Pharmacokinetic, Safety, and Pharmacodynamic Profiles of Saroglitazar Magnesium in Cholestatic Cirrhosis With Hepatic Impairment and Participants With Renal Impairment

Abstract

Saroglitazar magnesium, a dual PPAR α/γ agonist, currently in Phase III for treating primary biliary cholangitis (PBC), was evaluated for its pharmacokinetic (PK) profile, safety, and pharmacodynamics in participants with cholestatic liver disease (CLD) across different levels of hepatic impairment (HI) and participants with severe renal impairment (RI). Three PK studies comparing saroglitazar with healthy controls were conducted: Study 1 involved daily oral doses of 1 or 2 mg for 4 weeks in 12 PBC cirrhosis participants with mild or moderate HI; Study 2 assessed single-dose PK (2 or 4 mg) in eight non-cirrhotic CLD participants; Study 3 evaluated single-dose PK (2 mg) in eight participants with severe RI. On day 1, saroglitazar exposure increased by 14.6-42% in mild HI vs. normal, but by day 28, levels were similar, indicating no accumulation. In moderate HI, exposure was significantly increased by 50.4-85% on days 1 and 28, with 34-46% lower clearance despite a similar half-life. The moderate HI group had a 59% higher exposure than the non-cirrhotic group. Saroglitazar (1 and 2 mg) reduced alkaline phosphatase (ALP) levels by 17-40% after 4 weeks in participants with abnormal baseline ALP. Single-dose PK in non-cirrhotic CLD (2 and 4 mg) and severe RI (2 mg) was comparable to matched controls without significant safety issues. Overall, saroglitazar (1 and 2 mg) was safe and well-tolerated in cholestatic cirrhosis with mild HI and participants with severe RI without major PK changes. Moderate HI increased exposure and decreased clearance without any safety concerns.

Figure 1

Comparison of C _max (ng/mL) and AUC (ng/mL hour) of saroglitazar in patients with mild or moderate hepatic impairment with participants with normal hepatic function at day 1 and day 28. Days 1 and 28 AUCs represent AUC_0–∞ and AUC_τ, respectively.

Figure 2

Comparison of MELD‐NA scores with C _max (a) and AUC_tau (b) of patients with mild and moderate hepatic impairment and participants with normal hepatic function after normalizing 1 and 2 mg doses at day 28.

Figure 3

Changes in mean ALP levels after 1 mg (N = 4) or 2 mg (N = 3) saroglitazar magnesium treatment for 2 or 4 weeks in participants with baseline ALP at > ULN. Error bars represent observed standard deviations.

Figure 4

(a) Mean plasma concentration (ng/mL) vs. time (hour) plots after single saroglitazar magnesium dose of 1, 2, and 4 mg in patients recruited in two different parts (Part A and Part B) of SARO.19.003 study. (b) Semi‐log representation. Analyte: Saroglitazar Parent Drug.