Model‐informed drug development (MIDD) is a powerful quantitative approach that plays an integral role in drug development and regulatory review. While applied throughout the life cycle of the development of new drugs, a key application of MIDD is to inform clinical trial design including dose selection and optimization. To date, physiologically‐based pharmacokinetic (PBPK) modeling, an established component of the MIDD toolkit, has mainly been used for assessment of drug–drug interactions (DDIs) and consequential dose adjustments in regulatory submissions. As a result of recent scientific advances and growing confidence in the utility of the approach, PBPK models are being increasingly applied to provide dose recommendations for subjects with differing ages, genetics, and disease states. In this review, we present our perspective on the current landscape of regulatory acceptance of PBPK applications supported by relevant case studies. We also discuss the recent progress and future challenges associated with expanding the utility of PBPK models into emerging areas for regulatory decision making, especially dose optimization in highly vulnerable and understudied populations and facilitating diversity in clinical trials.

中文翻译：

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基于 PBPK 建模的剂量优化：最先进的技术和未来

模型知情药物开发（MIDD）是一种强大的定量方法，在药物开发和监管审查中发挥着不可或缺的作用。尽管 MIDD 应用于新药开发的整个生命周期，但 MIDD 的一个关键应用是为临床试验设计（包括剂量选择和优化）提供信息。迄今为止，基于生理学的药代动力学 (PBPK) 模型是 MIDD 工具包的一个既定组成部分，主要用于评估药物相互作用 (DDI) 以及监管提交中相应的剂量调整。由于最近的科学进步以及对该方法实用性的信心不断增强，PBPK 模型越来越多地被应用于为不同年龄、遗传和疾病状态的受试者提供剂量建议。在这篇综述中，我们通过相关案例研究提出了对 PBPK 申请监管接受现状的看法。我们还讨论了将 PBPK 模型的实用性扩展到监管决策新兴领域的最新进展和未来挑战，特别是高度脆弱和研究不足的人群的剂量优化以及促进临床试验的多样性。