title: Population pharmacokinetics of zonisamide after oral administration in healthy Chinese volunteers.
abstract: To develop a population-based pharmacokinetic model for the oral antiepileptic drug zonisamide using a cohort of healthy (nonepileptic) subjects and evaluate the effect of individual factors on the pharmacokinetics of zonisamide. 30 young adults (21-39 years) in good health were randomly assigned to 3 equal groups (1:1 sex ratio) for single-dose administration of zonisamide at 200 mg, 300 mg, or 400 mg. An additional 9 subjects (22-24 years) were administered once daily zonisamide at 300 mg for 14 days, and comprised the multiple dosing group. Venous blood samples were collected for analysis prior to (baseline, 0 hours) and after (1-300 hours) drug administration, providing 607 total samples used to build the pharmacokinetic model. The population pharmacokinetic analysis was performed by ICON's nonlinear mixed-effect modeling (NONMEM) software. Validation of the final model was carried out by nonparametric bootstrapping and visual predictive check. The zonisamide pharmacokinetics was best described by a two-compartment model with first-order elimination. In the final model, the estimated value of clearance (CL) was 23.25 L/h, the volume of distribution of the central compartment (Vc) was 34.50 L, the intercompartmental clearance (Q) was 20.22 L/h, and the Ka was 0.026 h(-1). The peripheral volume of distribution (Vp) was 1,429 L for single dose and 1,003 L for multiple doses. Body weight was the significant covariate affecting CL, Vc, Vp, and Q. Otherwise, female subjects had a lower Q than male subjects. The pharmacokinetics of zonisamide after oral administration could be described using a linear first-order elimination two-compartment model, which may provide a reference for clinical use of zonisamide in Chinese adults.
authors.forename: Xuewen
authors.initials: X
authors.lastname: Qiu
authors.forename: Qing
authors.initials: Q
authors.lastname: Dai
authors.forename: Fengjun
authors.initials: F
authors.lastname: Sun
authors.forename: Yao
authors.initials: Y
authors.lastname: Liu
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.forename: Rongfeng
authors.initials: R
authors.lastname: Xiang
authors.forename: Mingjie
authors.initials: M
authors.lastname: Yu
authors.forename: Lirong
authors.initials: L
authors.lastname: Xiong
authors.forename: Shanshan
authors.initials: S
authors.lastname: Bi
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Yongchuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Peiyuan
authors.initials: P
authors.lastname: Xia
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D044466:Asian People; D002681:China; D004334:Drug Administration Schedule; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016014:Linear Models; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D055815:Young Adult; D000078305:Zonisamide
chemical_list: D000927:Anticonvulsants; D007555:Isoxazoles; D000078305:Zonisamide