Leil Tarek A, Zee Pamela, Suryawanshi Satyendra, Male Christoph, Portman Ronald
1 Bristol-Myers Squibb Company, Lawrenceville, NJ, USA.
2 Department of Paediatrics, Medical University of Vienna, Vienna, Austria.
Ther Innov Regul Sci. 2013 Sep;47(5):557-565. doi: 10.1177/2168479013500286.
Confirmation of efficacy in pediatric drug development has traditionally required large, fully powered efficacy studies that have proven to have major feasibility and ethical challenges. Extrapolation of efficacy in the framework provided by the US Food and Drug Administration and European Medicines Agency is an appropriate solution when there is similarity of disease. When there is uncertainty regarding the degree of disease similarity, partial extrapolation may be utilized. The authors propose a more quantitative approach to partial extrapolation (ie, quantitative extrapolation), involving (1) integration of adult pharmacokinetic (PK), pharmacodynamic (PD), and clinical outcome data using pharmacometric models, (2) extrapolation using the adult pharmacometric model to predict PD and efficacy outcomes in pediatric subjects, and (3) validation of pediatric predictions with a streamlined plan of pediatric trials (ie, a quantitative extrapolation plan). A case study is presented for quantitative extrapolation using dipeptidyl peptidase 4 (DPP-4) inhibitors. In this example, the authors demonstrate how adult PK, PD, and HbA1c data can be integrated using a pharmacometric model for DPP-4 inhibitors with pediatric dose selection and efficacy validated with relatively few pediatric subjects.
在儿科药物研发中，传统上确认疗效需要进行大规模、具备充分效力的疗效研究，而这些研究已证明存在重大的可行性和伦理挑战。在美国食品药品监督管理局和欧洲药品管理局提供的框架内，当疾病具有相似性时，外推疗效是一种合适的解决方案。当疾病相似程度存在不确定性时，可以采用部分外推法。作者提出了一种更具定量性的部分外推方法（即定量外推），包括：（1）使用药代动力学模型整合成人药代动力学（PK）、药效学（PD）和临床结局数据；（2）使用成人药代动力学模型进行外推，以预测儿科受试者的PD和疗效结局；（3）通过简化的儿科试验计划（即定量外推计划）验证儿科预测结果。本文给出了一个使用二肽基肽酶4（DPP-4）抑制剂进行定量外推的案例研究。在这个例子中，作者展示了如何使用DPP-4抑制剂的药代动力学模型整合成人PK、PD和糖化血红蛋白（HbA1c）数据，并通过相对较少的儿科受试者验证儿科剂量选择和疗效。
