for the experimenter.
4. the process of claim 1 wherein that the hepatic insufficiency among the experimenter comprises the Child-Pugh A diagnosis as far as the experimenter.
5. the process of claim 1 wherein that the hepatic insufficiency among the experimenter comprises the Child-Pugh B diagnosis as far as the experimenter.
6. the process of claim 1 wherein the system of rifaximin exposes to comprise it being at least 5 times the exposure of not suffering from the hepatic insufficiency experimenter among the said experimenter who suffers from hepatic insufficiency.
7. the process of claim 1 wherein the said system of suffering from rifaximin among the hepatic insufficiency experimenter exposes to comprise it being at least 9.6 times the exposure of not suffering from the hepatic insufficiency experimenter.
8. the process of claim 1 wherein the said system of suffering from rifaximin among the hepatic insufficiency experimenter exposes to comprise it being at least 13.1 times the exposure of not suffering from the hepatic insufficiency experimenter.
9. the process of claim 1 wherein that it is about 5 times of extremely about 13.1 times exposures of not suffering from the hepatic insufficiency experimenter that said system's exposure of suffering from rifaximin among the hepatic insufficiency experimenter comprises.
10. the process of claim 1 wherein and saidly suffer from the hepatic insufficiency experimenter and comprise the experimenter who suffers from hepatic encephalopathy.
11. also comprising with food, the method for claim 1, said method give rifaximin.
12. the method for claim 11, the wherein said system of suffering from hepatic insufficiency experimenter's rifaximin exposes to comprise it being at least 10 times the exposure of not suffering from the hepatic insufficiency experimenter.
13. the method for claim 11, the wherein said system of suffering from hepatic insufficiency experimenter's rifaximin exposes to comprise it being at least 2 times the exposure of not suffering from the hepatic insufficiency experimenter.
14. the method for claim 11, the system of the wherein said rifaximin of suffering from the hepatic insufficiency experimenter expose comprise be do not suffer from the hepatic insufficiency experimenter at least about 2 times to about 10 times exposures.
15. the method for claim 1, said method also comprise the experimenter who selects to be prone to suffer from or suffer from traveler's diarrhea.
Inform the experimenter 16. the method for claim 15, said method also comprise: compare with the population of subjects of not suffering from hepatic insufficiency, the elimination factor of rifaximin reduces in the hepatic insufficiency population of subjects.
17. after orally give, increase rifaximin PC (C among the experimenter Max) method, said method comprises:
Select the hepatic insufficiency experimenter; With
Give said hepatic insufficiency experimenter with the rifaximin oral administration, wherein compare with the experimenter who does not suffer from hepatic insufficiency, the PC of rifaximin increases in said hepatic insufficiency experimenter.
18. the method for claim 17, wherein said hepatic insufficiency experimenter has the alanine aminotransferase (ALT) of rising.
19. the method for claim 17, the wherein said PC of rifaximin of suffering from or be prone to suffering from the experimenter of hepatic insufficiency comprises it being at least 2 times the exposure of not suffering from the hepatic insufficiency experimenter.
Give rifaximin 20. the method for claim 17, said method also comprise with food, the time that wherein reaches maximal plasma concentration is postponed.
21. the method for claim 17, said method also comprise the experimenter who selects to be prone to suffer from or suffer from traveler's diarrhea.
Inform the experimenter 22. the method for claim 21, said method also comprise: compare with the population of subjects of not suffering from hepatic insufficiency, the elimination factor of rifaximin reduces in the hepatic insufficiency population of subjects.
23. after orally give, reduce the method for rifaximin elimination factor among the experimenter, said method comprises:
Select the hepatic insufficiency experimenter; With
Give said hepatic insufficiency experimenter with the rifaximin oral administration, wherein compare with the experimenter who does not suffer from hepatic insufficiency, the elimination factor of rifaximin reduces among the said hepatic insufficiency experimenter.
24. the method for claim 23 is wherein compared with the experimenter who does not suffer from hepatic insufficiency, the elimination factor of rifaximin reduces at least 25% among the said hepatic insufficiency experimenter.
25. the method for claim 23, wherein the hepatic insufficiency among the experimenter has Child-Pugh A scoring.
26. the method for claim 23, wherein the hepatic insufficiency among the experimenter has Child-Pugh B scoring.
27. the method for claim 23 wherein reduces the bioavailability that elimination factor also comprises increases rifaximin among the said hepatic insufficiency experimenter.
28. the method for claim 23, wherein said hepatic insufficiency experimenter comprises at least a symptom, symptom with hepatic encephalopathy or the experimenter who at least once shows effect.
29. the method for claim 23, wherein said hepatic insufficiency experimenter has at least one body shunting.
30. the method for claim 23, said method also comprise the experimenter who selects to be prone to suffer from or suffer from traveler's diarrhea.
Inform said experimenter 31. the method for claim 30, said method also comprise: compare with the population of subjects of not suffering from hepatic insufficiency, the elimination factor of rifaximin reduces in the hepatic insufficiency population of subjects.
32. confirm to be used for the method for treatment effective dose of experimenter's rifaximin, said method comprises:
Select the hepatic encephalopathy experimenter; With
Said hepatic encephalopathy experimenter is measured the treatment effective dose.
33. the method for claim 32, wherein said experimenter suffers from traveler's diarrhea.
34. the method for claim 32, the dosage that wherein will compare increase with the experimenter who does not suffer from hepatic encephalopathy gives said experimenter.
35. the method for claim 32, the dosage that wherein will compare minimizing with the experimenter who does not suffer from hepatic encephalopathy gives said experimenter.
36. also comprising, the method for claim 32, said method inform that said experimenter is with the next item down or multinomial:
Compare with the population of subjects of not suffering from hepatic insufficiency, the elimination factor of rifaximin reduces in the hepatic insufficiency population of subjects;
Compare with the population of subjects of not suffering from hepatic insufficiency, the system of rifaximin exposes in the hepatic insufficiency population of subjects increases;
Compare with the population of subjects of not suffering from hepatic insufficiency, the PC of rifaximin increases in the hepatic insufficiency population of subjects; With
Compare with the population of subjects of not suffering from hepatic insufficiency, the clearance rate of rifaximin reduces in the hepatic insufficiency population of subjects.
37. confirm to be used for the method for treatment effective dose of experimenter's rifaximin, said method comprises:
Select the hepatic insufficiency experimenter;
With hepatic insufficiency with the next item down or multinomial relevant: the system of rifaximin exposes to be increased, the PC of rifaximin increases or the clearance rate of rifaximin reduces; With
Through consider said suffer among the hepatic insufficiency experimenter below at least one confirm the treatment effective dose: the system of rifaximin exposes to be increased, the PC of rifaximin increases or the clearance rate of rifaximin reduces.
38. the method for claim 37, wherein the hepatic insufficiency among the experimenter comprises the Child-Pugh A diagnosis for the experimenter.
39. the method for claim 37, wherein the hepatic insufficiency among the experimenter comprises the Child-Pugh B diagnosis for the experimenter.
40. the method for claim 37, wherein the hepatic insufficiency among the experimenter comprises that whole hepatopathy model in latter stage (MELD) scoring is less than 11 for the experimenter.
41. the method for claim 37, wherein the hepatic insufficiency among the experimenter comprises that whole hepatopathy model in latter stage (MELD) scoring is 11-18 for the experimenter.
42. the method for claim 37, wherein the hepatic insufficiency among the experimenter has the ALT of rising for the experimenter.
43. the method for claim 37, wherein the hepatic insufficiency among the experimenter has at least one body shunting among the experimenter.
44. the method for claim 37, wherein the hepatic insufficiency among the experimenter has at least hepatic encephalopathy outbreak.
45. the method for claim 37, said method also comprise the experimenter who selects to be prone to suffer from or suffer from traveler's diarrhea.
46. also comprising, the method for claim 45, said method know that said experimenter is with the next item down or multinomial:
Compare with the population of subjects of not suffering from hepatic insufficiency, the elimination factor of rifaximin reduces in the hepatic insufficiency population of subjects;
Compare with the population of subjects of not suffering from hepatic insufficiency, the system of rifaximin exposes in the hepatic insufficiency population of subjects increases;
Compare with the population of subjects of not suffering from hepatic insufficiency, the PC of rifaximin increases in the hepatic insufficiency population of subjects; Or
Compare with the population of subjects of not suffering from hepatic insufficiency, the clearance rate of rifaximin reduces in the hepatic insufficiency population of subjects.
47. the method for treatment traveler's diarrhea (TD), said method comprises:
Selection suffers from or is prone to suffer from the experimenter of TD;
Instruct said experimenter's oral administration to take rifaximin; With
Inform that said experimenter is with the next item down or multinomial:
Compare with the population of subjects of not suffering from hepatic insufficiency, the elimination factor of rifaximin reduces in the hepatic insufficiency population of subjects;
Compare with the population of subjects of not suffering from hepatic insufficiency, the system of rifaximin exposes in the hepatic insufficiency population of subjects increases;
Compare with the population of subjects of not suffering from hepatic insufficiency, the PC of rifaximin increases in the hepatic insufficiency population of subjects; Or
Compare with the population of subjects of not suffering from hepatic insufficiency, the clearance rate of rifaximin reduces in the hepatic insufficiency population of subjects.
48. the method for claim 47, wherein the hepatic insufficiency among the experimenter comprises that whole hepatopathy model in latter stage (MELD) scoring is less than 11 for the experimenter.
49. the method for claim 47, wherein the hepatic insufficiency among the experimenter comprises that whole hepatopathy model in latter stage (MELD) scoring is 11-18 for the experimenter.
50. the method for claim 47, wherein the hepatic insufficiency among the experimenter comprises Child-Pugh A diagnosis for the experimenter.
51. the method for claim 47, wherein the hepatic insufficiency among the experimenter comprises Child-Pugh B diagnosis for the experimenter.
52. the method for claim 47, wherein said hepatic insufficiency experimenter comprises the experimenter who suffers from hepatic encephalopathy.
53. also comprising, the method for claim 47, said method differentiate the experimenter who suffers from hepatic insufficiency.
54. the method for claim 53 wherein detects said experimenter's hepatic insufficiency.
55. the method for claim 47, said method also comprise according to said hepatic insufficiency experimenter and do not suffer from the experimenter's of hepatic insufficiency the dosage that relatively changes rifaximin.
56. the method for claim 47, said method also comprise according to said hepatic insufficiency experimenter and do not suffer from the experimenter's of hepatic insufficiency the dosage regimen that relatively changes rifaximin.
57. the method for claim 47, said method comprise that also the system of informing said experimenter's rifaximin exposes and/or the PC of rifaximin changes with food.
58. medicine box, said medicine box comprise rifaximin or its pharmaceutical composition, and the operation instructions that are used for hepatic insufficiency experimenter administration.
59. the medicine box of claim 58, wherein said medicine box comprises the operation instructions that are used for rifaximin is given the hepatic encephalopathy experimenter.
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