Shenghui Mei1,2, Weixing Feng3,4, Leting Zhu1, Xingang Li1, Yazhen Yu4, Weili Yang4, Baoqin Gao4, Xiaojuan Wu4, Fang Fang5, Zhigang Zhao6,7. 1. Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, 6 Tiantan Xili, Dongcheng District, Beijing, 100050, People's Republic of China. 2. Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing, 100045, People's Republic of China. 3. Department of Neurology, Beijing Children's Hospital, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing, 100045, People's Republic of China. 4. Department of Pediatrics, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China. 5. Department of Neurology, Beijing Children's Hospital, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing, 100045, People's Republic of China. 13910150389@163.com. 6. Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, 6 Tiantan Xili, Dongcheng District, Beijing, 100050, People's Republic of China. ttyyzzg1022@126.com. 7. Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing, 100045, People's Republic of China. ttyyzzg1022@126.com.
Abstract
PURPOSE: Valproic acid (VPA) is an important drug in seizure control with great inter-individual differences in metabolism and treatment effect. This study aims to identify the effects of genetic variants on VPA clearance in a population pharmacokinetic (popPK) model in children with epilepsy. METHODS: A total of 325 VPA plasma concentrations from 290 children with epilepsy were used to develop the popPK model by using the nonlinear mixed-effects modeling method. The one-compartment model was established to describe the pharmacokinetics of VPA. Twelve single nucleotide polymorphisms involved in the pharmacokinetics of VPA were identified by MassARRAY system and their effects on VPA clearance were evaluated. RESULTS: In the two final popPK models, inclusion of a combined genotype of four variants (rs1042597, rs28365062, rs4986893, and rs4244285), total daily dose (TDD), and body surface area (BSA) significantly reduced inter-individual variability for clearance over the base model. The inter-individual clearance equals to 0.73 × (TDD/628.92)0.59 × eUGT-CYP for TDD included model and 0.70 × (BSA/0.99)0.57 × eUGT-CYP for BSA included model. The precision of all parameters were acceptable (relative standard error < 32.81%). Bootstrap and visual predictive check results indicated that both two final popPK models were stable with acceptable predictive ability. CONCLUSION: TDD, BSA, and genotype might affect VPA clearance in children. The popPK models may be useful for dosing adjustment in children on VPA therapy.
PURPOSE:Valproic acid (VPA) is an important drug in seizure control with great inter-individual differences in metabolism and treatment effect. This study aims to identify the effects of genetic variants on VPA clearance in a population pharmacokinetic (popPK) model in children with epilepsy. METHODS: A total of 325 VPA plasma concentrations from 290 children with epilepsy were used to develop the popPK model by using the nonlinear mixed-effects modeling method. The one-compartment model was established to describe the pharmacokinetics of VPA. Twelve single nucleotide polymorphisms involved in the pharmacokinetics of VPA were identified by MassARRAY system and their effects on VPA clearance were evaluated. RESULTS: In the two final popPK models, inclusion of a combined genotype of four variants (rs1042597, rs28365062, rs4986893, and rs4244285), total daily dose (TDD), and body surface area (BSA) significantly reduced inter-individual variability for clearance over the base model. The inter-individual clearance equals to 0.73 × (TDD/628.92)0.59 × eUGT-CYP for TDD included model and 0.70 × (BSA/0.99)0.57 × eUGT-CYP for BSA included model. The precision of all parameters were acceptable (relative standard error < 32.81%). Bootstrap and visual predictive check results indicated that both two final popPK models were stable with acceptable predictive ability. CONCLUSION:TDD, BSA, and genotype might affect VPA clearance in children. The popPK models may be useful for dosing adjustment in children on VPA therapy.
Entities:
Keywords:
Children; Clearance; Cytochrome P450 family 2 subfamily C member 19; Nonlinear mixed-effects modeling; Population pharmacokinetic model; Uridine diphosphate glucuronosyltransferase; Valproic acid
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