Pharmacokinetics and Drug Interactions with Zonisamide

Summary:  Polypharmacy is a widely employed treatment strategy in epilepsy, particularly for individuals with poorly controlled seizures. Drug combinations should be carefully considered to minimize the potential for unfavorable interactions. Older‐generation antiepileptic drugs (AEDs) are well known for their pharmacokinetic interaction potential, which generally results from alterations in the metabolism of concomitant drugs due to effects on the cytochrome P450 (CYP) and uridine glucuronyl transferase enzyme systems. Newer agents, such as zonisamide, are less likely to cause adverse drug interactions. A series of interaction studies has revealed zonisamide to be without effect on the steady‐state pharmacokinetics of carbamazepine, phenytoin, sodium valproate, or lamotrigine. However, zonisamide is principally inactivated by CYP3A4‐dependent reduction. Consequently, carbamazepine, phenytoin, and phenobarbital all increase its clearance, an interaction that may necessitate a dosage increase, but which will also permit more rapid attainment of steady‐state zonisamide concentrations. Otherwise, zonisamide is essentially devoid of clinically significant interactions with other AEDs, oral contraceptives and, indeed, all other classes of therapeutic agents investigated to date. As a result, it is reasonable to conclude that zonisamide has a favorable pharmacokinetic profile and that it may be a useful and uncomplicated agent when employed as adjunctive therapy in refractory epilepsy.