van der Laan Jan Willem, van Malderen Karen, de Jager Nico, Duarte Dinah, Egger Gunter F, Lavergne Fabien, Roque Cláudio Gouveia, Vieira Isabel, Wiesner Lutz, Carleer Jacqueline
Section on Pharmacological, Toxicological, and Kinetic Assessment, Medical Evaluation Board (MEB), Utrecht, the Netherlands.
Division of Toxicology, Leiden Academic Center for Drug Research, Leiden, the Netherlands.
Int J Toxicol. 2019 Nov/Dec;38(6):456-475. doi: 10.1177/1091581819883569. Epub 2019 Oct 29.
Central nervous system (CNS)-targeted products are an important category of pediatric pharmaceuticals. In view of the significant postnatal maturation of the CNS, juvenile animal studies (JAS) are performed to support pediatric development of these new medicines. In this project, the design and results of juvenile toxicity studies from 15 drug compounds for the treatment of neurologic or psychiatric conditions were analyzed. Studies were conducted mostly in rats; sometimes in addition in dogs and monkeys. The study design of the pivotal JAS was variable, even for compounds with a similar therapeutic indication. Age of the juvenile animals was not consistently related to the starting age of the intended patient population. Of 15 compounds analyzed, 6 JAS detected more severe toxicities and 6 JAS evidenced novel CNS effects compared to their adult counterparts. The effects of CNS on acoustic startle and learning and memory were observed at high dosages. Reversibility was tested in most cases and revealed some small effects that were retained or only uncovered after termination of treatment. The interpretation of the relevance of these findings was often hampered by the lack of matching end points in the adult studies or inappropriate study designs. Detailed clinical observation and motor activity measures were the most powerful end points to detect juvenile CNS effects. The need for more detailed behavioral examinations in JAS, for example, on learning and memory, should, therefore, be decided upon on a case-by-case basis, based on specific concerns in order to avoid overloading the studies.
中枢神经系统（CNS）靶向产品是儿科药物的一个重要类别。鉴于中枢神经系统在出生后显著成熟，需开展幼年动物研究（JAS）以支持这些新药的儿科研发。在本项目中，分析了15种用于治疗神经或精神疾病的药物化合物的幼年毒性研究设计和结果。研究主要在大鼠中进行，有时也会在犬类和猴类中开展。关键幼年动物研究的设计各不相同，即使是治疗指征相似的化合物也是如此。幼年动物的年龄与预期患者群体的起始年龄并非始终相关。在分析的15种化合物中，6项幼年动物研究发现了比成年动物更严重的毒性，6项幼年动物研究证明了与成年动物相比新的中枢神经系统效应。在高剂量下观察到中枢神经系统对听觉惊吓以及学习和记忆的影响。大多数情况下对可逆性进行了测试，结果显示在治疗终止后仍保留或才发现一些微小效应。这些发现的相关性解读常常因成年研究中缺乏匹配的终点或不恰当的研究设计而受阻。详细的临床观察和运动活动测量是检测幼年中枢神经系统效应最有效的终点。因此，应根据具体情况，基于特定关注点，决定是否需要在幼年动物研究中进行更详细的行为检查，例如关于学习和记忆的检查，以避免研究负担过重。
