Novartis Pharma AG, Basel, Switzerland.
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Clin Transl Sci. 2024 Sep;17(9):e70028. doi: 10.1111/cts.70028.
A drug-drug interaction (DDI) study was conducted to evaluate the effect of icenticaftor (QBW251) on the pharmacokinetics (PK) of a 5-probe cytochrome P450 (CYP) substrate cocktail, guided by in vitro studies in human hepatocytes and liver microsomes. Another DDI study investigated the effect of icenticaftor on the PK and pharmacodynamics (PD) of a monophasic oral contraceptive (OC) containing ethinyl estradiol (EE) and levonorgestrel (LVG) in premenopausal healthy female subjects. The static-mechanistic DDI assessment indicated that icenticaftor may moderately induce the metabolic clearance of co-medications metabolized by CYP3A4 (area under the concentration-time curve [AUC] ratio: 0.47) and potentially CYP2C; icenticaftor may also weakly inhibit the metabolic clearance of co-medications metabolized by CYP1A2 and CYP3A4 (AUC ratio: 1.35 and 1.86, respectively) and moderately inhibit CYP2B6 (AUC ratio: 2.11). In the CYP substrate cocktail DDI study, icenticaftor 300 mg twice daily (b.i.d.) moderately inhibited CYP1A2 (AUC ratio: 3.35) and CYP2C19 (AUC ratio: 2.70). As expected from the results of the in vitro studies, weak induction was observed for CYP3A4 (AUC ratio: 0.51) and CYP2C8 (AUC ratio: 0.66). In the OC DDI study, co-administration of icenticaftor 450 mg b.i.d. with monophasic OC containing 30-μg EE and 150-μg LVG once daily reduced the plasma exposure of both components by approximately 50% and led to increased levels of follicle-stimulating hormone and luteinizing hormone. These results provide valuable guidance for the use of icenticaftor in patients taking concomitant medications that are substrates of CYP enzymes or patients using OCs.
一项药物相互作用（DDI）研究旨在评估 icenticaftor（QBW251）对 5 探针细胞色素 P450（CYP）底物鸡尾酒药代动力学（PK）的影响，该研究基于人肝细胞和肝微粒体的体外研究。另一项 DDI 研究调查了 icenticaftor 对含有炔雌醇（EE）和左炔诺孕酮（LVG）的单相口服避孕药（OC）在绝经前健康女性受试者中 PK 和药效学（PD）的影响。静态机械 DDI 评估表明，icenticaftor 可能会适度诱导同时使用的经 CYP3A4 代谢的药物的代谢清除率（AUC 比值：0.47），并可能诱导 CYP2C；icenticaftor 还可能轻度抑制经 CYP1A2 和 CYP3A4 代谢的同时使用药物的代谢清除率（AUC 比值：1.35 和 1.86），并适度抑制 CYP2B6（AUC 比值：2.11）。在 CYP 底物鸡尾酒 DDI 研究中，icenticaftor 每天两次 300mg（b.i.d.）中度抑制 CYP1A2（AUC 比值：3.35）和 CYP2C19（AUC 比值：2.70）。与体外研究结果一致，观察到 CYP3A4（AUC 比值：0.51）和 CYP2C8（AUC 比值：0.66）的弱诱导。在 OC DDI 研究中，icenticaftor 每天两次 450mg 与含有 30μg EE 和 150μg LVG 的单相 OC 联合给药将两种成分的血浆暴露量降低约 50%，并导致促卵泡激素和黄体生成素水平升高。这些结果为 icenticaftor 在同时使用 CYP 酶底物的患者或使用 OC 的患者中的使用提供了有价值的指导。
