Pharmacokinetic and pharmacodynamic interactions between metoprolol and dronedarone in extensive and poor CYP2D6 metabolizers healthy subjects

As dronedarone a new noniodinated antiarrhythmic agent structurally related to amiodarone could inhibit CYP2D6 and is planned to be associated with beta-blockers, interactions with CYP2D6 metabolized beta-blockers such as metoprolol, have to be studied. Forty-nine healthy male subjects genotyped for CYP2D6 were included in a randomized, double-blind, placebo-controlled study. Metoprolol was administrated during 13 days (200 mg/day). After the initial 5 days, subjects received placebo (n = 12), 800 mg (n = 6), 1200 mg (n = 9), or 1600 mg (n = 17) of dronedarone daily during eight additional days. Pharmacokinetic parameters of metoprolol were investigated at day 5 and at day 13 in 44 subjects, 39 extensive metabolizers and five poor metabolizers for CYP2D6. Cardiac contractility function was evaluated by the rate-corrected electromechanical systole duration (QS(2i)) and the mean velocity of endocardial circumferential fiber shortening (Vcf(mean)). C-max and AUC(0-24 h) of metoprolol increased from days 5 to 13 in proportion to dronedarone dose only in CYP2D6 extensive metabolizers genotyped subjects (P < 0.001). In all subjects, from days 5 to 13, VCfnean decreased and QS(2i) significantly increased in dronedarone groups. The VCfawan changes were however significant only with the 1600 mg dronedarone dose compared with placebo while QS2i changes induced by addition of dronedarone were significant compared with placebo at all dose levels. Between days 5 and 13, QS(2i) and Vcf(mean) changes were significantly correlated with both dronedarone concentrations at day 13 and with metoprolol concentration changes between days 5 and 13. Plasma metoprolol concentrations were highest in poor metabolizer subjects and dronedarone did not further increase their level but increased QS2i in the two subjects receiving the 1600 mg dose. Addition of dronedarone (800-1600 mg daily) to metoprolol (200 mg daily) increases bioavailability of metoprolol in CYP2D6 extensive metabolizers and induces an additive dronedarone dose-dependent negative inotropic effect. Nevertheless at 800 mg daily (anticipated therapeutic dose) these effects were modest.