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Population pharmacokinetics of valproate in Chinese children with epilepsy

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Aim: 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·(1-HS) (h−1), V/F=2.88+0.157·WT (L), CL/F=0.1060.98·CO+ 0.0157·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. Conclusion: The PPK model of VPA in Chinese epileptic children was successfully established. It will be valuable to facilitate individualized dosage regimens.
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Keywords: Bayesian method; NONMEM software; children; epilepsy; individualized dosage regimens; population pharmacokinetics; valproic acid

Document Type: Research Article

Affiliations: 1: Department of Pediatrics, Peking University First Hospital, Beijing 100034, China 2: Department of Pharmacology, Xuan-wu Hospital of Capital Medical University, Education Ministry Key Laboratory for Neurodegenerative Diseases, Beijing 100053, China 3: School of Pharmaceutical Science, Peking University, Beijing 100083, China 4: Department of Pharmacy, Xuan-wu Hospital of Capital Medical University, Beijing 100053, China

Publication date: 01 October 2007

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