Influence of verapamil on the pharmacokinetics of oxcarbazepine and of the enantiomers of its 10-hydroxy metabolite in healthy volunteers.

Abstract

Oxcarbazepine (OXC), a second-generation antiepileptic, and its chiral metabolite 10-hydroxycarbazepine (MHD) are substrates of P-glycoprotein, which can be inhibited by verapamil. This study evaluated the influence of verapamil on the pharmacokinetics of OXC and MHD enantiomers in healthy volunteers. Healthy volunteers (n = 12) on occasion O (OXC monotherapy) received 300 mg OXC/12 h for 5 days, and on the O + V occasion (treatment with OXC + verapamil), they received 300 mg OXC/12 h and 80 mg verapamil/8 h for 5 days. Blood samples were collected over a period of 12 h. Total and free plasma concentrations of OXC and the MHD enantiomers were evaluated by LC-MS/MS. Noncompartmental pharmacokinetic analysis was performed using the WinNonlin program. The kinetic disposition of MHD was enantioselective with plasma accumulation (AUC(0-12) S-(+)/R-(-) ratio of 4.38) and lower fraction unbound (0.37 vs 0.42) of the S-(+)-MHD enantiomer. Treatment with verapamil reduced the OXC mean residence time (4.91 vs 4.20 h) and apparent volume of distribution (4.72 vs 3.15 L/kg). Verapamil also increased for both MHD enantiomers C max total [R-(-)-MHD: 2.65 vs 2.98 μg/mL and S-(+)-MHD: 10.15 vs 11.60 μg/mL], C average [R-(-)-MHD: 1.98 vs 2.18 μg/mL and S-(+)-MHD: 8.10 vs 8.83 μg/mL], and AUC(0-12) [R-(-)-MHD: 23.79 vs 26.19 μg h/mL and S-(+)-MHD: 97.87 vs 108.35 μg h/mL]. Verapamil increased the AUC values of both MDH enantiomers, which is probably related to the inhibition of intestinal P-glycoprotein. Considering that the exposure of both MHD enantiomers was increased in only 10 %, no OXC dose adjustment could be recommended in the situation of verapamil coadministration.