Development and Validation of a Population Pharmacokinetics Model of Perampanel for Pediatric Epilepsy Patients for Optimized Dosing.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-04-23 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S499085

Lingyan Yu, Fengqian Mao, Shunan Chen, Jieqiong Liu, Jiayu Xiao, Meng Chen, Huan Luo, Zhenwei Yu, Haibin Dai

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引用次数: 0

Abstract

Background: Perampanel exhibits substantial interindividual variability, and pharmacokinetic data in pediatric patients are scarce. The aim of this study was to develop a population pharmacokinetic (PPK) model to optimize the dosing of perampanel in children with epilepsy.

Methods: The PPK model was developed via a nonlinear mixed-effects modeling approach, utilizing a dataset comprising 454 plasma concentrations of perampanel obtained from 151 pediatric patients with epilepsy, 120 (79.5%) of whom were aged < 12 years. Goodness-of-fit plots and bootstrap analysis were employed to evaluate the final model. Monte Carlo simulations were utilized to suggest perampanel dosing strategies using a reference plasma concentration range of 100-1000 ng/mL.

Results: In the final PPK models of perampanel, linear centralized age, coadministration of oxcarbazepine (OXC), carbamazepine (CBZ), and valproic acid (VPA) were covariates of clearance (CL/F), and log-transformed body weight was a covariate of the apparent distribution volume (V). The CL/F was estimated via the formula CL/F=0.177*((age+10)/8.8)^1.31*1.51^OXC*0.745^VPA*1.88^CBZ. The relative standard errors (RSEs) for each fixed effect parameter were 15.2%, 14.2%, 12.0%, 7.92%, and 16.3%, respectively. The V was estimated via the formula V=227*LGBW with an RSE of 14.1%. The model demonstrated good robustness according to goodness-of-fit plots and bootstrap analysis. The simulation analysis resulted in a dosing regimen stratified by covariates.

Conclusion: A reliable perampanel PPK model for pediatric patients was successfully developed. This result could be helpful for dosing optimization in pediatric patients receiving perampanel, especially those aged under 12 years.

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开发和验证儿童癫痫患者Perampanel群体药代动力学模型以优化剂量。

背景：Perampanel显示出大量的个体间差异，儿科患者的药代动力学数据很少。本研究的目的是建立一个人群药代动力学（PPK）模型，以优化perampanel在癫痫儿童中的剂量。方法：PPK模型通过非线性混合效应建模方法建立，数据集包括151例儿童癫痫患者的454个perampanel血浆浓度，其中120例（79.5%）年龄< 12岁。采用拟合优度图和自举分析对最终模型进行评价。蒙特卡罗模拟利用参考血浆浓度范围100-1000 ng/mL来建议perampanel给药策略。结果：在perampanel的最终PPK模型中，线性集中年龄、奥卡西平（OXC）、卡马西平（CBZ）和丙戊酸（VPA）共给药是清除率（CL/F）的协变量，对数转换体重是表观分布体积(V)的协变量。CL/F计算公式为CL/F=0.177*((age+10)/8.8)1.31*1.51OXC*0.745VPA*1.88CBZ。各固定效应参数的相对标准误差（rse）分别为15.2%、14.2%、12.0%、7.92%和16.3%。V由公式V=227*LGBW估算，RSE为14.1%。通过拟合优度图和自举分析，表明该模型具有良好的鲁棒性。模拟分析得出了按协变量分层的给药方案。结论：成功建立了可靠的儿科患者perampanel PPK模型。该结果可能有助于儿科患者接受perampanel的剂量优化，特别是12岁以下的儿童。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.