Shengzhou Branch, the First Affiliated Hospital of Zhejiang University, School of Medicine, Shengzhou, Zhejiang, China.
Department of Pharmacy, the Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
Clin Ther. 2024 Mar;46(3):258-266. doi: 10.1016/j.clinthera.2024.01.008. Epub 2024 Feb 17.
Lacosamide (LCM) is a new-generation anti-seizure medication that is efficacious in patients with focal seizures with or without secondary generalization. Until now, the efficacy, safety, and tolerability of LCM are still lacking in Chinese epilepsy patients, particularly for pediatric populations and patients with renal or hepatic impairment.
This study was conducted to develop a physiologically based pharmacokinetic (PBPK) model to characterize the pharmacokinetics of LCM in Chinese populations and predict the pharmacokinetics of LCM in Chinese pediatric populations and patients with renal or hepatic impairment. Using data from clinical investigations, the developed PBPK model was validated by comparing predicted and observed blood concentration data.
Doses should be reduced to approximately 82%, 75%, 63%, and 76% of the Chinese healthy adult dose in patients with mild, moderate, and severe renal impairment and end-stage renal disease; and approximately 89%, 72%, and 36% of the Chinese healthy adult dose in patients with Child Pugh-A, B, and C hepatic impairment. For pediatric populations, intravenous doses should be adjusted to 1.75 mg/kg for newborns, 2.5 mg/kg for toddlers, 2.2 mg/kg mg for preschool and school age, and 2 mg/kg mg for adolescents to achieve an equivalent plasma exposure of 2 mg/kg LCM in adults. The oral doses should be adjusted to 20 mg for toddlers, 32 mg for preschool, 45 mg for school age, and 95 mg for adolescents to achieve an approximately equivalent plasma exposure of 100 mg LCM in adults.
The PBPK model of LCM can be utilized to optimize dosage regimens for special populations.
拉科酰胺（LCM）是一种新型抗癫痫药物，对有或无继发全面性发作的局灶性癫痫发作患者有效。到目前为止，LCM 的疗效、安全性和耐受性在中国癫痫患者中仍然缺乏，特别是在儿科人群和有肾或肝损伤的患者中。
本研究旨在建立一种基于生理学的药代动力学（PBPK）模型，以描述 LCM 在中国人中的药代动力学特征，并预测 LCM 在中国人儿科人群和有肾或肝损伤的患者中的药代动力学。利用临床研究数据，通过比较预测和观察的血药浓度数据来验证所建立的 PBPK 模型。
在轻、中、重度肾损伤和终末期肾病患者中，LCM 的剂量应分别减少至中国健康成年人剂量的约 82%、75%、63%和 76%；在 Child Pugh-A、B 和 C 肝损伤患者中，LCM 的剂量应分别减少至中国健康成年人剂量的约 89%、72%和 36%。对于儿科人群，静脉内给予 1.75 mg/kg 新生儿、2.5 mg/kg 幼儿、2.2 mg/kg 学龄前和学龄儿童以及 2 mg/kg mg 青少年，可使成人血浆暴露量相当于 2 mg/kg LCM；口服给予 20 mg 幼儿、32 mg 学龄前儿童、45 mg 学龄儿童和 95 mg 青少年，可使成人血浆暴露量相当于 100 mg LCM。
LCM 的 PBPK 模型可用于优化特殊人群的剂量方案。
