Novartis AG, Basel, Switzerland.
Novartis Institutes for Biomedical Research, Basel, Switzerland.
Cancer Chemother Pharmacol. 2019 Oct;84(4):749-757. doi: 10.1007/s00280-019-03907-1. Epub 2019 Jul 19.
Ruxolitinib is metabolized by cytochrome P450 (CYP)3A4 and CYP2C9. Dual inhibitors of these enzymes (like fluconazole) lead to increased ruxolitinib exposure relative to a single pathway inhibition of CYP3A4 or CYP2C9. The magnitude of this interaction, previously assessed via physiologically based pharmacokinetic (PBPK) models, was confirmed in an open-label, phase 1 study in healthy subjects.
The effect of multiple doses (200 mg) of fluconazole on single-dose (10 mg) PK of ruxolitinib was investigated including evaluation of the safety and tolerability. The PK parameters of ruxolitinib alone (reference) were compared to those of ruxolitinib combined with fluconazole (test). The point estimate and corresponding two-sided 90% confidence interval for the difference between means of test and reference parameters were determined.
All enrolled subjects (N = 15) completed the study. When coadministered with fluconazole, geometric means of ruxolitinib PK parameters C, AUC, and AUC increased by 47%, 234%, and 232%, respectively, vs ruxolitinib alone. The median T decreased slightly, apparent clearance decreased approximately threefold, and elimination half-life increased approximately 2.5-fold, upon ruxolitinib administration with fluconazole vs ruxolitinib alone. These results were consistent with the prospective predictions from a SimCYP PBPK model. Adverse events (AEs) were reported in six subjects (none were suspected to be related to ruxolitinib); no death or on-treatment serious AE was reported.
Coadministration of ruxolitinib with fluconazole significantly increased ruxolitinib systemic exposure; however, no AEs were attributed to ruxolitinib. Concomitant use of ruxolitinib with fluconazole (dose ≤ 200 mg) may require dose reduction/modification of ruxolitinib.
芦可替尼主要通过细胞色素 P450（CYP）3A4 和 CYP2C9 代谢。这些酶的双重抑制剂（如氟康唑）会导致芦可替尼暴露量增加，与 CYP3A4 或 CYP2C9 的单一途径抑制相比。通过生理基于药代动力学（PBPK）模型评估的这种相互作用的程度，在一项健康受试者的开放标签、I 期研究中得到了证实。
研究了氟康唑多次给药（200mg）对芦可替尼单剂量（10mg）药代动力学的影响，包括评估安全性和耐受性。单独使用芦可替尼（参比）的 PK 参数与芦可替尼联合氟康唑（试验）的 PK 参数进行了比较。确定了试验和参考参数均值之间差异的点估计值和相应的双侧 90%置信区间。
所有入组受试者（N=15）均完成了研究。与单独使用芦可替尼相比，当与氟康唑联合使用时，芦可替尼 PK 参数 C、AUC 和 AUC 的几何均数分别增加了 47%、234%和 232%。中位数 T 略有下降，表观清除率约降低三倍，消除半衰期约增加 2.5 倍。这些结果与 SimCYP PBPK 模型的前瞻性预测一致。15 名受试者中有 6 名报告了不良事件（AE）（均与芦可替尼无关）；未报告死亡或治疗期间严重 AE。
芦可替尼与氟康唑联合使用可显著增加芦可替尼的全身暴露量；然而，芦可替尼没有引起 AE。芦可替尼与氟康唑（剂量≤200mg）同时使用可能需要减少/修改芦可替尼的剂量。
