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

Autor: Weber EJ; Gilead Sciences, Inc., Foster City, CA, USA., Younis IR; Gilead Sciences, Inc., Foster City, CA, USA., Wang L; Gilead Sciences, Inc., Foster City, CA, USA., Xiao D; Gilead Sciences, Inc., Foster City, CA, USA., Barchuk WT; Gilead Sciences, Inc., Foster City, CA, USA., Othman AA; Gilead Sciences, Inc., Foster City, CA, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacology in drug development [Clin Pharmacol Drug Dev] 2024 Jun; Vol. 13 (6), pp. 677-687. Date of Electronic Publication: 2024 Feb 12.
DOI: 10.1002/cpdd.1384
Abstrakt: 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 C max by 6.1-fold, while omeprazole increased cilofexor AUC by 3.1-fold and C max by 4.8-fold. With a low-fat meal, omeprazole increased cilofexor exposure to a lesser extent (C max 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.
(© 2024 Gilead Sciences, Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
Databáze: MEDLINE
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