Methods of treating hepatic encephalopathy

• US 8,969,398 B2
• Filed: 02/15/2013
• Issued: 03/03/2015
• Est. Priority Date: 10/02/2008
• Status: Active Grant

• Current Assignee: Salix Pharmaceuticals Incorporated (Bausch Health Cos., Inc.)
• Original Assignee: Salix Pharmaceuticals Limited (Bausch Health Cos., Inc.)
• Inventors: Forbes, William
• Primary Examiner(s): Ivanova, Svetlana M
• Application Number:
  US13/768,617
• Publication Number:
  US 20130171090A1
• Time in Patent Office: 746 Days
• Field of Search: None
• US Class Current: 514/397
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/08 acyclic, e.g. paraformaldehyde
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61K 31/606 having amino groups
• CPC Class Codes: A61K 31/7016 Disaccharides, e.g. lactose, lactulose lactobionic acid A61K31/7032
• CPC Class Codes: A61K 31/785 Polymers containing nitrogen
• CPC Class Codes: A61K 38/14 Peptides containing saccharide radicals; Derivatives thereof , e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
• CPC Class Codes: A61K 38/31 Somatostatins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents

Abstract

The application describes treatment of hepatic encephalopathy using gastrointestinal specific antibiotics. One example of a gastrointestinal specific antibiotic is rifaximin.

Claims

1. A method of decreasing a subject'"'"'s risk of a hepatic encephalopathy (HE) breakthrough episode comprising administering rifaximin daily for a period of about 12 months or longer to a subject suffering from HE, thereby decreasing the subject'"'"'s risk of an HE breakthrough episode, wherein a breakthrough episode is defined as an increase of the Conn score to Grade ≧

2 or an increase in Conn score of 1 and asterixis grade of 1 for subjects having a baseline Conn score of 0.

2. The method of claim 1, wherein the risk of the episode for subjects having a last HE episode equal to, or greater than, 90 days prior to the administration of rifaximin is reduced by about 58%.

3. The method of claim 1, wherein the risk of the episode for subjects having a last HE episode equal to, or greater than, 90 days prior to the administration of rifaximin is reduced by between about 30% to 70%.

4. The method of claim 1, wherein the risk of the episode for subjects having a last HE episode greater than 90 days prior to the administration of rifaximin is decreased by between about 60%.

5. The method of claim 1, wherein the risk of the episode for subjects having a last HE episode greater than 90 days prior to the administration of rifaximin is decreased by between about 2% to 80%.

6. The method of claim 1, wherein the risk of the episode for subjects having two or fewer HE episodes in the six months prior to the administration of rifaximin is reduced by about 56%.

7. The method of claim 1, wherein the risk of the episode for subjects having 2 or fewer HE episodes in the six months prior to administration of rifaximin is reduced by between about 20% to 70%.

8. The method of claim 1, wherein the risk of the episode for subjects having greater than two HE episodes in the six months prior to administration of rifaximin is reduced by about 63%.

9. The method of claim 1, wherein the risk of the episode for subjects having greater than two HE episodes in the six months prior to the administration of rifaximin is reduced by between about 30% to about 80%.

10. The method of claim 1, wherein administering rifaximin daily comprises administering 550 mg of rifaximin to the subject two times per day (BID).

11. The method of claim 1, wherein administering rifaximin daily comprises administering 275 mg of rifaximin to the subject four times per day.

12. The method of claim 1, wherein administering rifaximin daily comprises administering 275 mg of rifaximin to the subject as two dosage forms two times per day.

13. The method of claim 1, wherein rifaximin is administered to the subject for two to three years.

14. The method of claim 1, wherein rifaximin is administered daily to the subject until the subject'"'"'s death.

15. The method of claim 1, further comprising administering lactulose.

16. The method of claim 1, further comprising administering one or more of align, alinia, pentasa, cholestyramine, sandostatin, vancomycin, lactose, amitiza, flagyl, zegerid, prevacid, or miralax.

17. The method of claim 1, wherein administration of rifaximin results in an increase in time to a first HE-related hospitalization of the subject.

18. The method of claim 1, wherein administration of rifaximin results in an increase in the time to development of spontaneous bacterial peritonitis (SBP) in the subject.

19. The method of claim 1, wherein administration of rifaximin results in a decrease in blood ammonia concentration from baseline in the subject.

20. The method of claim 19, wherein the decrease in blood ammonia concentration from baseline to 170 days is about 6 μ

g/dL.

21. The method of claim 1, wherein administration of rifaximin results in an increase in critical flicker frequency values from baseline in the subject.

22. The method of claim 1, wherein administration of rifaximin results in a decrease in daily lactulose consumption from baseline over time in the subject.

23. The method of claim 22, wherein the decrease in daily lactulose consumption is from between about 7 doses of lactulose to about 2 doses of lactulose.

24. The method of claim 1, wherein administration of rifaximin results in a change from baseline in Chronic Liver Disease Questionnaire (CLDQ) scores over time in the subject.

25. The method of claim 1, wherein administration of rifaximin results in a change from baseline in Epworth Sleepiness Scale scores over time in the subject.

26. The method of claim 1, wherein subjects having a MELD level of between about 1 to 24 respond to administration of rifaximin.

27. The method of claim 1, wherein subjects having a MELD level less than or equal to ten respond to administration of rifaximin.

28. The method of claim 1, wherein subjects having a MELD level between 11 and 18 respond to administration of rifaximin.

29. The method of claim 1, wherein subjects having a MELD level between 19 and 24 respond to administration of rifaximin.