Pharmacokinetic interaction between verapamil and everolimus in healthy subjects

Aims 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. Methods 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. Results During verapamil co‐administration, everolimus Cmax 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. Conclusions 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.