Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
Gossamer Bio, San Diego, California, USA.
Clin Transl Sci. 2019 May;12(3):267-275. doi: 10.1111/cts.12610. Epub 2019 Jan 29.
Drug-drug interaction (DDI) studies are described for tezacaftor/ivacaftor, a new cystic fibrosis transmembrane conductance regulator modulator therapy for the treatment of cystic fibrosis. Three phase I DDI studies were conducted in healthy subjects to characterize the DDI profile of tezacaftor/ivacaftor with cytochrome P450 (CYP)3A substrates, CYP3A inhibitors, and a permeability glycoprotein (P-gp) substrate. The effects of steady-state tezacaftor/ivacaftor on the pharmacokinetics (PKs) of digoxin (a P-gp substrate), midazolam, and ethinyl estradiol/norethindrone (CYP3A substrates) were evaluated. Effects of strong (itraconazole) and moderate (ciprofloxacin) CYP3A inhibitors on tezacaftor/ivacaftor PKs were also determined. Tezacaftor/ivacaftor increased digoxin area under the curve (AUC) by 30% but did not affect midazolam, ethinyl estradiol, or norethindrone exposures. Itraconazole increased the AUC of tezacaftor 4-fold and ivacaftor 15.6-fold. Ciprofloxacin had no significant effect on tezacaftor or ivacaftor exposure. Coadministration of tezacaftor/ivacaftor may increase exposure of sensitive P-gp substrates. Tezacaftor/ivacaftor is unlikely to impact exposure of drugs metabolized by CYP3A, including hormonal contraceptives. Strong CYP3A inhibitors significantly increase the exposures of tezacaftor and ivacaftor.
药物-药物相互作用（DDI）研究描述了一种新的囊性纤维化跨膜电导调节剂调节剂治疗药物——tezacaftor/ivacaftor，用于治疗囊性纤维化。在健康受试者中进行了三项 I 期 DDI 研究，以描述 tezacaftor/ivacaftor 与细胞色素 P450（CYP）3A 底物、CYP3A 抑制剂和渗透性糖蛋白（P-gp）底物的 DDI 概况。稳态 tezacaftor/ivacaftor 对地高辛（P-gp 底物）、咪达唑仑和炔雌醇/炔诺酮（CYP3A 底物）的药代动力学（PK）的影响进行了评估。还确定了强（酮康唑）和中度（环丙沙星）CYP3A 抑制剂对 tezacaftor/ivacaftor PK 的影响。Tezacaftor/ivacaftor 使地高辛 AUC 增加 30%，但不影响咪达唑仑、炔雌醇或炔诺酮的暴露量。酮康唑使 tezacaftor 的 AUC 增加 4 倍，ivacaftor 的 AUC 增加 15.6 倍。环丙沙星对 tezacaftor 或 ivacaftor 的暴露量无显著影响。Tezacaftor/ivacaftor 的共同给药可能会增加敏感 P-gp 底物的暴露量。Tezacaftor/ivacaftor 不太可能影响 CYP3A 代谢的药物的暴露量，包括激素避孕药。强 CYP3A 抑制剂显著增加了 tezacaftor 和 ivacaftor 的暴露量。
