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.

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Firsocostat, a liver-targeted acetyl-coenzyme A carboxylase inhibitor, and cilofexor, a nonsteroidal farnesoid X receptor agonist, are being developed in combination for treatment of nonalcoholic steatohepatitis. This phase 1 study evaluated firsocostat and cilofexor pharmacokinetics and tolerability in participants with severe renal impairment (SRI) and healthy matched controls (HMCs). Ten participants with SRI (estimated glomerular filtration rate by Modification of Diet in Renal Disease <30 mL/min/1.73 m 2 ), and 10 HMCs received single oral doses of firsocostat (20 mg) on day 1 and cilofexor (100 mg) on day 7 in a fasted state. Plasma concentrations of firsocostat (and nonactive metabolite GS-834773) and cilofexor (and nonactive metabolites GS-716070 and GS-1056756) were collected over 96 hours and quantified; plasma exposures (area under the concentration-time curve [AUC] and peak concentration [C max ]) and plasma protein binding were characterized. Firsocostat AUC was ≈40% higher in SRI versus HMC, while C max was 8% lower. Observed exposures of the firsocostat metabolite were ≈4.6-fold higher in SRI participants versus HMC. Exposures (AUC and C max ) of cilofexor and metabolites and percentages of protein binding of all analytes were similar between SRI and HMC groups. Treatment-emergent adverse events were generally mild and not considered related to study drug. A <50% increase in firsocostat exposure was observed among SRI participants but was deemed not clinically relevant. There was no apparent effect of SRI on cilofexor exposure. Based on this trial, firsocostat and cilofexor dosing are not expected to require modification in patients who are renally impaired.