药物引起的惊厥是药物开发中的一个严重问题,因此,必须在临床前安全性研究中评估候选药物的惊厥责任。然而,关于物种之间对人类惊厥药物引起的惊厥敏感性的差异的信息仍然有限。这里,我们从几个药理学类别中选择了11篇测试文章,并比较了三种类型的实验动物对惊厥的敏感性。通过腹膜内注射在小鼠中和通过静脉推注在大鼠中检查所有11个测试物品;并且11个测试物品中的6个,主要根据抽搐时人体药物血浆浓度数据的可用性进行选择,通过静脉输注在非人灵长类动物(NHP)中进行检查。在惊厥发作后不久或给药后5分钟测量测试物品的血浆浓度。所有11篇文章在小鼠中测试,在大鼠中测试的11篇文章中有10篇,在NHP中测试的所有6篇文章均具有先兆征象。虽然有一个普遍的趋势,大鼠和NHP表现出惊厥在较低的血浆药物浓度比小鼠,惊厥发作时的血浆浓度大致相当,在3倍差异内,跨动物物种。我们得出结论,老鼠,老鼠,本研究中检查的NHP通常对供试品引起的惊厥表现出相似的敏感性。因此,这些实验动物中的每一种都可用于在药物开发的早期阶段评估惊厥风险,根据吞吐量,成本,和测试文章的具体要求。
Drug-induced
convulsion is a serious concern in drug development, such that the
convulsion liability of drug candidates must be evaluated in preclinical safety studies. However, information on the differences among species regarding their sensitivity to convulsions induced by convulsant drugs in humans remains limited. Here, we selected 11 test articles from several pharmacological classes and compared the sensitivities of three types of laboratory animal to
convulsion. All 11 test articles were examined in mice via intraperitoneal injection and in rats via intravenous bolus; and 6 of the 11 test articles, selected mainly based on availabilities of data on drug plasma concentrations in humans at
convulsion, were examined in non-human primates (NHPs) via intravenous infusion. Plasma concentrations of the test articles shortly after
convulsion onset or 5 min after administration were measured. All 11 articles tested in mice, 10 of 11 articles tested in rats, and all 6 articles tested in NHPs induced convulsion with premonitory signs. Although there was a general tendency that rats and NHPs exhibited convulsions at lower plasma drug concentrations than did mice, the plasma concentrations at convulsion onset were generally comparable, within 3-fold differences, across the animal species. We conclude that the mice, rats, and NHPs examined in the present study generally showed similar sensitivities to convulsion induced by the test articles. Thus, each of these laboratory animals can be used for the assessment of
convulsion risk in the early stages of drug development, depending on throughput, cost, and test article-specific requirements.