Anhui Provincial Center for Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China.
CPT Pharmacometrics Syst Pharmacol. 2023 Jul;12(7):1001-1015. doi: 10.1002/psp4.12971. Epub 2023 Jun 2.
Levetiracetam (LEV) is an anti-epileptic drug approved for use in various populations. The pharmacokinetic (PK) behavior of LEV may be altered in the elderly and patients with renal and hepatic impairment. Thus, dosage adjustment is required. This study was conducted to investigate how the physiologically-based PK (PBPK) model describes the PKs of LEV in adult and elderly populations, as well as to predict the PKs of LEV in patients with renal and hepatic impairment in both populations. The whole-body PBPK models were developed using the reported physicochemical properties of LEV and clinical data. The models were validated using data from clinical studies with different dose ranges and different routes and intervals of administration. The fit performance of the models was assessed by comparing predicted and observed blood concentration data and PK parameters. It is recommended that the doses be reduced to ~70%, 60%, and 45% of the adult dose for the mild, moderate, and severe renal impairment populations and ~95%, 80%, and 57% of the adult dose for the Child Pugh-A (CP-A), Child Pugh-B (CP-B), and Child Pugh-C (CP-C) hepatic impairment populations, respectively. No dose adjustment is required for the healthy elderly population, but dose reduction is required for the elderly with organ dysfunction accordingly, on a scale similar to that of adults. A PBPK model of LEV was successfully developed to optimize dosing regimens for special populations.
左乙拉西坦（LEV）是一种抗癫痫药物，已获准用于各种人群。LEV 的药代动力学（PK）行为在老年人和肝肾功能不全的患者中可能会发生改变。因此，需要进行剂量调整。本研究旨在探讨生理药代动力学（PBPK）模型如何描述成人和老年人群中 LEV 的 PK 特性，并预测这两个人群中肝肾功能不全患者的 LEV PK。使用 LEV 的报告理化特性和临床数据开发了全身 PBPK 模型。使用不同剂量范围、不同给药途径和间隔的临床研究数据对模型进行了验证。通过比较预测的和观察到的血药浓度数据和 PK 参数来评估模型的拟合性能。建议将剂量分别减少到成人剂量的70%、60%和 45%，用于轻度、中度和重度肾功能不全人群；分别减少到成人剂量的95%、80%和 57%，用于 Child Pugh-A（CP-A）、Child Pugh-B（CP-B）和 Child Pugh-C（CP-C）肝功能不全人群。健康老年人不需要调整剂量，但对于有器官功能障碍的老年人，应相应减少剂量，减少幅度与成人相似。成功开发了 LEV 的 PBPK 模型，以优化特殊人群的给药方案。
