Pharmacokinetic effect of ketoconazole on solifenacin in healthy volunteers.

ABSTRACT

Solifenacin succinate (YM905) is a new, once-daily, orally administered muscarinic receptor antagonist designed to treat overactive bladder. The metabolism of solifenacin involves hepatic cytochrome P450 (CYP) 3A4; therefore, the pharmacokinetics of solifenacin may be affected by drugs that inhibit CYP3A4. This study aimed to examine the effects of co-administration of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of solifenacin in healthy volunteers. In a single-site, open-label, monosequence, crossover study, 17 healthy men and women aged 18 to 65 years received a single 10 mg oral dose of solifenacin, which is is the highest available dose. After a 14-day wash-out period, they began 20 days of oral ketoconazole at a dose of 200 mg once daily. A single 10 mg dose of solifenacin was administered again on day 7 of ketoconazole treatment. Pharmacokinetics was assessed using the standard measurements of maximum plasma concentration (Cmax), time to Cmax, area under the curve (AUC), and elimination half-life (t1/2). Co-administration of ketoconazole resulted in a 1.43 times increase in the C(max) of solifenacin and an approximately 2 times increase in AUC. The mean t1/2 of solifenacin was extended from 49.3 to 77.5 hr whereas time to Cmax did not change. No substantial increase in the overall rate of adverse events, and no significant effects on vital signs, electrocardiography, clinical laboratory values, or physical examinations were noted. Administration of 200 mg ketoconazole once daily in healthy male volunteers resulted in a 2 times increase in exposure of a single 10 mg dose of solifenacin. Since ketoconazole is one of the strongest inhibitors of CYP3A4, it is expected that co-administration of other CYP3A4 inhibitors will not result in a stronger increase in solifenacin exposure.