UCB Pharma, Global Biostatistics, Alfred-Nobel-Strasse 10, 40789, Monheim am Rhein, Germany,
Clin Pharmacokinet. 2013 Oct;52(10):897-906. doi: 10.1007/s40262-013-0080-7.
The antiepileptic drug lacosamide is eliminated predominantly via the kidneys. Therefore, an evaluation of the impact of renal impairment on its pharmacokinetic profile is an important component of its safety assessment. The objective of this study was to evaluate the pharmacokinetic profile of lacosamide among individuals with renal impairment (mild, moderate, or severe) and among patients with end-stage renal disease (ESRD), including those on hemodialysis.
This was an open-label, Phase I trial. The pharmacokinetics of a single oral 100-mg lacosamide dose were evaluated in five groups of participants: healthy controls, patients with mild, moderate, or severe renal impairment, and patients with ESRD (with and without hemodialysis).
Forty participants completed the trial, eight in each group. In healthy volunteers, renal clearance accounted for approximately 30 % of total body clearance [geometric mean 0.5897 l/h (coefficient of variation 37.9 %) vs 2.13 l/h (20.8 %)]. With severe renal impairment, renal clearance was approximately 11 % of total body clearance [0.1428 l/h (31.8 %) vs 1.34 l/h (26.9 %)]. Terminal half-life and systemic exposure were increased with renal impairment, while total body clearance, renal clearance, and urinary excretion were decreased. Strong positive correlations between creatinine clearance, renal clearance, and urinary excretion were observed. Among patients with ESRD, approximately 50 % of lacosamide was cleared from systemic circulation by 4-h hemodialysis. In patients with essentially no renal clearance, nonrenal clearance was still present (1.1 l/h). Lacosamide was well tolerated by healthy volunteers and patients.
In patients with mild-to-moderate renal impairment, lacosamide dose adjustment is not necessary, because total body clearance decreased by only approximately 20 %. Dose adjustment, however, is required for patients with severe renal impairment. Hemodialysis removes approximately 50 % of lacosamide from plasma; therefore, dose supplementation following hemodialysis should be considered.
抗癫痫药物拉科酰胺主要通过肾脏消除。因此，评估肾功能损害对其药代动力学特征的影响是其安全性评估的重要组成部分。本研究的目的是评估肾功能损害（轻度、中度或重度）和终末期肾病（ESRD）患者（包括接受血液透析的患者）中拉科酰胺的药代动力学特征。
这是一项开放标签、I 期临床试验。评估了单次口服 100mg 拉科酰胺剂量在五组参与者中的药代动力学：健康对照者、轻度、中度、重度肾功能损害患者和 ESRD 患者（包括血液透析患者）。
40 名参与者完成了试验，每组 8 名。在健康志愿者中，肾清除率约占总清除率的 30%[几何均数 0.5897 l/h（变异系数 37.9%）比 2.13 l/h（20.8%）]。严重肾功能损害时，肾清除率约为总清除率的 11%[0.1428 l/h（31.8%）比 1.34 l/h（26.9%）]。随着肾功能损害，终末半衰期和全身暴露增加，而总清除率、肾清除率和尿排泄减少。观察到肌酐清除率、肾清除率和尿排泄之间存在强烈的正相关。在 ESRD 患者中，大约 50%的拉科酰胺在 4 小时血液透析中从全身循环中清除。在几乎没有肾清除率的患者中，仍存在非肾清除率（1.1 l/h）。拉科酰胺在健康志愿者和患者中均耐受良好。
在轻度至中度肾功能损害患者中，不需要调整拉科酰胺剂量，因为总清除率仅下降约 20%。然而，对于严重肾功能损害的患者需要调整剂量。血液透析从血浆中清除大约 50%的拉科酰胺；因此，应考虑在血液透析后补充剂量。
