Understanding the Relative Roles of Pharmacogenetics and Ontogeny in Pediatric Drug Development and Regulatory Science
Understanding the Relative Roles of Pharmacogenetics and Ontogeny in Pediatric Drug Development and Regulatory Science
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DOI：
10.1177/0091270009360533
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发表时间：
2010-12-01
影响因子：
2.9
通讯作者：
van den Anker, John
中科院分区：
文献类型：
--
作者：
Leeder, J. Steven;Kearns, Gregory L.;van den Anker, John
对于临床医生、制药公司和监管机构来说，了解从早产儿和足月儿到婴儿、儿童、青少年和成年人的整个儿科年龄段的剂量-暴露-反应关系是一个重大挑战。在过去的30年里，对儿科治疗中常用的许多药物的临床研究为药物处置和作用的年龄差异提供了有价值的见解。然而，我们对遗传变异对儿童药物处置和反应的变异性的贡献的理解总体上落后于成年人。本文提出了一种系统的方法，可以用来评估个体发育和遗传变异对给定化合物的相对贡献。以非处方咳嗽和感冒药的安全性和有效性所造成的当前监管困境为例，说明了该战略的应用。分析结果可用于辅助研究设计，以便在不同年龄和发育阶段的儿科人群中产生最大信息量的数据，从而提高研究设计的效率。
Understanding the dose-exposure-response relationship across the pediatric age spectrum from preterm and term newborns to infants, children, adolescents, and adults is a major challenge for clinicians, pharmaceutical companies, and regulatory agencies. Over the past 3 decades, clinical investigations of many drugs commonly used in pediatric therapeutics have provided valuable insights into age-associated differences in drug disposition and action. However, our understanding of the contribution of genetic variation to variability in drug disposition and response in children generally has lagged behind that of adults. This article proposes a systematic approach that can be used to assess the relative contributions of ontogeny and genetic variation for a given compound. Application of the strategy is illustrated using the current regulatory dilemma posed by the safety and effectiveness of over-the-counter cough and cold remedies as an example. The results of the analysis can be used to aid in the design of studies to yield maximally informative data in pediatric populations of different ages and developmental stages and thereby improve the efficiency of study design.