Rioux Nathalie, Waters Nigel J
Epizyme Inc., Cambridge, Massachusetts.
Epizyme Inc., Cambridge, Massachusetts
Drug Metab Dispos. 2016 Jul;44(7):934-43. doi: 10.1124/dmd.115.068031. Epub 2016 Mar 2.
Childhood cancer represents more than 100 rare and ultra-rare diseases, with an estimated 12,400 new cases diagnosed each year in the United States. As such, this much smaller patient population has led to pediatric oncology drug development lagging behind that for adult cancers. Developing drugs for pediatric malignancies also brings with it a number of unique trial design considerations, including flexible enrollment approaches, age-appropriate formulation, acceptable sampling schedules, and balancing the need for age-stratified dosing regimens, given the smaller patient populations. The regulatory landscape for pediatric pharmacotherapy has evolved with U.S. Food and Drug Administration (FDA) legislation such as the 2012 FDA Safety and Innovation Act. In parallel, regulatory authorities have recommended the application of physiologically based pharmacokinetic (PBPK) modeling, for example, in the recently issued FDA Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases. PBPK modeling provides a quantitative and systems-based framework that allows the effects of intrinsic and extrinsic factors on drug exposure to be modeled in a mechanistic fashion. The application of PBPK modeling in drug development for pediatric cancers is relatively nascent, with several retrospective analyses of cytotoxic therapies, and latterly for targeted agents such as obatoclax and imatinib. More recently, we have employed PBPK modeling in a prospective manner to inform the first pediatric trials of pinometostat and tazemetostat in genetically defined populations (mixed lineage leukemia-rearranged and integrase interactor-1-deficient sarcomas, respectively). In this review, we evaluate the application of PBPK modeling in pediatric cancer drug development and discuss the important challenges that lie ahead in this field.
儿童癌症涵盖100多种罕见和超罕见疾病，在美国，每年估计有12400例新病例被诊断出来。因此，如此规模小得多的患者群体导致儿科肿瘤药物的开发落后于成人癌症药物的开发。开发儿科恶性肿瘤药物还带来了许多独特的试验设计考量，包括灵活的入组方法、适合年龄的剂型、可接受的采样时间表，以及鉴于患者群体较小，要平衡对年龄分层给药方案的需求。随着美国食品药品监督管理局（FDA）的立法，如2012年的《FDA安全与创新法案》，儿科药物治疗的监管环境不断演变。与此同时，监管机构推荐应用基于生理学的药代动力学（PBPK）模型，例如，在最近发布的FDA加速儿科罕见病治疗药物开发战略计划中。PBPK模型提供了一个基于定量和系统的框架，使内在和外在因素对药物暴露的影响能够以一种机制性的方式进行建模。PBPK模型在儿科癌症药物开发中的应用相对较新，已有多项对细胞毒性疗法的回顾性分析，以及最近针对诸如 obatoclax 和伊马替尼等靶向药物的分析。最近，我们以前瞻性的方式应用PBPK模型，为在基因定义人群中进行的首次匹诺司他和他泽司他儿科试验提供信息（分别为混合谱系白血病重排和整合酶相互作用因子1缺陷型肉瘤）。在本综述中，我们评估PBPK模型在儿科癌症药物开发中的应用，并讨论该领域未来面临的重要挑战。
