Effect of Renal Impairment on the Pharmacokinetics of Firsocostat, an Acetyl-CoA Carboxylase (ACC) Inhibitor, and Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor (FXR) Agonist.

Firsocostat, a liver-targeted acetyl-CoA carboxylase inhibitor, and cilofexor, a nonsteroidal farnesoid X receptor agonist, are being developed in combination for treatment of nonalcoholic steatohepatitis. This Phase 1 study evaluated firsocostat and cilofexor pharmacokinetics and tolerability in participants with severe renal impairment (SRI) and healthy matched controls (HMCs). Ten participants with SRI (estimated glomerular filtration rate by Modification of Diet in Renal Disease [eGFR MDRD ] <30 mL/min/1.73 m 2 ) and 10 HMCs received single oral doses of firsocostat (20 mg) on Day 1 and cilofexor (100 mg) on Day 7 in a fasted state. Plasma concentrations of firsocostat (and nonactive metabolite GS-834773) and cilofexor (and nonactive metabolites GS-716070 and GS-1056756) were collected over 96 hours and quantified; plasma exposures (area under the concentration-time curve [AUC] and peak concentration [C max ]) and plasma protein binding was characterized. Firsocostat AUC was approximately 40% higher in SRI vs HMC, while C max was 8% lower. Observed exposures of the firsocostat metabolite were approximately 4.6-fold higher in SRI participants vs HMC. Exposures (AUC and C max ) of cilofexor and metabolites and percentages of protein binding of all analytes were similar between SRI and HMC groups. Treatment-emergent adverse events were generally mild and not considered related to study drug. A <50% increase in firsocostat exposure was observed among SRI participants but was deemed not clinically relevant. There was no apparent effect of SRI on cilofexor exposure. Based on this trial, firsocostat and cilofexor dosing are not expected to require modification in renally impaired patients. This article is protected by copyright. All rights reserved.