Effect of Renal Impairment on the Pharmacokinetics of Firsocostat, an Acetyl‐Coenzyme A Carboxylase Inhibitor, and Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist

Abstract

Firsocostat, a liver-targeted acetyl-coenzyme A 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 <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 were characterized. Firsocostat AUC was ≈40% higher in SRI versus HMC, while C max was 8% lower. Observed exposures of the firsocostat metabolite were ≈4.6-fold higher in SRI participants versus 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 patients who are renally impaired.

Evaluation of the Effects of Meal Type and Acid‐Reducing Agents on the Pharmacokinetics of Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist

“…Participants in cohort 1 (n = 20) were randomized 1:1 to receive cilofexor 100 mg administered under nonfasting conditions with either a light-fat meal (approximately 400 kcal with about 20% of the calories from fat) or a high-fat meal (approximately 800-1000 kcal with about 50% of the calories from fat) and under fasting conditions (no food or drink consumption, except for water, for at least 10 hours overnight) in 1 of 2 treatment sequences. A washout period of 7 days occurred between each treatment period (on days 2-8 and days [10][11][12][13][14][15][16].…”

“…9 The pharmacokinetics of cilofexor have been previously characterized in healthy participants (10-300 mg dose range) and participants with hepatic impairment (10 or 30 mg dose) or renal impairment (100 mg dose). [10][11][12] In plasma, cilofexor is highly protein bound (>99%) and cilofexor exposures are approximately dose proportional across the dose range of 30-100 mg; however, they are less than dose proportional from 10 to 300 mg, which is likely due to pH-dependent solubility. 10 In vitro data indicate that cilofexor exhibits low and pH-dependent solubility (data on file, Gilead Sciences, Inc.).…”

Herb-drug interactions of silybinin and cilofexor in beagle dogs based on pharmacokinetics by UPLC-MS/MS

“…In the HMCs group, Cilofexor was rapidly absorbed, whereas in the SRI group, its Tmax was longer and Cmax slightly lower. AUC last and AUC inf of Cilofexor were similar between participants with SRI and HMCs ( Weber et al, 2023 ). In another report it was demonstrated that a plateau in intestinal FXR activation was reached at Cilofexor doses greater than or equal to 30 mg (showing good safety and tolerability between doses of 10–300 mg).…”

Pharmacokinetics and Safety of Firsocostat, an Acetyl‐Coenzyme A Carboxylase Inhibitor, in Participants with Mild, Moderate, and Severe Hepatic Impairment

“…Dose‐proportional pharmacokinetic profiles of firsocostat were observed in studies following single‐dose administration of 30 to 500 mg in healthy participants 12 and multiple‐dose administration of 20 to 200 mg in healthy participants 10,13 . Firsocostat elimination half‐life was approximately 5 to 7 h in healthy volunteers 13,14 . More than 90% of the firsocostat dose is eliminated in feces 13 .…”

“…This proportion mainly comprises unchanged firsocostat (44% of the administered dose), the desethylene–firsocostat–amide metabolite (18% of the administered dose; produced via oxidation/N‐dealkylation), and several trace metabolites (each accounting for 1% to 6% of the administered dose; Gilead Sciences, Inc., data on file). Firsocostat is metabolized by uridine diphospho‐glucuronosyltransferase (UGT) 1A3, 1A8, and 1A1 13 and to a lesser extent by cytochrome P450 (CYP) 3A 14 . The glucuronide conjugate of firsocostat is also an inhibitor of ACC1 and ACC2 but is much less potent than firsocostat 14 .…”