Model-based approaches, including population pharmacokinetic-pharmacodynamic modeling, have become an essential component in the clinical phases of oncology drug development. Over the past two decades, models have evolved to describe the temporal dynamics of biomarkers and tumor size, treatment-related adverse events, and their links to survival. Integrated models, defined here as models that incorporate at least two pharmacodynamic/ outcome variables, are applied to answer drug development questions through simulations, e.g., to support the exploration of alternative dosing strategies and study designs in subgroups of patients or other tumor indications. It is expected that these pharmacometric approaches will be expanded as regulatory authorities place further emphasis on early and individualized dosage optimization and inclusive patient-focused development strategies. This review provides an overview of integrated models in the literature, examples of the considerations that need to be made when applying these advanced pharmacometric approaches, and an outlook on the expected further expansion of model-informed drug development of anticancer drugs.

中文翻译：

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临床肿瘤药物开发中生物标志物、生存和安全性的综合建模


基于模型的方法，包括群体药代动力学-药效学建模，已成为肿瘤药物开发临床阶段的重要组成部分。在过去的二十年里，模型已经发展到描述生物标志物和肿瘤大小的时间动态、治疗相关的不良事件及其与生存的联系。集成模型，此处定义为包含至少两个药效学/结果变量的模型，用于通过模拟回答药物开发问题，例如，支持在患者亚组或其他肿瘤适应症中探索替代给药策略和研究设计。随着监管机构进一步强调早期和个体化剂量优化以及包容性的以患者为中心的开发策略，预计这些定量药理方法将得到扩展。本综述概述了文献中的集成模型，应用这些先进的药理学方法时需要考虑的考虑因素的示例，并展望了抗癌药物的模型指导药物开发的预期进一步扩展。