Population analysis of the dose-dependent pharmacokinetics of zonisamide in epileptic patients.
The pharmacokinetics of zonisamide was studied using routine therapeutic drug monitoring data from 68 epileptic patients. The 266 serum concentration data at steady-state after repetitive oral administration were analyzed using the nonlinear mixed effects model (NONMEM) program designed for estimation of population pharmacokinetic parameters. A one-compartment model with dose-dependent clearance was used for the pharmacokinetic analysis of zonisamide. The volume of distribution (V) was estimated to be 1.27 l/kg in a typical 33-kg patient, assuming that the bioavailability of orally administered zonisamide is 100%. The maximal daily dose to be cleared (Vmax) and the concentration giving half maximal clearance (a Michaelis-Menten constant) was 27.6 mg/d/kg and 45.9 micrograms/ml, respectively. The parameter of a power function of weight to adjust V and Vmax was estimated to be 0.741. In addition, Vmax for zonisamide appears to be 13% increased in patients receiving carbamazepine concurrently. The population pharmacokinetic parameters of zonisamide will be useful for designing dosage regimens in epileptic patients.
Hashimoto
Y
Y
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Japan.
Odani
A
A
Tanigawara
Y
Y
Yasuhara
M
M
Okuno
T
T
Hori
R
R
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D002220:Carbamazepine / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004827:Epilepsy / Q000097:blood*; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D012984:Software; D000078305:Zonisamide
D000927:Anticonvulsants; D007555:Isoxazoles; D002220:Carbamazepine; D000078305:Zonisamide