Methods of Treating Hepatorenal Syndrome and Hepatic Encephalopathy with Thromboxane-A2 Receptor Antagonists

Abstract

The present invention is directed to methods of treating hepatorenal syndrome by administration of a therapeutically effective amount of a thromboxane A.sub.2 receptor antagonist to a patient in need thereof. The present invention is also directed to methods of treating hepatic encephalopathy and cerebral edema by administration of a therapeutically effective amount of a thromboxane A.sub.2 receptor antagonist to a patient in need thereof.

Claims

1-7. (canceled)

8. A method of preventing or treating hepatorenal syndrome comprising: administering to a patient in need thereof a therapeutically effective amount of a [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino) carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic acid (Ifetroban), and pharmaceutically acceptable salts thereof to a patient in need thereof.

9. The method of claim 8, wherein the hepatorenal syndrome is type I or type II.

10. (canceled)

11. The method of claim 8, wherein the thromboxane A.sub.2 receptor antagonist is administered orally.

12. The method of claim 8, wherein the thromboxane A.sub.2 receptor antagonist is administered parenterally.

13. (canceled)

14. The method of claim 8, wherein the thromboxane A.sub.2 receptor antagonist is [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo [2.2.1]hept-2-yl]methyl]-benzenepropanoic acid, monosodium salt (Ifetroban Sodium).

15-31. (canceled)

32. The method of claim 8, wherein the ifetroban administration provides an ifetroban plasma concentration from about 1 ng/ml to about 1,000 ng/ml, and the administration of ifetroban to the patient results in an increase in renal blood flow.

33. The method of claim 8, wherein the ifetroban administration provides an ifetroban plasma concentration from about 1 ng/ml to about 1,000 ng/ml, and administration of ifetroban to the patient results in an increase in glomerular filtration rate.

34. The method of claim 8, wherein the ifetroban administration provides an ifetroban plasma concentration from about 1 ng/ml to about 1,000 ng/ml, and the administration of ifetroban to the patient results in a decrease in serum creatinine.

35. The method of claim 8, wherein the ifetroban is orally admininistered as ifetroban sodium to the patient in an amount from about 10mg to about 400 mg, per day.

36. The method of claim 35, further comprising administering to the patient a daily dose of ifetroban sodium from about 10 mg to about 50 mg on day 1 and 2, from about 50 mg to about 250 mg ifetroban sodium on days 3 and 4, and at least about 250 mg through day 14 of treatment.

37. The method of claim 8, wherein the amount of ifetroban admininistered is ifetroban sodium in an amount from about 10 mg to about 500 mg, per day.

38. The method of claim 8, wherein the ifetroban is administered orally, intranasally, rectally, vaginally, sublingually, buccally, parenterally, or transdermally.

39. The method of claim 14, wherein a daily dose of ifetroban sodium from about 10 mg to about 250 mg is administered, based on ifetroban free acid amounts.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0138] The following examples are not meant to be limiting and represent certain embodiments of the present invention.

Example 1

[0139] In this example, ifetroban sodium tablets are prepared with the following ingredients listed in Table 1:

TABLE-US-00001 TABLE 1 Ingredients Percent by weight Na salt of Ifetroban 35 Mannitol 50 Microcrystalline Cellulose 8 Crospovidone 3.0 Magnesium Oxide 2.0 Magnesium Stearate 1.5 Colloidal Silica 0.3

[0140] The sodium salt of ifetroban, magnesium oxide, mannitol, microcrystalline cellulose, and crospovidone is mixed together for about 2 to about 10 minutes employing a suitable mixer. The resulting mixture is passed through a #12 to #40 mesh size screen. Thereafter, magnesium stearate and colloidal silica are added and mixing is continued for about 1 to about 3 minutes.

[0141] The resulting homogeneous mixture is then compressed into tablets each containing 35 mg, ifetroban sodium salt.

Example II

[0142] In this example, 1000 tablets each containing 400 mg of Ifetroban sodium are produced from the following ingredients listed in Table 2:

TABLE-US-00002 TABLE 2 Ingredients Amount Na salt of Ifetroban 400 gm Corn Starch  50 g Gelatin 7.5 g Microcrystalline Cellulose (Avicel)  25 g Magnesium Stearate 2.5 g

Example III

[0143] In this example. An injectable solution of ifetroban sodium is prepared for intravenous use with the following ingredients listed in Table 3:

TABLE-US-00003 TABLE 3 Ingredients Amount Ifetroban Sodium 2500 mg Methyl Paraben   5 mg Propyl Paraben   1 mg Sodium Chloride 25,000 mg   Water for injection q.s. 5 liter

[0144] The sodium salt of ifetroban, preservatives and sodium chloride are dissolved in 3 liters of water for injection and then the volume is brought up to 5 liters. The solution is filtered through a sterile filter and aseptically filled into pre-sterilized vials which are then closed with pre-sterilized rubber closures. Each vial contains a concentration of 75 mg of active ingredient per 150 ml of solution.

Example IV

Ifetroban Pharmacokinetic and Pharmacodynamic Safety Study

[0145] The plan to develop ifetroban to treat hepatorenal syndrome (HRS) is based on the hypothesis that high levels of liver-derived isoprostanes mediate renal vasospasm via thromboxane receptor (TPr) activation, and the TPr antagonist, ifetroban, will block isoprostane-dependent renal vasoconstriction, improve renal blood flow and reverse HRS. Development of ifetroban for this indication requires first the study of safety and pharmacokinetics of ifetroban in HRS patients. At the same time, evidence is sought that ifetroban can increase renal blood flow and be beneficial as HRS treatment.

[0146] The following clinical study is a Phase II, prospective, double-blind, placebo controlled multi-center study that will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ifetroban administered as multiple daily oral doses in hepatorenal syndrome type 1 patients. Hepatorenal syndrome type 1 patients will be assigned according to a dose escalation randomization schedule. Escalation to the higher doses will be contingent upon the safety and tolerability of the preceding dose. Patients may receive study drug for a maximum of 14 days but will be discontinued from the study earlier for treatment failure (defined as serum creatinine (SCr) level≧2× the baseline value after day 7, dialysis, or death) or liver transplantation. Patients who achieve treatment success may be discontinued or continue on therapy at the investigator's discretion until the maximum of 14 days. If judged by the investigator to be potentially beneficial, patients who demonstrate at least a partial response during the initial 14-day treatment course and then develop recurrence of hepatorenal syndrome type 1 during the follow-up period will be eligible to be retreated with the highest well-tolerated dose of ifetroban for up to an additional 14 days.

[0147] The primary pharmacodynamic measure of renal function will be creatinine clearance, which should increase if renal function improves.

[0148] Secondary outcomes will be evaluated, including changes in SCr and BUN levels, change in urine output and estimated GFR, and dialysis requirements.

[0149] Thirty-six (36) adult male or female (≧18 years of age) hepatorenal syndrome type 1 patients will be enrolled and assigned according to a randomization schedule to three (3) groups of twelve (12) patients each to receive on days 1 and 2 either placebo, low-dose ifetroban or high-dose ifetroban as daily oral doses.

[0150] Ifetroban study drug will be provided as look-alike capsules containing 0, 10, 50 or 125 mg of ifetroban sodium measured as free acid equivalents.

[0151] Placebo will be supplied in look-alike capsules containing formulation with no ifetroban.

Three (3) groups of twelve (12) patients each will receive on days 1 and 2 either placebo, 10 mg ifetroban or 50 mg ifetroban as daily oral doses. On days 3 and 4, daily oral doses will be increased to 50 mg ifetroban, 125 mg ifetroban and 250 mg ifetroban, respectively. On days 5 and 6, daily oral doses in all groups will be 250 mg ifetroban. Treatment will continue with daily doses of the highest well-tolerated dose for the duration of hospitalization or through day 14.

Example V

Ifetroban Pharmacokinetic and Pharmacodynamic Safety Study

[0152] The plan to develop ifetroban to treat hepatic encephalopathy is based on the hypothesis that high levels of liver-derived isoprostanes mediate microvascular constriction and permeability via thromboxane receptor (TPr) activation, and the TPr antagonist, ifetroban, will block isoprostane-dependent microvascular constriction and permeability, normalize cerebral blood flow and reverse or prevent progression of hepatic encephalopathy. Development of ifetroban for this indication requires first the study of safety and pharmacokinetics of ifetroban in hepatic encephalopathy patients. At the same time, evidence is sought that ifetroban can improve indices of hepatic encephalopathy, such as neuropsychiatric function and heart rate variability, and be beneficial as hepatic encephalopathy treatment.

[0153] The following clinical study is a Phase II, prospective, double-blind, placebo controlled multi-center study that will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ifetroban administered as one or more daily oral doses in hepatic encephalopathy patients. Hepatic encephalopathy patients will be assigned according to a dose escalation randomization schedule. Escalation to the higher doses will be contingent upon the safety and tolerability of the preceding dose. Patients may receive study drug for a maximum of 14 days but will be discontinued from the study earlier for treatment failure (defined as worsening of encephalopathy, development of coma, or death) or liver transplantation. Patients who achieve treatment success may be discontinued or continue on therapy at the investigator's discretion until the maximum of 14 days. If judged by the investigator to be potentially beneficial, patients who demonstrate at least a partial response during the initial 14-day treatment course and then develop recurrence of hepatic encephalopathy during the follow-up period will be eligible to be retreated with the highest well-tolerated dose of ifetroban for up to an additional 14 days.

[0154] The primary pharmacodynamic measure of hepatic encephalopathy will be heart rate variability which should increase if hepatic encephalopathy improves.

[0155] Secondary outcomes will be evaluated, including asterixis, which should moderate if hepatic encephalopathy improves, and changes in serum creatinine which should decrease if renal function improves.

[0156] Thirty-six (36) adult male or female (>18 years of age) patients [MO3] will be enrolled and assigned according to a randomization schedule to three (3) groups of twelve (12) patients each to receive on days 1 and 2 either placebo, low-dose ifetroban or high-dose ifetroban as daily oral doses.

[0157] Ifetroban study drug will be provided as look-alike capsules containing 0, 10, 50 or 125 mg of ifetroban sodium measured as free acid equivalents.

[0158] Placebo will be supplied in look-alike capsules containing formulation with no ifetroban.

[0159] Three (3) groups of twelve (12) patients each will receive on days 1 and 2 either placebo, 10 mg ifetroban or 50 mg ifetroban as daily oral doses. On days 3 and 4, daily oral doses will be increased to 50 mg ifetroban, 125 mg ifetroban and 250 mg ifetroban, respectively. On days 5 and 6, daily oral doses in all groups will be 250 mg ifetroban. Treatment will continue with daily doses of the highest well-tolerated dose for the duration of hospitalization or through day 14.

[0160] In the preceding specification, the invention has been described with reference to specific exemplary embodiments and examples thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention as set forth in the claims that follow. The specification and drawings are accordingly to be regarded in an illustrative manner rather than a restrictive sense.