Division of Clinical Pharmacology and Medical Toxicology, Department of Pediatrics, Children's Mercy Hospitals and Clinics, School of Medicine, University of Missouri-Kansas City, 2401 Gillham Road, Kansas City, MO 64108, USA.
J Clin Pharmacol. 2010 Dec;50(12):1377-87. doi: 10.1177/0091270009360533. Epub 2010 Feb 11.
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.
理解从早产儿和足月儿到婴儿、儿童、青少年和成年人的儿科年龄谱中的剂量-暴露-反应关系，是临床医生、制药公司和监管机构面临的主要挑战。在过去的 30 年中，许多常用于儿科治疗的药物的临床研究为药物处置和作用与年龄相关的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变异性的贡献的理解总体上落后于成人。本文提出了一种系统的方法，可用于评估特定化合物的个体发育和遗传变异的相对贡献。该策略的应用通过以非处方咳嗽和感冒药物的安全性和有效性所带来的当前监管困境为例进行了说明。分析结果可用于帮助设计研究，在不同年龄和发育阶段的儿科人群中获得最具信息性的数据，从而提高研究设计的效率。
