Pharmacokinetic Research Unit, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand.
Center of Excellence for Environmental Health and Toxicology, Naresuan University, Phitsanulok, Thailand.
Br J Clin Pharmacol. 2018 May;84(5):816-834. doi: 10.1111/bcp.13510. Epub 2018 Feb 28.
Population pharmacokinetics is an essential tool that helps guide individualized dosing regimens. The aims of this systematic review are to provide knowledge concerning population pharmacokinetics of valproic acid (VPA) and to identify factors influencing VPA pharmacokinetic variability.
PubMed and Embase databases were systematically searched from inception to June, 2017. Relevant articles from reference lists were also included. All population pharmacokinetic studies of VPA conducted in humans and that employed a nonlinear mixed effect modelling approach were included in this review.
Twenty-six studies were included in this review. Most studies characterized VPA pharmacokinetics as a one-compartment model. Three studies reported a two-compartment model. Body weight, dose and age were significant predictors for VPA volume of distribution (V ). The estimated V for one-compartment models ranged from 8.4 to 23.3 l. For two-compartment models, peripheral volumes of distribution ranged from 4.08 to 42.1 l. Frequently reported significant predictors for VPA clearance (CL ) included body weight, VPA dose, concomitant medications, gender and age. The estimated CL ranged from 0.206 to 1.154 l h and the inter-individual variability ranged from 13.40 to 35.90%. Two studies reported population pharmacokinetics/pharmacodynamics of VPA in patients with epilepsy. Seventeen studies evaluated the performance of their final models.
Significant predictors influencing VPA pharmacokinetics as well as model methodologies are highlighted in this review. For clinical application, CL could be predicted using body weight, VPA dose, concomitant medications, gender or age. For future research, there is a knowledge gap regarding population pharmacokinetics/pharmacodynamics of VPA in a population other than epileptic patients.
群体药代动力学是指导个体化给药方案的重要工具。本系统评价的目的是提供关于丙戊酸（VPA）群体药代动力学的知识，并确定影响 VPA 药代动力学变异性的因素。
系统检索了 PubMed 和 Embase 数据库，检索时间从建库至 2017 年 6 月。还包括参考文献中的相关文章。本综述纳入了所有在人体中进行的、采用非线性混合效应模型方法的 VPA 群体药代动力学研究。
本综述纳入了 26 项研究。大多数研究将 VPA 药代动力学特征描述为单室模型。有 3 项研究报告了双室模型。体重、剂量和年龄是 VPA 分布容积（V ）的显著预测因子。单室模型的估计 V 值范围为 8.4 至 23.3 l。对于双室模型，外周分布容积范围为 4.08 至 42.1 l。经常报道的 VPA 清除率（CL ）的显著预测因子包括体重、VPA 剂量、伴随药物、性别和年龄。估计的 CL 值范围为 0.206 至 1.154 l/h，个体间变异性范围为 13.40 至 35.90%。有 2 项研究报告了癫痫患者 VPA 的群体药代动力学/药效学。有 17 项研究评估了他们最终模型的性能。
本综述强调了影响 VPA 药代动力学的显著预测因子和模型方法。在临床应用中，可以使用体重、VPA 剂量、伴随药物、性别或年龄来预测 CL。对于未来的研究，在除癫痫患者以外的人群中，VPA 的群体药代动力学/药效学仍存在知识空白。
