Antiepileptic drug development in children - Considerations for a revisited strategy
Antiepileptic drug development in children - Considerations for a revisited strategy
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DOI：
10.2165/00003495-200868010-00002
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发表时间：
2008-01-01
期刊：
影响因子：
11.5
通讯作者：
Pons, Gerard
中科院分区：
文献类型：
--
作者：
Chiron, Catherine;Dulac, Olivier;Pons, Gerard
欧洲委员会和欧洲议会已经认识到对儿童新药进行适当评估的特殊需要。对市场上可用的抗癫痫药物(AEDs)的评估表明，儿童癫痫综合征的治疗试验存在不足。目前，AEDs的发展主要是在局灶性癫痫的儿童身上进行的，而婴儿和特定的与年龄相关的癫痫综合征，特别是癫痫脑病，被忽视了。婴儿癫痫仍然是“治疗性孤儿”，尽管他们是癫痫领域最常见和最有害的疾病。为了避免在儿童中进行AED试验所面临的困难，我们解决了在不降低质量的情况下提高可行性的问题，同时最佳地考虑了儿科伦理要求。在这篇综述中，我们首先提出了儿童癫痫的问题，这些问题需要对儿童随机对照试验(RCT)进行特殊考虑。然后，我们试图确定成人数据可以在多大程度上推断到儿童身上。最后，我们回顾了可用于评估儿童抗癫痫药物的创新方法。儿童癫痫的主要特异性(异质性、严重性、认知影响、药物耐药性、症状特异性疗效谱)与大脑发育有关，在建立儿童抗癫痫药物评估的具体指南时应予以考虑。将疗效数据从成人外推到儿童可能在局灶性癫痫中是可能的，但在需要特定年龄试验的婴儿中除外。癫痫脑病在成人中不存在，需要特定的试验。药代动力学数据需要低于较低的年龄限制才能外推成人数据，以病例对病例的方法确定。任何儿科年龄都需要安全数据。在每个儿科特定癫痫综合征的小但同质人群中的随机对照试验、序贯或应答者浓缩设计的使用以及群体药代动力学是以有效的方式评估儿童药物的潜在的有希望的方法。
The European Commission and the European Parliament have acknowledged the specific need for a proper evaluation of new drugs in children. The evaluation of the antiepileptic drugs (AEDs) available on the market illustrates the deficit in therapeutic trials for childhood epilepsy syndromes. Currently, the development of AEDs is mainly performed in children with focal epilepsy, whereas infants and the specific age-related epilepsy syndromes, particularly epileptic encephalopathies, are neglected. Infantile epilepsies remain 'therapeutic orphans', although they are the most frequent and deleterious disorders in the area of epilepsy. In order to circumvent the difficulties faced when conducting AED trials in children, we addressed the question of improving feasibility without decreasing quality, while optimally taking into account paediatric ethical requirements.For this review, we first raise the issues of paediatric epilepsies that require special considerations for randomized controlled trials (RCTs) in children. Then, we attempt to determine to what extent adult data could be extrapolated to children. Finally, we review innovative approaches that could be used in the evaluation of AEDs in children.The main specificities of paediatric epilepsies (heterogeneity, severity, cognitive impact, pharmacoresistance, syndrome-specific efficacy profile) are related to brain development and should be taken into consideration when establishing specific guidelines for the evaluation of AEDs in children. Extrapolating efficacy data from adults to children may be possible in focal epilepsy except in infants who need age-specific trials. Epileptic encephalopathies do not exist in adults and require specific trials. Pharmacokinetic data are required below a lower age limit for extrapolation of adult data to be determined in a case-to-case approach. Safety data are required at any paediatric age. RCTs in small but homogeneous populations in each paediatric-specific epileptic syndrome, the use of sequential or responder-enrichment designs, and population pharmacokinetics represent potentially promising approaches to evaluate drugs in children in an efficient, way.