COMPOSITIONS FOR IMPROVING KIDNEY FUNCTION IN PATIENTS WITH HEPATORENAL SYNDROME
The principles and embodiments of the present disclosure relate to a composition for improving kidney function in an adult patient with hepatorenal syndrome with rapid reduction in kidney function. The composition includes terlipressin acetate having a formula of C 52 H 74 N 16 O 15 S 2 ·(C 2 H 4 O 2 ) n , where n is 2.8.
1 . A method for improve kidney function in an adult patient with hepatorenal syndrome with rapid reduction in kidney function, the method comprising:
reconstituting a lyophilized composition comprising terlipressin acetate and glacial acetic acid in sodium chloride, wherein the terlipressin acetate has a formula of C 52 H 74 N 16 O 15 S 2 ·(C 2 H 4 O 2 ) n , and wherein n is 2.8; and
administering the reconstituted composition by slow intravenous (IV) bolus injection over 2 minutes.
2 . The method of claim 1 , further comprising achieving a verified HRS reversal in the adult patient 29.1% of the time.
3 . The method of claim 2 , wherein verified HRS reversal comprises 2 consecutive SCr values of ≤1.5 mg/dL, obtained at least 2 hours apart while on treatment by day 14 or discharge.
4 . The method of claim 1 , further comprising achieving a durability of HRS reversal in the adult patient 31.7% of the time.
5 . The method of claim 4 , wherein durability of HRS reversal comprises an absence of renal replacement therapy (RRT) for at least 10 days.
6 . The method of claim 1 , further comprising achieving a verified HRS reversal without HRS recurrence by day 30 in the adult patient 24.1% of the time.
7 . The method of claim 1 , wherein the patient is administered a dose of 1 mg terlipressin acetate every 6 hours for a period of up to 14 days and no clinically meaningful changes in QTc from baseline are detected based on a Fridericia correction method.
8 . The method of claim 1 , further comprising 19.5% or less occurrence in the adult patient of a side effect selected from abdominal pain, nausea, respiratory failure, diarrhea, or dyspnea.
9 . The method of claim 1 , further comprising achieving a median C max of 70.5 ng/ml wherein the terlipressin acetate dosage is 1.0 mg.
10 . The method of claim 1 , further comprising achieving an AUC 24 h of 23 ng×hr/mL wherein the terlipressin acetate dosage is 1.0 mg.
11 . The method of claim 1 , further comprising achieving a C ave of 14.2 ng/ml wherein the terlipressin acetate dosage is 1.0 mg.
12 . The method of claim 1 , wherein the initial the terlipressin acetate dose is 1.0 mg.
13 . The method of claim 12 , further comprising increasing the dose to 2 mg terlipressin acetate at day 4.
14 . The method of claim 1 , further comprising obtaining a baseline oxygen saturation (SpO 2 ) prior to administering the composition.
15 . The method of claim 14 , wherein the composition is not administered if the SpO 2 is <90%.
16 . The method of claim 15 , wherein the composition is administered if the SpO 2 improves to ≥90%.
17 . The method of claim 16 , further comprising continuously monitoring oxygen saturation during administration using continuous pulse oximetry.
18 . The method of claim 17 , wherein administration is discontinued if the SpO 2 decreases below 90%.
19 . The method of claim 1 , wherein a patient with a serum creatinine>5 mg/dl is unlikely to experience benefit.
20 . The method of claim 19 , further comprising assessing the serum creatinine of the patient before administering, wherein the composition is not administered if the patient has a serum creatinine>5 mg/dL.
21 . The method of claim 1 , wherein a patient with volume overload or with acute-on-chronic liver failure (ACLF) Grade 3 is at increased risk.
22 . The method of claim 21 , further comprising assessing the ACLF Grade of the patient before administering, wherein the composition is not administered if the patient is ACLF Grade 3.
23 . The method of claim 1 , wherein following a 1 mg IV injection of terlipressin acetate to the adult patient, the median C max , AUC 24 h and C ave of terlipressin at steady state is 70.5 ng/ml, 123 ng×hr/mL and 14.2 ng/ml, respectively.
24 . A method for improving kidney function in an adult patient with hepatorenal syndrome with rapid reduction in kidney function, the method comprising:
obtaining a baseline oxygen saturation (SpO 2 ) of the patient;
administering intravenously by bolus injection every 6 hours a composition comprising terlipressin acetate having a formula of C 52 H 74 N 16 O 15 S 2 ·(C 2 H 4 O 2 ) n , wherein n is 2.8; and
continuously monitoring the SpO 2 of the patient during administration of the composition,
wherein the composition is not administered or the administration is discontinued if the SpO 2 is below 90%.
25 . The method of claim 24 , wherein administering occurs from days 1 to 3.
26 . The method of claim 24 , further comprising assessing the serum creatinine of the patient before administering, wherein the composition is not administered if the patient has a serum creatinine>5 mg/dL.
27 . The method of claim 24 , further comprising assessing the ACLF Grade of the patient before administering, wherein the composition is not administered if the patient is ACLF Grade 3.
28 . The method of claim 24 , wherein following a 1 mg IV injection of terlipressin acetate to the adult patient, the median C max , AUC 24 h and C ave of terlipressin at steady state is 70.5 ng/ml, 123 ng×hr/mL and 14.2 ng/ml, respectively.