左乙拉西坦缓释片在中国健康受试者中的药代动力学、安全性及与速释片相比的相对生物利用度

Pharmacokinetics and Safety of Levetiracetam Extended-Release Tablets and Relative Bioavailability Compared with Immediate-Release Tablets in Healthy Chinese Subjects.

作者信息

Wang Meng, Wang Mengmeng, Zhang Quanying, Zong Shunlin, Lv Chengzhe

机构信息

Clinical Pharmacology Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.

Department of Pharmaceutics, Children's Hospital of Soochow University, No. 92 Zhongnan Street, Suzhou, 215025, China.

出版信息

Eur J Drug Metab Pharmacokinet. 2018 Aug;43(4):405-413. doi: 10.1007/s13318-018-0461-2.

DOI:10.1007/s13318-018-0461-2

PMID:29383569

Abstract

BACKGROUND AND OBJECTIVES

Levetiracetam is a second-generation antiepileptic drug and distributed ubiquitously in the central nervous system. The extended-release formulation of levetiracetam was developed to provide patients with the convenience of once-daily dosing, to improve drug compliance and tolerability. The objective of this study was to evaluate the pharmacokinetics and safety of levetiracetam extended-release (ER) tablets in healthy Chinese subjects following single and multiple doses.

METHODS

Two panels of 34 healthy subjects were enrolled. Trial 1 was a two-way crossover between levetiracetam ER tablets and immediate-release (IR) tablets under fasting conditions. Trial 2 was a four-way crossover single-dose study between levetiracetam ER fasted and ER with food.

RESULTS

Intake of single and multiple levetiracetam ER tablets resulted in a 42.3% lower maximum plasma concentration (C) and a 33.6% lower minimum steady-state plasma concentration (C) than IR tablet intake, while the median time to C (t) was significantly delayed. The 90% CI of the ER/IR ratios for area under the curve (AUC) from zero to last measurable sample (AUC), AUC from zero to infinity (AUC), AUC at steady state (AUC, τ = 24 h), C at steady state (C) and average concentration at steady state (C) were contained within the 80-125% range of bioequivalence. The C and AUC were dose proportional across the dose cohorts. Following a high-fat meal, levetiracetam ER tablets resulted in a 14.4% higher C. The 90% confidence interval (CIs) of the fed/fasted ratios for C and AUC were entirely contained within the 80-125% range of bioequivalence acceptance, except the t was delayed (P < 0.05). The most frequent treatment-emergent adverse events were somnolence, dizziness and thirst.

CONCLUSIONS

After single and multiple doses, the absorption of levetiracetam ER was equal to IR, the t was significantly delayed, and the C and C were significantly decreased. Food did not affect the absorption of the levetiracetam ER tablet, but the C increased and the t was delayed. The levetiracetam ER tablet was well tolerated and found to be dose proportional from 500 to 2000 mg in healthy Chinese subjects.

摘要

背景与目的

左乙拉西坦是第二代抗癫痫药物，在中枢神经系统中广泛分布。左乙拉西坦缓释制剂的研发旨在为患者提供每日一次给药的便利，提高药物依从性和耐受性。本研究的目的是评估左乙拉西坦缓释（ER）片在健康中国受试者单次和多次给药后的药代动力学和安全性。

方法

招募了两组各34名健康受试者。试验1是在禁食条件下左乙拉西坦ER片与速释（IR）片的双向交叉试验。试验2是左乙拉西坦ER禁食与进食后ER的四向交叉单剂量研究。

结果

与服用IR片相比，单次和多次服用左乙拉西坦ER片导致最大血浆浓度（Cmax）降低42.3%，最低稳态血浆浓度（Cmin）降低33.6%，而达到Cmax的中位时间（tmax）显著延迟。从零到最后可测量样本的曲线下面积（AUC）、从零到无穷大的AUC（AUC∞）、稳态下的AUC（AUCss，τ = 24小时）、稳态下的Cmax（Cmax）和稳态下的平均浓度（Cavg）的ER/IR比值的90%置信区间（CI）包含在生物等效性的80 - 125%范围内。Cmax和AUC在各个剂量组中与剂量成比例。高脂餐后，左乙拉西坦ER片导致Cmax升高14.4%。Cmax和AUC的进食/禁食比值的90%置信区间（CIs）完全包含在生物等效性接受的80 - 125%范围内，除了tmax延迟（P < 0.05）。最常见的治疗中出现的不良事件是嗜睡、头晕和口渴。