Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA, 94404, USA.
Clin Pharmacokinet. 2023 Apr;62(4):609-621. doi: 10.1007/s40262-023-01214-w. Epub 2023 Mar 11.
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.
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.
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.
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.
西洛非司他是一种正在开发用于治疗非酒精性脂肪性肝炎和原发性硬化性胆管炎的选择性法尼醇 X 受体（FXR）激动剂。我们的目的是评估西洛非司他作为受害者和肇事者的潜在药物相互作用。
在这项 I 期研究中，健康成年参与者（每组 18-24 人，共 6 个队列）接受西洛非司他联合细胞色素 P-450（CYP）酶和药物转运体的肇事者或底物给药。
共有 131 名参与者完成了研究。作为受害者，当与单剂量环孢素（600 mg；有机阴离子转运多肽[OATP]/P-糖蛋白[P-gp]/CYP3A 抑制剂）、单剂量利福平（600 mg；OATP1B1/1B3 抑制剂）和多剂量吉非贝齐（600 mg 每日 2 次[BID]；CYP2C8 抑制剂）联合给药时，西洛非司他的 AUC 分别为 651%、795%和 175%，与单独给予西洛非司他相比。当与多剂量利福平（600 mg；OATP/CYP/P-gp 诱导剂）联合给药时，西洛非司他的 AUC 为 33%。多剂量伏立康唑（200 mg BID；CYP3A4 抑制剂）和葡萄柚汁（16 盎司；肠道 OATP 抑制剂）不影响西洛非司他的暴露。作为肇事者，多剂量西洛非司他不影响咪达唑仑（2 mg；CYP3A 底物）、普伐他汀（40 mg；OATP 底物）或达比加群酯（75 mg；肠道 P-gp 底物）的暴露，但阿托伐他汀（10 mg；OATP/CYP3A4 底物）的 AUC 与单独给予阿托伐他汀相比增加了 139%。
西洛非司他可与 P-gp、CYP3A4 或 CYP2C8 的抑制剂联合使用，无需调整剂量。西洛非司他可与 OATP、BCRP、P-gp 和/或 CYP3A4 底物（包括他汀类药物）联合使用，无需调整剂量。然而，不建议将西洛非司他与强效肝 OATP 抑制剂联合使用，或与强效或中度的 OATP/CYP2C8 诱导剂联合使用。
