Lack of pharmacokinetic interactions between steady-state zonisamide and valproic acid in patients with epilepsy

Objectives: This study evaluated the effect of the addition of zonisamide on valproic acid (valproate sodium) pharmacokinetics under steady-state conditions in patients with epilepsy. A second aim was to characterise zonisamide pharmacokinetics in the presence of valproic acid. Methods: Twenty-two patients (males and females, 18-55 years of age) with their seizure disorder stabilised on valproic acid monotherapy were included in a two-centre, open-label, one-way drug-interaction trial. The zonisamide dose was gradually increased from 100 mg./day to 400 mg/day. Three pharmacokinetic profiles were obtained: on days -7 and -1, to assess pharmacokinetic parameters of oral valproic acid administered alone, and on day 35, after 14 days of zonisamide treatment at the maximal tolerated dose, to evaluate the effect of zonisamide on valproic acid pharmacokinetics and to characterise zonisamide pharmacokinetics in the presence of valproic acid. Results: Seventeen patients completed the study, with 16 patients contributing to the pharmacokinetic analyses. Coadministration of zonisamide and valproic acid appeared reasonably well tolerated. Steady-state dosing of Zonisamide (200mg twice daily) had no statistically significant effect on the mean (+/- SD) maximum observed plasma concentration (C-max) [70.8 +/- 20.5 vs 69.2 +/- 27.0 mu g/mL], area under the plasma concentration-time curve from the time of dosing to 12 hours post-dose (AUC(12)) [689.3 +/- 250.4 vs 661.8 +/- 251.3 mu g center dot h/mL] or other evaluated pharmacokinetic parameters for valproic acid measured before and after zonisamide administration. Furthermore, 90% confidence intervals for the ratio of the geometric means (day 35/day -1) of valproic acid pharmacokinetic exposure measures fell only slightly outside the 'no effect' range of 0.80-1.25. In the presence of valproic acid, mean zonisamide oral clearance (1.23 L/h) and elimination half-life (52.5 hours) are generally consistent with values reported for healthy volunteers receiving zonisamide monotherapy. Conclusion: There is no apparent clinically significant effect of steady-state dosing of zonisamide on valproic acid pharmacokinetics, and valproic acid did not appear to affect the pharmacokinetics of zonisamide, indicating that no dosage adjustment of either drug should be required when they are used in combination in patients with epilepsy.