Mehrotra Nitin, Bhattaram Atul, Earp Justin C, Florian Jeffry, Krudys Kevin, Lee Jee Eun, Lee Joo Yeon, Liu Jiang, Mulugeta Yeruk, Yu Jingyu, Zhao Ping, Sinha Vikram
Division of Pharmacometrics, Office of Clinical Pharmacology (N.M., A.B., J.C.E., J.F., K.K., J.E.L., J.L., Y.M., J.Y., P.Z., V.S.), and Division of Biometrics VII, Office of Biostatistics (J.Y.L.), Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland
Division of Pharmacometrics, Office of Clinical Pharmacology (N.M., A.B., J.C.E., J.F., K.K., J.E.L., J.L., Y.M., J.Y., P.Z., V.S.), and Division of Biometrics VII, Office of Biostatistics (J.Y.L.), Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.
Drug Metab Dispos. 2016 Jul;44(7):924-33. doi: 10.1124/dmd.116.069559. Epub 2016 Apr 14.
Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twice-daily regimen, different once-daily dosing regimens for treatment-naïve human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy.
剂量选择是儿科药物研发过程中的关键决策之一。有一些监管举措促进了基于模型的儿科药物研发的应用。药物计量学或定量临床药理学能够开发出可描述影响儿科患者药代动力学和/或药效动力学因素的模型。本手稿描述了一些使用药物计量学分析来支持儿科药物批准和标签制定的实例。特别强调了儿科药代动力学与成人药代动力学比较的作用以及剂量/暴露-反应分析在剂量选择中的应用。儿科埃索美拉唑的剂量选择基于与成人的药代动力学匹配，而对于阿达木单抗，暴露-反应、药代动力学、疗效和安全性数据共同有助于推荐儿科克罗恩病的剂量。对于vigabatrin，证明儿科与成人之间具有相似的剂量反应关系使得能够选择儿科剂量。基于每日两次给药方案的达芦那韦儿科临床研究的基于模型的药代动力学模拟和安全性数据，对3至<12岁初治的人类免疫缺陷病毒1感染儿科受试者的不同每日一次给药方案进行了评估。基于生理的药代动力学建模（PBPK）在预测儿科药代动力学方面的作用正在迅速发展。然而，监管审查经验和对科学现状的理解表明，PBPK在儿科药代动力学预测方面缺乏既定的预测性能。展望未来，药物计量学将继续在儿科药物研发中发挥关键作用，为剂量选择、试验设计以及评估与成人疾病的相似性以支持疗效外推等决策做出贡献。
