Evaluation of the Potential for Cytochrome P450 and Transporter-Mediated Drug-Drug Interactions for Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor (FXR) Agonist.

Abstract

BACKGROUND AND OBJECTIVE:

Cilofexor is a selective farnesoid X receptor (FXR) agonist in development for the treatment of nonalcoholic steatohepatitis and primary sclerosing cholangitis. Our objective was to evaluate potential drug-drug interactions of cilofexor as a victim and as a perpetrator.

METHODS:

In this Phase 1 study, healthy adult participants (n = 18-24 per each of the 6 cohorts) were administered cilofexor in combination with either perpetrators or substrates of cytochrome P-450 (CYP) enzymes and drug transporters.

RESULTS:

In total, 131 participants completed the study. As a victim, cilofexor area under the curve (AUC) was 651%, 795%, and 175% when administered following single-dose cyclosporine (600 mg; organic anion transporting polypeptide [OATP]/P-glycoprotein [P-gp]/CYP3A inhibitor), single-dose rifampin (600 mg; OATP1B1/1B3 inhibitor), and multiple-dose gemfibrozil (600 mg twice daily [BID]; CYP2C8 inhibitor), respectively, compared with the administration of cilofexor alone. Cilofexor AUC was 33% when administered following multiple-dose rifampin (600 mg; OATP/CYP/P-gp inducer). Multiple-dose voriconazole (200 mg BID; CYP3A4 inhibitor) and grapefruit juice (16 ounces; intestinal OATP inhibitor) did not affect cilofexor exposure. As a perpetrator, multiple-dose cilofexor did not affect the exposure of midazolam (2 mg; CYP3A substrate), pravastatin (40 mg; OATP substrate), or dabigatran etexilate (75 mg; intestinal P-gp substrate), but atorvastatin (10 mg; OATP/CYP3A4 substrate) AUC was 139% compared with atorvastatin administered alone.

CONCLUSION:

Cilofexor may be coadministered with inhibitors of P-gp, CYP3A4, or CYP2C8 without the need for dose modification. Cilofexor may be coadministered with OATP, BCRP, P-gp, and/or CYP3A4 substrates-including statins-without dose modification. However, coadministration of cilofexor with strong hepatic OATP inhibitors, or with strong or moderate inducers of OATP/CYP2C8, is not recommended.

• Authors: Islam Younis, Elijah Weber, Cara Nelson, Brian J Kirby, Gong Shen, Deqing Xiao, Timothy R Watkins, Ahmed A Othman
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 62 Issue 4 Pg. 609-621 (04 2023) ISSN: 1179-1926 [Electronic] Switzerland
• PMID: 36906733 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s).

Chemical References

• Rifampin
• Cytochrome P-450 CYP2C8
• cilofexor
• Cytochrome P-450 CYP3A
• Atorvastatin
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Neoplasm Proteins
• Pharmaceutical Preparations
• Cytochrome P-450 Enzyme System
• Membrane Transport Proteins
• Cytochrome P-450 CYP3A Inhibitors
• Organic Anion Transporters

Topics

• Adult
• Humans
• Rifampin
• Cytochrome P-450 CYP2C8
• Cytochrome P-450 CYP3A (metabolism)
• Atorvastatin
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Neoplasm Proteins
• Pharmaceutical Preparations
• Drug Interactions
• Cytochrome P-450 Enzyme System
• Membrane Transport Proteins
• Cytochrome P-450 CYP3A Inhibitors (pharmacology)
• Organic Anion Transporters