Pigeolet Etienne, Jacqmin Philippe, Sargentini-Maier Maria-Laura, Stockis Armel
Global Pharmacometrics, UCB Pharma SA, Braine-l'Alleud, Belgium.
Clin Pharmacokinet. 2007;46(6):503-12. doi: 10.2165/00003088-200746060-00004.
To assess the population pharmacokinetics of levetiracetam, a second-generation antiepileptic drug, in adult Japanese and Western populations.
Data were pooled from ten matched clinical trials conducted in Japan and in Europe and the USA, in which levetiracetam was administered orally to healthy subjects and subjects with epilepsy. Overall, 5408 plasma concentrations were available from 524 subjects in six clinical pharmacology studies and two confirmatory and two long-term safety studies of add-on treatment for partial epilepsy. A one-compartment open model with first-order absorption and elimination was fitted to the plasma concentrations using nonlinear mixed-effects modelling with first-order estimation.
Ethnicity had no statistically significant effect on the pharmacokinetics of levetiracetam in the presence of the other covariates. Bodyweight, sex, creatinine clearance and concomitant intake of enzyme inducers or valproic acid had a statistically significant effect on apparent plasma clearance of levetiracetam. Bodyweight, disease and valproic acid had a statistically significant effect on the volume of distribution. Levetiracetam exposure (the area under the plasma concentration-time curve over the 12-hour dosing interval at steady state) was 12% higher in females than in males. Decreasing bodyweight from 70 kg to 40 kg was predicted to increase exposure by 16%, while halving creatinine clearance was predicted to increase exposure by 10%. Enzyme inducers reduced exposure by 8%, while valproic acid resulted in a 23% increase in exposure. The latter effect was assumed to arise from the known association between valproic acid and increased body fat, since levetiracetam is negligibly metabolised by cytochrome P450 enzymes.
Population pharmacokinetic analysis points to the absence of ethnic differences in the pharmacokinetics of levetiracetam between Japanese and Western populations, other than those arising from bodyweight differences. Small, clinically non-relevant differences between individual demographic characteristics suggest that dose adjustment is usually not necessary.
评估第二代抗癫痫药物左乙拉西坦在成年日本人群和西方人群中的群体药代动力学。
数据来自在日本以及欧洲和美国进行的十项匹配的临床试验，其中左乙拉西坦口服给药于健康受试者和癫痫患者。总体而言，在六项临床药理学研究以及两项部分性癫痫附加治疗的确证性研究和两项长期安全性研究中，从524名受试者获得了5408个血浆浓度数据。使用一阶估计的非线性混合效应模型，将具有一级吸收和消除的单室开放模型拟合到血浆浓度数据。
在存在其他协变量的情况下，种族对左乙拉西坦的药代动力学没有统计学上的显著影响。体重、性别、肌酐清除率以及酶诱导剂或丙戊酸的同时服用对左乙拉西坦的表观血浆清除率有统计学上的显著影响。体重、疾病和丙戊酸对分布容积有统计学上的显著影响。女性的左乙拉西坦暴露量（稳态下12小时给药间隔的血浆浓度-时间曲线下面积）比男性高12%。预计体重从70 kg降至40 kg会使暴露量增加16%，而肌酐清除率减半预计会使暴露量增加10%。酶诱导剂使暴露量降低8%，而丙戊酸使暴露量增加23%。后一种效应被认为是由于丙戊酸与体脂增加之间的已知关联所致，因为左乙拉西坦经细胞色素P450酶的代谢可忽略不计。
群体药代动力学分析表明，除了体重差异导致的不同外，日本人群和西方人群在左乙拉西坦药代动力学方面不存在种族差异。个体人口统计学特征之间微小的、临床无关紧要的差异表明通常无需调整剂量。
