Pharmacokinetic interaction between verapamil and everolimus in healthy subjects.
OBJECTIVE
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 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.


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.
Kovarik
J M
JM
Novartis Pharmaceuticals, Basel, Switzerland. john.kovarik@pharma.novartis.com
Beyer
D
D
Bizot
M N
MN
Jiang
Q
Q
Allison
M J
MJ
Schmouder
R L
RL
D000704:Analysis of Variance; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D018592:Cross-Over Studies; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D014700:Verapamil / Q000008:administration & dosage / Q000494:pharmacology*
D002120:Calcium Channel Agonists; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D000068338:Everolimus; D014700:Verapamil; D020123:Sirolimus