A population pharmacokinetic model of valproic acid in pediatric patients with epilepsy: a non-linear pharmacokinetic model based on protein-binding saturation

Ding, J; Wang, Y; Lin, W; Wang, C; Zhao, L; Li, X; Zhao, Z; Miao, L; Jiao, Z

Journal article

A population pharmacokinetic model of valproic acid in pediatric patients with epilepsy: a non-linear pharmacokinetic model based on protein-binding saturation

Abstract:: Background and Objective

Valproic acid (VPA) follows a non-linear pharmacokinetic profile in terms of protein-binding saturation. The total daily dose regarding VPA clearance is a simple power function, which may partially explain the non-linearity of the pharmacokinetic profile; however, it may be confounded by the therapeutic drug monitoring effect. The aim of this study was to develop a population pharmacokinetic model for VPA based on protein-binding saturation in pediatric patients with epilepsy.

Methods

A total of 1,107 VPA serum trough concentrations at steady state were collected from 902 epileptic pediatric patients aged from 3 weeks to 14 years at three hospitals. The population pharmacokinetic model was developed using NONMEM® software. The ability of three candidate models (the simple power exponent model, the dose-dependent maximum effect [DDE] model, and the protein-binding model) to describe the non-linear pharmacokinetic profile of VPA was investigated, and potential covariates were screened using a stepwise approach. Bootstrap, normalized prediction distribution errors and external evaluations from two independent studies were performed to determine the stability and predictive performance of the candidate models.

Results

The age-dependent exponent model described the effects of body weight and age on the clearance well. Co-medication with carbamazepine was identified as a significant covariate. The DDE model best fitted the aim of this study, although there were no obvious differences in the predictive performances. The condition number was less than 500, and the precision of the parameter estimates was less than 30 %, indicating stability and validity of the final model.

Conclusion

The DDE model successfully described the non-linear pharmacokinetics of VPA. Furthermore, the proposed population pharmacokinetic model of VPA can be used to design rational dosage regimens to achieve desirable serum concentrations.

Publication status:: Published

Peer review status:: Peer reviewed

Actions

Email

Email this record

Send the bibliographic details of this record to your email address.

Your Email
Please enter the email address that the record information will be sent to.

-
Your message (optional)
Please add any additional information to be included within the email.
Cite

Cite this record

APA Style

Ding, J., Wang, Y., Lin, W., Wang, C., Zhao, L., Li, X., Zhao, Z., Miao, L., & Jiao, Z. (2014). A population pharmacokinetic model of valproic acid in pediatric patients with epilepsy: a non-linear pharmacokinetic model based on protein-binding saturation. Clinical Pharmacokinetics, 54(3), 305–317.

MLA Style

Ding, J., et al. “A Population Pharmacokinetic Model of Valproic Acid in Pediatric Patients with Epilepsy: a Non-Linear Pharmacokinetic Model Based on Protein-Binding Saturation.” Clinical Pharmacokinetics, vol. 54, no. 3, Springer, 2014, pp. 305–17.

Chicago Style

Ding, J, Y Wang, W Lin, C Wang, L Zhao, X Li, Z Zhao, L Miao, and Z Jiao. 2014. “A Population Pharmacokinetic Model of Valproic Acid in Pediatric Patients with Epilepsy: a Non-Linear Pharmacokinetic Model Based on Protein-Binding Saturation.” Clinical Pharmacokinetics 54 (3): 305–17.
Share
Print