基于生理学的药代动力学模型预测卡马西平或丙戊酸联合治疗的儿科患者拉莫三嗪暴露和剂量优化。

Physiologically based pharmacokinetic models for predicting lamotrigine exposure and dose optimization in pediatric patients receiving combination therapy with carbamazepine or valproic acid.

机构信息

Anhui Provincial Center for Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China.

Wannan Medical College, Wuhu, China.

出版信息

Pharmacotherapy. 2024 Sep;44(9):711-721. doi: 10.1002/phar.4603. Epub 2024 Aug 29.

DOI:10.1002/phar.4603

PMID:39206763

Abstract

INTRODUCTION

Lamotrigine (LTG) is an antiepileptic drug that has been used in pediatric epilepsy as a combination therapy or monotherapy after stabilization in recent years. However, there are significant drug-drug interactions (DDI) between LTG and combined drugs such as carbamazepine (CBZ) and valproic acid (VPA). It is particularly important to consider the risk of DDI in combination therapy for intractable epilepsy in pediatric patients. Therefore, it is necessary to adjust the dosage of LTG accordingly. The aim of this study was to establish and validate a pediatric physiologically based pharmacokinetic (PBPK) model for predicting LTG exposure. The model is designed to explore the potential for quantifying pharmacokinetic (PK) DDI of LTG when administered concurrently with CBZ or VPA in pediatric patients.

METHOD

Adult and pediatric PBPK models for LTG and VPA were developed using PK-Sim® software in combination with physiological information and drug-specific parameters, and a DDI model was developed in combination with the published CBZ model. The models were validated against available PK data.

RESULTS

Predictive and observational results in adults, children, and the DDI model were in good agreement. The recommended doses of LTG for preschool children (2-6 years) and school-aged children (6-12 years) in the absence of drug interactions were 1.47 and 1.2 times higher than those for adults, respectively; 3.1 and 2.6 times higher than those for adults in combination with CBZ; and 0.67 and 0.57 times lower than those for adults in combination with VPA. In addition, plasma exposures in adolescents (12-18 years) were similar to those in adults at the same doses.

CONCLUSION

We have successfully developed PBPK models and DDI models for LTG in adults and children, which provide a reference for rational drug use in the pediatric population.

摘要

简介

拉莫三嗪（LTG）是一种抗癫痫药物，近年来已在儿科癫痫中作为联合治疗或稳定后的单药治疗使用。然而，LTG 与卡马西平（CBZ）和丙戊酸（VPA）等联合药物之间存在显著的药物相互作用（DDI）。因此，在儿科患者的难治性癫痫联合治疗中，需要考虑 DDI 的风险，相应地调整 LTG 的剂量。本研究旨在建立和验证一种预测 LTG 暴露的儿科生理药代动力学（PBPK）模型。该模型旨在探索当 LTG 与 CBZ 或 VPA 同时给药时，定量评估 LTG 的药代动力学（PK）DDI 的潜力。

方法

使用 PK-Sim®软件结合生理信息和药物特异性参数开发了 LTG 和 VPA 的成人和儿科 PBPK 模型，并结合已发表的 CBZ 模型开发了 DDI 模型。使用可用的 PK 数据对模型进行了验证。

结果

成人、儿童和 DDI 模型的预测和观察结果均吻合良好。在没有药物相互作用的情况下，学龄前儿童（2-6 岁）和学龄儿童（6-12 岁）的 LTG 推荐剂量分别比成人高 1.47 倍和 1.2 倍；与 CBZ 联合使用时，比成人高 3.1 倍和 2.6 倍；与 VPA 联合使用时，比成人低 0.67 倍和 0.57 倍。此外，青少年（12-18 岁）的血浆暴露与相同剂量下的成人相似。