METHODS AND COMPOSITIONS FOR IMPROVING KIDNEY FUNCTION IN PATIENTS WITH HEPATORENAL SYNDROME
The principles and embodiments of the present disclosure relate to methods for using terlipressin to treat a patient having impaired renal function associated with liver disease. A method of improving kidney function in an adult patient with hepatorenal syndrome with rapid reduction in kidney function may include determining the patient’s acute-on-chronic liver failure (ACLF) grade and baseline serum creatinine level; obtaining a baseline oxygenation saturation (SpO 2 ) of the patient; administering a dose of terlipressin acetate to the patient by intravenous (IV) injection; and monitoring the patient’s oxygenation saturation with pulse oximetry.
1 . A method of improving kidney function in an adult patient with hepatorenal syndrome with rapid reduction in kidney function comprising administering a 1 mg IV injection of terlipressin acetate to a patient in need thereof, wherein the administering provides a derived typical population PK parameter of clearance for terlipressin of 27.4 L/hr and a derived typical population PK parameter of clearance for lysine-vasopressin of 318 L/hr.
2 . The method of claim 1 , 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 , wherein n is 2.8.
3 . A method of improving kidney function in an adult patient with hepatorenal syndrome with rapid reduction in kidney function comprising administering a 1 mg IV injection of terlipressin acetate to a patient in need thereof, wherein the administering provides a C max of 70.5 ng/mL at steady state, a AUC 24h of 123 ng×hr/mL, and a C ave of 14.2 ng/mL.
4 . The method of claim 3 , 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 , wherein n is 2.8.
5 . A method of improving kidney function in an adult patient with hepatorenal syndrome with rapid reduction in kidney function comprising:
administering a 1 mg dose of a composition comprising terlipressin acetate to the patient by intravenous (IV) injection,
wherein the composition and lysine-vasopressin exhibit linear pharmacokinetics and plasma concentrations of terlipressin demonstrate proportional increases with the dose administered.
6 . The method of claim 5 , 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 , wherein n is 2.8.
7 . The method of claim 5 , wherein the dose of the composition provides a C max of 37.06 ng/mL to 142.92 ng/mL.
8 . The method of claim 7 , wherein the dose of the composition provides a mean C max of about 70.5 ng/mL.
9 . The method of claim 5 , wherein the dose of the composition provides a C ave of 8.34 ng/mL to 22.92 ng/mL.
10 . The method of claim 9 , wherein the dose of the composition provides a mean C ave of about 14.2 ng/mL.
11 . The method of claim 5 , wherein the dose of the composition provides an AUC 24h of 61.21 ng×hr/mL to 245.86 ng×hr/mL.
12 . The method of claim 11 , wherein the dose of the composition provides a mean AUC 24h of about 123 ng×hr/mL.
13 . The method of claim 5 , wherein the lysine-vasopressin provides a C max of 0.40 ng/mL to 3.36 ng/mL.
14 . The method of claim 13 , wherein the lysine-vasopressin provides a mean C max of about 1.2 ng/mL.
15 . The method of claim 5 , wherein the lysine-vasopressin provides a C ave of 0.188 ng/mL to 1.49 ng/mL.
16 . The method of claim 15 , wherein the lysine-vasopressin provides a mean C ave of about 0.5 ng/mL.
17 . The method of claim 5 , wherein the lysine-vasopressin provides an AUC 24h 3.78 ng×hr/mL to 33.49 ng×hr/mL.
18 . The method of claim 17 , wherein the lysine-vasopressin provides a mean AUC 24h of 11.2 ng×hr/mL.
19 . The method of claim 5 , wherein a derived typical population PK parameter of clearance for terlipressin is 24.8 L/hr to 31.1 L/hr.
20 . The method of claim 19 , wherein a mean typical population PK parameter of clearance for terlipressin is about 27.4 L/hr.
21 . The method of claim 5 , wherein a typical population PK parameter of clearance for lysine-vasopressin is 283 L/hr to 363 L/hr.
22 . The method of claim 21 , wherein a mean typical population PK parameter of clearance for lysine-vasopressin is about 318 L/hr.
23 . The method of claim 5 , wherein a terminal half-life of terlipressin is about 0.9 hours.
24 . The method of claim 5 , wherein a terminal half-life for lysine-vasopressin is about 3 hours.
25 . The method of claim 5 , wherein there are no dose-dependent changes in the elimination rate constant of terlipressin in a healthy patient.