Pharmacokinetic interaction between cyclosporine and the dihydropyridine calcium antagonist felodipine

Abstract

Objective: In a double blind, randomised, placebo-controlled, cross-over study 12 healthy male volunteers were allocated to receive felodipine + placebo, cyclosporine + placebo, and felodipine + cyclosporine in order to investigate the interaction between the calcium channel blocker felodipine and cyclosporine as it affects the pharmacokinetics of felodipine, dehydrofelodipine, and cyclosporine, and 24-hour blood pressure measurements.

Methods:

Single doses of cyclosporine (capsules, 5 mg/kg body weight) and of felodipine (extended release (ER) tablets 10 mg) were given at a 1–2 week interval. Plasma drug concentrations were followed for 2 days after drug intake.

Results:

For cyclosporine, C_max was increased after combined treatment (16%) compared to cyclosporine alone, but felodipine did not influence other kinetic parameters of cyclosporine. For felodipine, combined treatment with cyclosporine and felodipine increased AUC and C_max (58% and 151%, respectively) and lowered mean residence time (24%) significantly compared to felodipine alone. For the metabolite dehydrofelodipine, too, AUC and C_max were increased after the combined treatment (43% and 94%, respectively). Mean 24-hour systolic and diastolic blood pressures were significantly lower after felodipine, both when felodipine was given alone (121/68 mmHg) and in combination with cyclosporine (122/68 mmHg) compared to cyclosporine alone (127/73 mmHg).

Conclusion:

A combined single dose of cyclosporine and felodipine in healthy subjects increased the AUC and C_max of felodipine suggesting a cyclosporine-induced decrease in the first-pass metabolism of felodipine, whereas the AUC of cyclosporine was only slightly increased by felodipine.