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

Abstract

Cilofexor is a nonsteroidal farnesoid X receptor agonist being developed in combination with firsocostat/semaglutide for the treatment of nonalcoholic steatohepatitis. This phase 1 study evaluated the effects of food and acid‐reducing agents (ARAs) on the pharmacokinetics of cilofexor (100‐ or 30‐mg fixed‐dose combination with firsocostat) in healthy participants. Cohorts 1 (n = 20, 100 mg) and 2 (n = 30, 30 mg) followed a 3‐period, 2‐sequence crossover design and evaluated effects of light‐fat and high‐fat meals. Cohort 3 (n = 30, 100 mg fasting) followed a 2‐period, 2‐sequence crossover design and evaluated the effects of a 40‐mg single dose of famotidine. Cohort 4 (n = 18, 100 mg) followed a 3‐period, 2‐sequence crossover design and evaluated the effects of a 40‐mg once‐daily regimen of omeprazole administered under fasting conditions or following a light‐fat meal. Administration with light‐fat or high‐fat meals resulted in no change and an ∼35% reduction in cilofexor AUC, respectively, relative to the fasting conditions. Under fasting conditions, famotidine increased cilofexor AUC by 3.2‐fold and Cmax by 6.1‐fold, while omeprazole increased cilofexor AUC by 3.1‐fold and Cmax by 4.8‐fold. With a low‐fat meal, omeprazole increased cilofexor exposure to a lesser extent (Cmax 2.5‐fold, AUC 2.1‐fold) than fasting conditions. This study suggests that caution should be exercised when cilofexor is administered with ARAs under fed conditions; coadministration of cilofexor (100 or 30 mg) with ARAs under fasting conditions is not recommended with the current clinical trial formulations.