Treatment of ascites

Abstract

To provide treatment of ascites.SOLUTION: There is provided a method for treating ascites patients by administering peptide drug terlipressin by continuous infusion. The patients include those whose ascites condition has not progressed to the hepatorenal syndrome (HRS). The administration may be accomplished with a continuous infusion pump.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 267,510, filed December 15, 2015, and U.S. Provisional Patent Application No. 62 / 186,638, filed July 13, 2015, each of which is incorporated herein by reference in its entirety.

[0002] Field The present disclosure relates to a method for treating patients with ascites by administering the peptide drug terlipressin. [Background technology]

[0003] background Ascites is a frequent and life-threatening complication of advanced cirrhosis, with a 40% predicted mortality rate within two years of diagnosis. To date, the US FDA has not approved any therapy specifically to treat ascites, but several medications (e.g., diuretics) are used off-label with limited and temporary efficacy. Studies have shown that intravenous (VI) terlipressin administered every 4 to 6 hours can be lifesaving in hospitalized patients with type 1 hepatorenal syndrome (HRS). HRS is an early stage of renal failure and often occurs in patients with ascites that has become refractory to diuretic treatment. Furthermore, investigational studies have shown that VI terlipressin administered every 4 to 6 hours can significantly reduce the risk of ascites. The combination of injections and diuretics has been shown to clear refractory ascites in hospitalized patients and reduce the need for large-volume paracentesis (removal of ascites with a needle). However, these intermittent high-dose IV injections (typically 1 mg or 2 mg per dose) carry a high risk of side effects. More recent studies in hospitalized HRS patients have shown that continuous infusion of terlipressin can achieve similar efficacy to intermittent injections with a much better safety profile. However, to date, there have been no published studies using continuous low-dose infusion terlipressin to manage ascites in non-hospitalized cirrhotic patients. Summary of the Invention [Problem to be solved by the invention]

[0004] Accordingly, the present inventors have recognized a need in the art for a method that can treat patients with ascites on an outpatient basis and avoid or delay the need for hospitalization due to HRS or other life-threatening complications. [Means for solving the problem]

[0005] overview In one aspect, the present disclosure relates to a method for treating a patient diagnosed with ascites due to cirrhosis, the method comprising administering terlipressin or a salt thereof as a continuous infusion, the patient's condition being such that the patient's condition has not progressed to HRS.

[0006] In another aspect, the present disclosure relates to a method for reducing the amount of ascites during an abdominal paracentesis procedure in a patient with ascites, the method comprising administering terlipressin or a salt thereof as a continuous infusion.

[0007] In yet another aspect, the present disclosure relates to a method for reducing the number of monthly paracentesis procedures in a patient with ascites, the method comprising administering terlipressin or a salt thereof as a continuous infusion.

[0008] Furthermore, the present disclosure relates to a method for improving renal function in a patient with ascites, the method comprising administering terlipressin or a salt thereof as a continuous infusion.

[0009] The present disclosure also relates to a method for treating hyponatremia in a patient with ascites, comprising administering terlipressin or a salt thereof to the patient as a continuous infusion.

[0010] In another aspect, the present disclosure relates to methods for improving the health status of ascites patients with cirrhosis due to Hepatitis C. The methods include methods comprising the administration of a Hepatitis C antiviral drug in combination with the administration of terlipressin or a salt thereof as a continuous infusion.

[0011] In another aspect, the disclosure relates to a method for improving Model for End-Stage Liver Disease (MELD) scores in patients with ascites, the method comprising administering terlipressin or a salt thereof by continuous infusion.

[0012] In each embodiment of the present invention, the patient's condition may not have progressed to HRS. The dose of terlipressin may range from about 1.0 mg to about 12.0 mg per day, and the dose of terlipressin may be increased stepwise during treatment. Furthermore, terlipressin may be administered for about 1 day to about 12 months. Furthermore, continuous terlipressin may be administered using a portable infusion pump. DETAILED DESCRIPTION OF THE INVENTION

[0013] explanation Terlipressin is a synthetic vasopressin approved in many countries outside the United States to treat life-threatening complications of cirrhosis, including hepatorenal syndrome (HRS) and esophageal bleeding (EBV). Its use is limited to hospital settings due to its short half-life (26 min) (Nilsson et al., 1990) and the need for intravenous bolus administration, typically every 4–6 hours. Furthermore, terlipressin can cause adverse reactions in up to 40% of patients. Severe adverse reactions, including myocardial infarction, arrhythmias, and intestinal infarction, can require treatment interruption in up to 10% of patients (Angeli, 2011). Indeed, due to its rapid vasoconstrictive properties, IV bolus-administered terlipressin should be used with caution in patients with severe asthma, severe hypertension, advanced atherosclerosis, cardiac arrhythmias, and coronary insufficiency.

[0014] In one aspect, the present disclosure relates to the administration of terlipressin or a salt thereof to treat patients with ascites, for example, due to advanced liver cirrhosis. These patients are typically not hospitalized (i.e., outpatients) and can include patients whose condition has not progressed to HRS type 2 (outpatient HRS patients) or HRS type 1 (requiring hospitalization). Treatment involves continuous infusion of terlipressin via a pump device, typically a portable, ambulatory pump, for several hours, which can continue for up to several days, weeks, or months. Treatment is effective in reducing or eliminating ascites in most patients on an outpatient basis.

[0015] Patients with cirrhosis and type 1 hepatorenal syndrome (HRS-1) have been safely treated with continuous terlipressin. Doses ranged from 2.0 mg to 12.0 mg per 24 hours (Angeli et al., 2009: 2 mg / 24 hours to 12 mg / 24 hours; Gerbes, 2009: starting dose). (Robertson, et al., 2014: 3 mg / day; Ding, 2013: 4 mg / day; Cavallin 2015: 3 mg / day–12 mg / day). However, none of these studies evaluated or reported on the effect of terlipressin infusion on ascites burden or the effect of continuous infusion terlipressin in patients whose condition had not progressed to HRS.

[0016] Ambulatory pumps are commonly used to infuse parenteral medications directly into the bloodstream via catheter to improve efficacy and / or reduce toxicity. This has been demonstrated in hospitalized hepatorenal syndrome (HRS) patients and patients with esophageal bleeding (EBV) using slow bolus IV injections. This has been found to be safer than approved terlipressin drug therapies, which require administering terlipressin to patients with glaucoma. Thus, in one embodiment of the present disclosure, terlipressin is continuously administered via a pump at an administration rate of about 0.5 mg to about 20 mg every 24 hours, more specifically, for example, about 1 mg to about 12 mg every 24 hours, and more specifically, for example, about 5 mg to about 15 mg every 24 hours, or, for example, about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg every 24 hours. Administration can typically continue for at least about one day and may continue for about 12 months or longer, if necessary, as a bridge for the patient until transplantation becomes possible. For example, administration can be continued for about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, or 12 months. Optionally, the dose of terlipressin is gradually increased during treatment. For example, a patient may begin treatment with 2 mg / day and increase the dose to 3 mg / day or up to 12 mg / day during treatment.

[0017] Thus, in various aspects, the present disclosure relates to a method for treating a patient diagnosed with ascites due to liver cirrhosis. The method can improve renal function in patients with ascites and reduce the amount of ascites during a paracentesis procedure in the patient. Furthermore, the method can be used to reduce the risk of spontaneous bacterial peritonitis, improve the Model for End-Stage Liver Disease (MELD) score in patients with ascites, and / or treat hyponatremia in patients with ascites. In another aspect, the method disclosed herein can be used in combination with a hepatitis C antiviral drug to improve the health status of patients with ascites and liver cirrhosis due to hepatitis C. In each case, terlipressin or a salt thereof is administered using a continuous infusion pump. In each of these aspects, the patient's ascites condition can be in a state that has not progressed to hepatorenal syndrome.

[0018] The use of ambulatory pump delivery for continuous infusion of terlipressin avoids the need for patient hospitalization and makes such therapy available to the majority of patients with ascites who are not already hospitalized with severe complications that often occur secondary to advanced ascites, such as postperitoneal paracentesis circulatory failure, HRS, EVB, hepatic encephalopathy, spontaneous bacterial peritonitis, and other life-threatening conditions. [Example]

[0019] The following is set forth for illustrative purposes only and is not intended to limit the scope of the disclosure, which has been broadly described above.

[0020] Example 1: Treatment of Ascites with Continuous Infusion Pump Terlipressin Therapy Fifteen subjects with confirmed cirrhotic ascites but not HRS type 1 or 2 were administered continuous low-dose (2.0 mg to 3.0 mg per 24 hours) terlipressin via ambulatory infusion pump. Over the course of 1 to 28 days of treatment, these patients are expected to experience a decrease in the severity and volume of ascites. This approach is also expected to reduce the number of paracentesis procedures required for ascites removal over a 28-day period compared with the 28-day period prior to treatment, potentially avoiding paracentesis entirely in some patients. Furthermore, the average volume of ascites removed after initiation of continuous infusion pump terlipressin therapy should be significantly less than before treatment. Furthermore, improvements in patient health can be safely achieved without serious side effects. Therefore, continuous infusion pump (CIP) terlipressin is a potentially life-saving solution for these critically ill patients who are still ambulatory (not yet hospitalized for treatment) and who do not have HRS type 1 or 2.

[0021] Example 2: Treatment of Ascites with Continuous Infusion Pump Terlipressin Therapy We evaluated the improvement of ascites in six patients with HRS treated with continuous infusion terlipressin. All patients had diuretic-refractory or diuretic-unresponsive ascites (five of six had hyponatremia). The following parameters were assessed before, during, and after treatment: number of paracentesis procedures per month, amount of ascites removed, body weight, serum sodium, urinary sodium excretion, serum creatinine, serum urea, and whether diuretics were included in the treatment plan. None of the six patients had a complete data set for all parameters. The effect of continuous infusion terlipressin on each parameter is shown in Tables 1–7.

[0022] Reduction in the frequency of abdominal paracentesis and amount of ascites during treatment The average number of paracentesis procedures per month decreased from three before the start of continuous infusion therapy to two during treatment, and the average amount of ascites removed per month decreased by 55%.

[0023] [Table 1]

[0024] Weight loss during treatment The average weight per patient, a proxy for ascites in the abdominal cavity, decreased by 11% or 9 kg (about 19.8 lbs).

[0025] [Table 2]

[0026] The need for diuretics to combat ascites During treatment, four of six patients experienced improvement in ascites without the need for diuretics.

[0027] [Table 3]

[0028] Increased urinary sodium excretion during treatment The observed improvements in ascites and renal function were further supported by a substantial increase in urinary sodium excretion. Mean urinary sodium increased from 7 mEq / 24 h to 127 mEq / 24 h in three of six patients recorded before and after initiation of continuous-infusion terlipressin therapy.

[0029] [Table 4]

[0030] Improvement of plasma sodium Treatment with continuous infusion terlipressin cured severe hyponatremia in two patients. Plasma Na increased by 15% in patient #4 and 19% in patient #6. Importantly, plasma sodium remained normal in patient #6 after treatment was discontinued ("post-treatment" data were available for one of the two patients).

[0031] [Table 5]

[0032] Reduction of blood urea during treatment Patient serum urea concentrations decreased by an average of 45% across all patients. This increase in urea clearance indicates improved renal function.

[0033] [Table 6]

[0034] Decreased serum creatinine Serum creatinine levels, a metabolic waste product, indicate kidney health. Treated patients experienced a mean 47% reduction in serum creatinine levels, which coincided with a reduction in serum urea, indicating improved kidney function and contributing to a reduction in the severity of ascites.

[0035] [Table 7]

[0036] All references cited in this disclosure are hereby incorporated by reference. Nilsson, G. et al., 1990. Nilsson G, Lindblom P, OhlPharmacokinetics of Terlipressin After Single iv Doses to Healthy Volunteers. Drugs Under Experimental and Clinical Research, Volume 16, pp. 307-314. Angeli, P., 2011. Terlipressin for Hepatorenal Syndrome: Novel Strategies and Future Perspectives. Frontiers of Gastrointestinal Research, Volume 28, pp.198-197. Angeli, P. et al., 2009. Terlipressin Given as Continuous Intravenous Infusion Versus Terlipressin Given as Intravenous Boluses in the Treatment of Type 1 Hepatorenal Syndrome (HRS) in Patients with Cirrhosis. Journal of Hepatology, 50(Supplement 1), p.S73. Gerbes AL, Huber E, Guelberg V. 2009 Terlipressin for hepatorenal syndrome: continuous innfusion as an alternative to iv bolus administration. 2009 Gastroenterology. 137 (3): 1179; author reply 1179-81 Ding, C. et al., 2013. Hemodynamic effects of continuous versus bolus infusion of terlipressin for portal hypertension: A randomized comparison. Journal of Gastroenterology and Hepatology, 28(7), pp.1242-1246. Robertson, M. et al., 2014. Continuous outpatient terlipressin infusion for hepatorenal syndrome as a bridge to successful liver transplantation. Hepatology Mar 2014. Hepatology, Volume March, pp.1-2. Cavallin M, et al., 2015 Terlipressin Plus Alubmin Versus Midodrine and Octreotide Plus Alubmin in the Treatmentn of Hepatorenal Syndrome: A Randomized Trial. Hepatology, 2015 (in press) Fimiani, B. et al., 2011. The Use of Terlipressin in Cirrhotic Patients with Refractory Ascites and Normal Renal Function: A Multicentric Study. European Journal of Internal Medicine, Volume 22, pp. 587-590. Krag, A. et al., 2007. Telipressin Improves Renal Function in Patients with Cirrhosis and Ascites Without Hepatorenal Syndrome. Hepatology, 46(6), pp.1863-1871.

[0037] Although various specific embodiments of the present disclosure have been described herein, it should be understood that the disclosure is not limited to those precise embodiments, and that those skilled in the art may make various changes or modifications without departing from the scope and spirit of the present disclosure.

Claims

1. A pharmaceutical composition comprising terlipressin or a salt thereof for reducing the risk of spontaneous bacterial peritonitis, improving Model for End-Stage Liver Disease (MELD) scores, and / or treating hyponatremia in patients with ascites, wherein the pharmaceutical composition is administered as a continuous infusion dose ranging from 1.0 mg to 12.0 mg of terlipressin or a salt thereof per day.

2. A pharmaceutical composition comprising terlipressin or a salt thereof for treating a patient with ascites due to cirrhosis, wherein the patient has not developed at least one severe complication of advanced ascites, including esophageal bleeding (EVB), hepatic encephalopathy, and spontaneous bacterial peritonitis, and the pharmaceutical composition is administered as a continuous infusion dose of terlipressin or a salt thereof in the range of 1.0 mg to 12.0 mg per day.

3. A pharmaceutical composition comprising terlipressin or a salt thereof for treating a patient with ascites due to cirrhosis, wherein the patient is not experiencing esophageal bleeding (EVB), and the pharmaceutical composition is administered as a continuous infusion dose ranging from 1.0 mg to 12.0 mg of terlipressin or a salt thereof per day.

4. A pharmaceutical composition comprising terlipressin or a salt thereof for treating a patient with ascites due to cirrhosis, wherein the patient does not have hepatic encephalopathy, and the pharmaceutical composition is administered as a continuous infusion dose ranging from 1.0 mg to 12.0 mg of terlipressin or a salt thereof per day.

5. A pharmaceutical composition comprising terlipressin or a salt thereof for treating a patient with ascites due to cirrhosis, wherein the patient does not have spontaneous bacterial peritonitis, and the pharmaceutical composition is administered as a continuous infusion dose ranging from 1.0 mg to 12.0 mg of terlipressin or a salt thereof per day.

6. A pharmaceutical composition according to any one of claims 2 to 5, wherein administration of the pharmaceutical composition delays hospitalization of the patient.

7. A pharmaceutical composition described in any one of claims 1 to 6, wherein administration of the pharmaceutical composition is continued until liver transplantation is possible.

8. The pharmaceutical composition described in claim 7, wherein administration continues for at least about 1 day and may continue for about 12 months.

9. A pharmaceutical composition described in any one of claims 1 to 8, wherein the patient is an outpatient.

10. A pharmaceutical composition described in any one of claims 1 to 9, wherein the patient does not develop type 1 hepatorenal syndrome (HRS).

11. A pharmaceutical composition described in any one of claims 1 to 9, wherein the patient does not develop type 2 HRS.

12. A pharmaceutical composition described in any one of claims 1 to 11, wherein the continuous infusion is about 2 mg to 3 mg of terlipressin per day.

13. A pharmaceutical composition described in any one of claims 1 to 12, wherein the continuous infusion is about 3 mg of terlipressin per day.

14. The pharmaceutical composition of any one of claims 1 to 13, wherein the continuous infusion is administered by a portable infusion pump.

15. A pharmaceutical composition described in any one of claims 1 to 14, wherein the period of continuous infusion is from about 1 day to about 12 months.

16. A pharmaceutical composition described in any one of claims 1 to 15, wherein continuous infusion is provided on an outpatient basis.

17. A pharmaceutical composition described in any one of claims 1 or 9 to 16, wherein the reduction in the risk of spontaneous bacterial peritonitis includes a reduction in serum creatinine levels.

18. A pharmaceutical composition described in any one of claims 1 or 9 to 16, wherein the reduction in the risk of spontaneous bacterial peritonitis includes an increase in urinary sodium excretion.