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Evaluation of the Potential for Cytochrome P450 and Transporter-Mediated Drug-Drug Interactions for Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor (FXR) Agonist.
- Source :
-
Clinical pharmacokinetics [Clin Pharmacokinet] 2023 Apr; Vol. 62 (4), pp. 609-621. Date of Electronic Publication: 2023 Mar 11. - Publication Year :
- 2023
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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.<br />Methods: In this Phase 1 study, healthy adult participants (nā=ā18-24 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.<br />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.<br />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.<br /> (© 2023. The Author(s).)
- Subjects :
- Adult
Humans
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
Rifampin
Organic Anion Transporters
Subjects
Details
- Language :
- English
- ISSN :
- 1179-1926
- Volume :
- 62
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Clinical pharmacokinetics
- Publication Type :
- Academic Journal
- Accession number :
- 36906733
- Full Text :
- https://doi.org/10.1007/s40262-023-01214-w