Effect of Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist.

Abstract

Cilofexor is a nonsteroidal farnesoid X receptor agonist in clinical development for treatment of nonalcoholic steatohepatitis. This work characterized the pharmacokinetics, pharmacodynamics, safety, and tolerability of cilofexor in participants with normal hepatic function or hepatic impairment (HI). Participants with stable mild, moderate, or severe HI (Child-Pugh [CP] A, B, or C, respectively, [n = 10/group]) and healthy matched controls with normal hepatic function received a single oral dose of cilofexor (30 mg for CP-A or B; 10 mg for CP-C) with a standardized meal. Overall, 56 participants received cilofexor and completed the study. Cilofexor area under the plasma concentration-time curve was 76%, 2.5-fold, and 6.3-fold higher in participants with mild, moderate, or severe HI, respectively, relative to the area under the plasma concentration-time curve in matched participants with normal hepatic function. Cilofexor unbound fraction was 38%, 2-fold, and 3.16-fold higher in participants with mild, moderate, and severe HI, respectively, relative to participants with normal hepatic function. Moderate correlations were identified between cilofexor exposure and CP score or laboratory tests components of CP score. Serum 7α-hydroxy-4-cholesten-3-one and plasma fibroblast growth factor 19 were similar in participants with mild, moderate, or severe HI and participants with normal hepatic function. Cilofexor was generally well tolerated; all cilofexor-related adverse events were mild in severity. Cilofexor can be administered to patients with mild HI without dose adjustment. Caution and dose modification are warranted when administering cilofexor to patients with moderate or severe HI.

• Authors: Islam R Younis, Chia-Hsiang Hsueh, Cara Nelson, Andrew N Billin, Mun Sang Yue, Deqing Xiao, Timothy R Watkins, Ahmed A Othman
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 63 Issue 9 Pg. 1017-1025 (09 2023) ISSN: 1552-4604 [Electronic] England
• PMID: 37128693 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 Gilead Sciences, Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Chemical References

• cilofexor

Topics

• Humans
• Area Under Curve
• Liver Diseases (metabolism)