Population pharmacokinetics of valproate in Chinese children with epilepsy.
OBJECTIVE
The aim of the present study is to establish a population pharmacokinetic (PPK) model of valproate (VPA) in Chinese epileptic children to promote the reasonable use of anti-epileptic drugs.


METHODS
Sparse data of VPA serum concentrations from 417 epileptic children were collected. These patients were divided into 2 groups: the PPK model group (n=317) and the PPK valid group (n=100). The PPK parameter values of VPA were calculated by NONMEM software using the data of the PPK model group. A basic model and a final model were set up. To validate the 2 models, the concentrations of PPK valid group were predicted by each model, respectively. The mean prediction error (MPE), mean squared prediction error (MSPE), root mean squared prediction error (RMSPE), weight residues (WRES), and the 95% confidence intervals (95% CI) were also calculated. Then, the values between the 2 models were compared.


RESULTS
The PPK of VPA was determined by a 1-compartment model with a first-order absorption process. The basic model was: Ka=3.09 (h(-1)), V/F=20.4 (L), CL/F=0.296 (L/h). The final model was: Ka=0.251+2.24 x (1-HS) (h(-1)), V/F=2.88+0.157 x WT (L), CL/F=0.106(0.98 x CO)+ 0.0157 x AGE (L/h). For the basic model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were -23.53 (-30.36, -16.70), 3728.96 (2872.72, 4585.20), 39.62 (34.34, 44.90), and -0.06 (-0.14, 0.02), respectively. For the final model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were -1.16 (-4.85, 2.53), 1002.83 (1050.64, 1143.61), 23.04 (21.12, 24.96), and 0.08 (-0.04, 0.20), respectively. The final model was more optimal than the basic model.


CONCLUSIONS
The PPK model of VPA in Chinese epileptic children was successfully established. It will be valuable to facilitate individualized dosage regimens.
Jiang
De-Chun
DC
Department of Pharmacy, Xuan-wu Hospital of Capital Medical University, Beijing 100053, China.
Wang
Li
L
Wang
Yu-Qin
YQ
Li
Lin
L
Lu
Wei
W
Bai
Xiang-Rong
XR
D000293:Adolescent; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001499:Bayes Theorem; D002648:Child; D002675:Child, Preschool; D002681:China; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008954:Models, Biological; D014635:Valproic Acid / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000927:Anticonvulsants; D014635:Valproic Acid