PDF(Pubmed)
Abstract：
Levetiracetam (LEV), a well-established anti-seizure medication (ASM), was launched before the original ICH S7B nonclinical guidance assessing QT prolongation potential and the introduction of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm. No information was available on its effects on cardiac channels. The goal of this work was to \"pressure test\" the CiPA approach with LEV and check the concordance of nonclinical core and follow-up S7B assays with clinical and post-marketing data. The following experiments were conducted with LEV (0.25-7.5 mM): patch clamp assays on hERG (acute or trafficking effects), NaV 1.5, CaV 1.2, Kir 2.1, KV 7.1/mink, KV 1.5, KV 4.3, and HCN4; in silico electrophysiology modeling (Virtual Assay® software) in control, large-variability, and high-risk human ventricular cell populations; electrophysiology measurements in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and dog Purkinje fibers; ECG measurements in conscious telemetered dogs after single oral administration (150, 300, and 600 mg/kg). Except a slight inhibition (<10%) of hERG and KV 7.1/mink at 7.5 mM, that is, 30-fold the free therapeutic plasma concentration (FTPC) at 1500 mg, LEV did not affect any other cardiac channels or hERG trafficking. In both virtual and real human cardiomyocytes, and in dog Purkinje fibers, LEV induced no relevant changes in electrophysiological parameters or arrhythmia. No QTc prolongation was noted up to 2.7 mM unbound plasma levels in conscious dogs, corresponding to 10-fold the FTPC. Nonclinical assessment integrating CiPA assays shows the absence of QT prolongation and proarrhythmic risk of LEV up to at least 10-fold the FTPC and the good concordance with clinical and postmarketing data, although this does not exclude very rare occurrence of QT prolongation cases in patients with underlying risk factors.
摘要：
左乙拉西坦(LEV),一种公认的抗癫痫药物(ASM)，在最初的ICHS7B非临床指导评估QT延长潜力和引入体外综合心律失常分析（CiPA）范例之前启动。没有关于其对心脏通道的影响的信息。这项工作的目标是用LEV对CiPA方法进行“压力测试”，并检查非临床核心和后续S7B测定与临床和上市后数据的一致性。使用LEV（0.25-7.5mM）进行以下实验：对hERG（急性或贩运效应）的膜片钳测定，NaV1.5,CaV1.2,Kir2.1,KV7.1/水貂,KV1.5、KV4.3和HCN4；控制中的计算机电生理建模（VirtualAssay®软件），大可变性，和高风险的人心室细胞群；人诱导多能干细胞（hiPSC）衍生的心肌细胞和狗Purkinje纤维的电生理学测量；一次口服给药后有意识的遥测狗的ECG测量（150、300和600mg/kg）。除了在7.5mM时对hERG和KV7.1/mink有轻微抑制(<10%),也就是说,1500mg时的游离治疗血浆浓度（FTPC）的30倍，LEV不影响任何其他心脏通道或hERG运输。在虚拟和真实的人类心肌细胞中，在狗浦肯野纤维中，LEV未引起电生理参数或心律失常的相关变化。在清醒的狗中，未发现QTc延长至2.7mM未结合血浆水平，相当于FTPC的10倍。结合CiPA测定的非临床评估显示，QT延长和LEV的心律失常风险不存在，至少是FTPC的10倍，并且与临床和上市后数据具有良好的一致性。尽管这并不排除在具有潜在危险因素的患者中非常罕见的QT延长病例。
