Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan.
Institute of Pharmacy, Faculty of Pharmaceutical and Allied Health Sciences, Lahore College for Women University, Lahore, Pakistan.
PLoS One. 2022 Aug 24;17(8):e0272622. doi: 10.1371/journal.pone.0272622. eCollection 2022.
The pharmacokinetics of valproic acid have been evaluated in a variety of populations however, the comparison in two different populations was yet to be reported. This study is aimed to compare the pharmacokinetics of valproic acid in Pakistani and South Korean patients.
The therapeutic drug monitoring (TDM) data of valproic acid from 92 Pakistani patients with 218 samples was combined with the data of 99 South Korean patients with 335 samples in order to form a pooled dataset of 191 patients with 553 samples. Population pharmacokinetic model was developed on NONMEM® software by using first order conditional estimation method for estimation of pharmacokinetic parameters. The influence of different covariates including ethnicity was evaluated the stepwise covariate modelling. The final model was evaluated for predictive performance and robustness by using goodness of fit plots and bootstrap analysis respectively.
The data was better described by one compartment model with first order elimination. The value for clearance (CL) of valproic in pooled data was 0.931 L/h with 43.4% interindividual variability (IIV) while volume of distribution (Vd) was 16.6 L with 22.3% IIV. In covariate analysis, ethnicity and body weight were significant covariates for CL while body weight was also significant for Vd.
A significant difference in CL of valproic acid among Pakistani and South Korean patients was observed. The model can be used for the dose tailoring of valproic acid based on ethnicity and body weight of Pakistani and South Korean patients.
已有多种人群的丙戊酸药代动力学研究报告，但不同人群间的比较尚未见报道。本研究旨在比较巴基斯坦和韩国患者丙戊酸的药代动力学。
将 92 例巴基斯坦患者的 218 个丙戊酸治疗药物监测（TDM）数据与 99 例韩国患者的 335 个数据合并，形成一个包含 191 例患者 553 个样本的合并数据集。采用 NONMEM®软件的一阶条件估计法进行群体药代动力学模型构建，以估算药代动力学参数。采用逐步协变量建模法评估不同协变量（包括种族）的影响。采用拟合度图和 Bootstrap 分析分别评估最终模型的预测性能和稳健性。
数据采用单室模型和一级消除过程描述，丙戊酸清除率（CL）的合并数据值为 0.931 L/h，个体间变异（IIV）为 43.4%，分布容积（Vd）为 16.6 L，IIV 为 22.3%。在协变量分析中，种族和体重是 CL 的显著协变量，而体重也是 Vd 的显著协变量。
观察到巴基斯坦和韩国患者丙戊酸 CL 存在显著差异。该模型可用于基于巴基斯坦和韩国患者的种族和体重来调整丙戊酸的剂量。
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