Kovarik J M, Beyer D, Bizot M N, Jiang Q, Allison M J, Schmouder R L
Novartis Pharmaceuticals, Basel, Switzerland.
Br J Clin Pharmacol. 2005 Oct;60(4):434-7. doi: 10.1111/j.1365-2125.2005.02434.x.
We sought to define the influence of verapamil, an inhibitor of CYP3A and P-glycoprotein, on the pharmacokinetics of everolimus, a substrate of this enzyme and transporter.
This was a two-period, single-sequence, crossover study in 16 healthy subjects. In period 1 subjects received a single 2 mg oral dose of everolimus. In period 2 they received verapamil 80 mg three times daily for a total of 6 days and a single 2 mg dose of everolimus co-administered on the second day of verapamil therapy.
During verapamil co-administration, everolimus C(max) increased 2.3-fold (90% CI, 1.9, 2.7) from 21 +/- 8 to 47 +/- 18 ng ml(-1) and AUC increased 3.5-fold (90% CI, 3.1, 3.9) from 115 +/- 45 to 392 +/- 142 ng ml(-1) h. Everolimus half-life was only prolonged to a minor extent (32 +/- 6 vs. 37 +/- 6 h). Verapamil predose concentrations doubled from 32 +/- 16 to 74 +/- 42 ng ml(-1) after single dose administration of everolimus.
Multiple dosing with verapamil increased blood concentrations of everolimus after a single dose by an average 3.5-fold. During verapamil treatment, dose reduction for everolimus should be made guided by blood monitoring and for verapamil by blood pressure monitoring.
我们试图确定细胞色素P450 3A（CYP3A）和P-糖蛋白的抑制剂维拉帕米对该酶和转运蛋白的底物依维莫司药代动力学的影响。
这是一项针对16名健康受试者的两阶段、单序列、交叉研究。在第1阶段，受试者接受单次2mg口服依维莫司剂量。在第2阶段，他们每天3次接受80mg维拉帕米，共6天，并在维拉帕米治疗的第二天同时接受单次2mg依维莫司剂量。
在联合使用维拉帕米期间，依维莫司的Cmax从21±8 ng/ml增加2.3倍（90%CI，1.9，2.7）至47±18 ng/ml，AUC从115±45 ng/ml·h增加3.5倍（90%CI，3.1，3.9）至392±142 ng/ml·h。依维莫司的半衰期仅略有延长（32±6小时对37±6小时）。单次给予依维莫司后，维拉帕米给药前浓度从32±16 ng/ml增加一倍至74±42 ng/ml。
多次给予维拉帕米后，单次剂量依维莫司的血药浓度平均增加3.5倍。在维拉帕米治疗期间，依维莫司的剂量减少应以血液监测为指导，而维拉帕米则应以血压监测为指导。
