METHODS OF TREATING HEPATIC ENCEPHALOPATHY

• US 20100204173A1
• Filed: 10/02/2009
• Published: 08/12/2010
• Est. Priority Date: 10/02/2008
• Status: Abandoned Application

• Current Assignee: Salix Pharmaceuticals Limited (Bausch Health Cos., Inc.)
• Original Assignee: Salix Pharmaceuticals Limited (Bausch Health Cos., Inc.)
• Inventors: Forbes, William
• Application Number:
  US12/572,344
• Publication Number:
  US 20100204173A1
• Time in Patent Office: Days
• US Class Current: 514/53
• 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 treating or preventing hepatic encephalopathy (HE) comprising administering to a subject in need thereof a gastrointestinal (GI) specific antibiotic.

18. The method of claim 1, 3, 14, or 15 wherein the GI specific antibiotic comprises a rifamycin class antibiotic.

19. The method of claim 1, 3, 14, or 15, wherein the GI specific antibiotic comprises rifaximin.

20. The method of claim 19, wherein 550 mg of rifaximin is administered to the subject two times per day (BID).

21. The method of claim 19, wherein 275 mg of rifaximin is administered to the subject four times per day.

22. The method of claim 19, wherein 275 mg of rifaximin is administered to the subject as two dosage forms two times per day.

23. The method of claim 1, 3, 14, or 15, wherein the GI specific antibiotic is administered to the subject for six months.

24. The method of claim 1, 3, 14, or 15, wherein the GI specific antibiotic is administered to the subject for one year.

25. The method of claim 1, 3, 14, or 15, wherein the GI specific antibiotic is administered to the subject for two to three years.

26. The method of claim 1, 3, 14, or 15, wherein the GI specific antibiotic is administered daily to the subject until the subject'"'"'s death.

27. The method of claim 1, 3, 14, or 15, wherein a Conn score of the subject is improved over baseline following administration of a GI specific antibiotic.

28. The method of claim 1, 3, 14, or 15, wherein a quality of life (QoL) measurement is improved from baseline following administration of a GI specific antibiotic.

29. The method of claim 1, 3, 14, or 15, further comprising administering lactulose.

30. The method of claim 1, 3, 14, or 15, further comprising administering one or more of align, alinia, Lactulose, pentasa, cholestyramine, sandostatin, vancomycin, lactose, amitiza, flagyl, zegerid, prevacid, or miralax.

31. The method of claim 1, 3, 14, or 15, wherein a Conn score (mental state grade) of the subject decreases.

32. The method of claim 1, 3, 14, or 15, wherein time to a Conn score increase from baseline for the subject is increased.

33. The method of claim 32, wherein the delay in time to increase in Conn score of the subject is increased by about 54%.

34. The method of claim 32, wherein the delay in time to increase in Conn score is increased between about 30% to about 70%.

35. The method of claim 1, 3, 14, or 15, wherein administration of the GI specific antibiotic prevents an increase in Conn score of the subject.

36. The method of claim 1, 3, 14, or 15, wherein there is an increase of time to an increase from baseline in an asterixis grade of the subject.

37. The method of claim 1, 3, 14, or 15, wherein there is a delay in the time to increase in asterixis grade.

38. The method of claim 1, 3, 14, or 15, wherein there is an increase in time to a first HE-related hospitalization of the subject.

39. The method of claim 1, 3, 14, or 15, wherein there is an increase in the time to development of spontaneous bacterial peritonitis (SBP) of the subject.

40. The method of claim 1, 3, 14, or 15, wherein there is a decrease in blood ammonia concentration from baseline after administration of the GI specific antibiotic of the subject.

41. The method of claim 40, wherein the decrease in blood ammonia concentration from baseline to 170 days is about 6 μ

g/dL.

42. The method of claim 1, 3, 14, or 15, wherein there is an increase in critical flicker frequency values from baseline after administration of a GI specific antibiotic to the subject.

43. The method of claim 1, 3, 14, or 15, wherein there is a decrease in daily lactulose consumption from baseline over time after administration with the GI specific antibiotic to the subject.

44. The method of claim 43, wherein the decrease in daily lactulose consumption is from between about 7 doses of lactulose to about 2 doses of lactulose.

45. The method of claim 44, wherein lactulose use of the subject initially increases from baseline.

46. The method of claim 45, wherein the initial increase in lactulose use is from between about 1 and about 30 days.

47. The method of claim 1, 3, 14, or 15, wherein there is a shift in baseline in Conn scores over time after administration of the GI specific antibiotic to the subject.

48. The method of claim 47, wherein the shift in baseline in Conn scores is from between about 1 to about 2.

49. The method of claim 1, 3, 14, or 15, wherein there is a shift from baseline in asterixis grades over time after administration of the GI specific antibiotic to the subject.

50. The method of claim 1, 3, 14, or 15, wherein there is a change from baseline in Chronic Liver Disease Questionnaire (CLDQ) scores over time after administration of the GI specific antibiotic to the subject.

51. The method of claim 1, 3, 14, or 15, wherein there is a change from baseline in Epworth Sleepiness Scale scores over time after administration of the GI specific antibiotic to the subject.

52. The method of claim 1, 3, 14, or 15, wherein subjects having a meld level of between about 1 to 24 respond to treatment with GI specific antibiotics.

53. The method of claim 1, 3, 14, or 15, wherein subjects having a meld level less than or equal to ten respond to treatment with GI specific antibiotics.

54. The method of claim 1, 3, 14, or 15, wherein subjects having a meld level between 11 and 18 respond to treatment with GI specific antibiotics.

55. The method of claim 1, 3, 14, or 15, wherein subjects having a meld level between 19 and 24 respond to treatment with GI specific antibiotics.

3. A method of decreasing a subject'"'"'s risk of a hepatic encephalopathy (HE) breakthrough episode comprising administering a GI specific antibiotic to a subject suffering from HE.

4. The method of claim 3, wherein the risk of the episode for subjects having a last HE episode equal to, or greater than, 90 days prior to the administration is reduced by about 58%.

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

6. The method of claim 3, wherein the risk of the episode for subjects having a last HE episode greater than 90 days prior to the administration is decreased by between about 60%.

7. The method of claim 3, wherein the risk of the episode for subjects having a last HE episode greater than 90 days prior to the administration is decreased by between about 2% to 80%.

8. The method of claim 3, wherein the risk of the episode for subjects having two or fewer HE episodes in the six months prior to the administration is reduced by about 56%.

9. The method of claim 3, wherein the risk of the episode for subjects having 2 or fewer HE episodes in the six months prior to administration is reduced by between about 20% to 70%.

10. The method of claim 3, wherein the risk of the episode for subjects having greater than two HE episodes in the six months prior to rifaximin administration is reduced by about 63%.

11. The method of claim 3, wherein the risk of the episode for subjects having greater than two HE episodes in the six months prior to the administration is reduced by between about 30% to about 80%.

12. The method of claim 3, wherein the risk of the episode is decreased by about 58%.

13. The method of claim 3, wherein the risk of the episode is decreased by between about 40% to about 70%.

14. A method of maintaining remission of HE in a subject comprising administering a GI specific antibiotic to a subject suffering from HE.

15. A method of reducing the frequency of hospitalization visits by an HE patient, comprising administering a GI specific antibiotic to a subject suffering from HE.

16. The method of claim 15, wherein administration of rifaximin reduces hospitalization frequency by about 48%.

17. The method of claim 15, wherein administration of rifaximin reduces hospitalization frequency by from between about 13% to about 69%.

56. A method of treating or preventing HE comprising administering 550 mg of rifaximin for more than 28 days.

57. A method of decreasing lactulose use in a subject, comprising:

administering rifaximin to a subject daily that is being treated with lactulose; and

tapering lactulose consumption.

58. The method of claim 57, wherein tapering comprises reducing lactulose consumption by 1, 2, 3, 4, 5, 6 or more unit dose cups of lactulose from a baseline level.

59. The method of claim 57, wherein tapering comprises reducing lactulose consumption by 5, 10, 15, 20, 25, 30, 34, 40, 45, 50, 55, 60, 65, or 70 g lactulose from a baseline level.

60. The method of claim 57, wherein tapering comprises reducing lactulose consumption.

61. The method of claim 57, wherein the tapering is from a baseline to no consumption of lactulose.

62. A method of maintaining remission of HE in a subject comprising administering 550 mg of rifaximin BID.

63. A method of increasing time to hospitalization for HE comprising, administering to a subject 550 mg of rifaximin two times per day (BID).

64. A method of treating a patient suffering from hepatic encephalopathy, comprising:

advising a patient suffering from hepatic encephalopathy that administration of rifaximin may induce cytochrome P450 activity; and

administering rifaximin to the patient in order to treat the hepatic encephalopathy.

65. The method of claim 64, wherein the cytochrome P450 activity is cytochrome P450 3A4 (CYP3A4) activity.

66. The method of claim 64, wherein administering rifaximin comprises administering 1100 mg of rifaximin per day to the patient.

67. The method of claim 64, wherein administering rifaximin comprises administering rifaximin twice per day to the patient.

68. The method of claim 64, further comprising advising a patient that is taking a cytochrome P450 substrate to seek additional medical guidance.

69. The method of claim 64, wherein advising the patient comprises providing the patient with written material.

70. The method of claim 69, wherein the written material is on a drug label.

71. A method of administering rifaximin as a treatment for hepatic encephalopathy, comprising:

advising a health care worker that patients being administered rifaximin as a treatment for hepatic encephalopathy may induce cytochrome P450 activity; and

administering the rifaximin to the patient in order to treat the hepatic encephalopathy.

72. The method of claim 71, wherein the healthcare worker is a doctor, a nurse, or a pharmacist.

73. The method of claim 71, wherein advising the health care worker comprises providing the health care worker with written advice.

74. The method of claim 71, wherein the cytochrome P450 activity is cytochrome P450 3A4 (CYP3A4) activity.

75. A method of increasing the time between breakthrough events for a patient suffering from hepatic encephalopathy, comprising administering to the patient an effective amount of rifaximin that extends the time between hepatic encephalopathy breakthrough events.

76. The method of claim 75, wherein the time between breakthrough events for the patient is extended to greater than six months.

77. The method of claim 75, wherein the time between breakthrough events for the patient is extended to greater than twelve months.

78. The method of claim 75, wherein the effective amount of rifaximin comprises 1100 mg of rifaximin per day.

79. A method of lowering the risk of antibacterial resistance when treating chronically with an antibacterial composition, comprising administering rifaximin chronically to treat irritable bowel syndrome, travelers'"'"' diarrhea, small intestinal bacterial overgrowth, Crohn'"'"'s disease, pancreatitis, pancreatic insufficiency, peritonitis, hepatic encephalopathy, pouchitis, infectious diarrhea, inflammatory bowel disease, diverticular disease, Clostridium, C. difficile disease, H. pylori infection, enteritis and colitis and other related conditions. A method of alleviating caretaker burden comprising, administering rifaximin to a subject in need thereof to treat hepatic encephalopathy.

80. A method of reducing hospitalization rate comprising, administering rifaximin to a subject in need thereof to treat hepatic encephalopathy.

81. The method of claim 80, wherein the subject is less likely to have improper nutrition compared to a subject not administered rifaximin.

82. The method of claim 80, wherein the rate of non-adherence to therapy is decreased in the subject compared to a subject not administered rifaximin.

83. The method of claim 80, wherein the subject is less likely to further escalate into more severe symptoms compared to a to a subject not administered rifaximin.

84. The method of claim 80, wherein the more severe symptoms comprise one or more of increased somnolence, gross disorientation and stupor.

85. A method of reducing the economic cost related to liver cirrhosis and/or associated HE comprising administering a subject suffering from HE a rifamycin class antibiotic.

86. A method of increasing the mental status in a subject comprising, administering rifaximin to the subject, thereby increasing the mental status in a subject.

87. The method of claim 86, wherein the mental status is measured using a Conn Score.

88. The method of claim 86, wherein the mental status is measured using asterixis grade.

89. The method of decreasing the number of overt HE episodes in a subject comprising, administering rifaximin to the subject, thereby decreasing the number of overt HE episodes.

90. The method of claim 89, wherein the subject has liver disease.

91. The method of claim 89, wherein the subject has decreased numbers of overt HE episodes for at least 2 years.

92. The method of claim 89, wherein the effective amount of rifaximin comprises 1650 mg of rifaximin per day.

93. A method for increasing the chance of survival of a subject having HE, comprising administering to the subject rifaximin, thereby increasing the chance of survival for the subject.

94. A method of administering rifaximin as a treatment for hepatic encephalopathy, comprising:

advising a health care worker that rifaximin does not increase the risk of QT prolongation; and

administering the rifaximin to the patient in order to treat the hepatic encephalopathy.

2. The method of claim 1, wherein the GI specific antibiotic maintains remission of HE in the subject.

95. The method of claim 94, further comprising the step of advising the health care worker that there is a greater than 30 fold difference in the hERG 1050 value and the unbound Cmax value.

96. The method of claim 95, wherein the subject is administered 1650 mg/day of rifazimin for at least 7 days.

94-1. A method of administering rifaximin as a treatment for hepatic encephalopathy, comprising:

advising a health care worker that rifaximin does not significantly alter the C_max, AUC_0-t, or AUC_0-∞

of midazolam; and

administering the rifaximin to the patient in order to treat the hepatic encephalopathy.

95-2. The method of claim 94, wherein the subject is administered 1650 mg/day of rifazimin.