为了取代传统的最大耐受剂量（MTD）方法，肿瘤学中提出了一种依赖于模型知情药物开发（MIDD）方法的剂量优化和剂量选择范例。在这里，我们报告了我们在第一阶段应用 MIDD 方法，为 datopotamab deruxtecan (Dato-DXd) 后期开发的剂量选择提供信息。 Dato-DXd 是一种针对 TROP2 的抗体药物偶联物，正在开发用于晚期/转移性非小细胞肺癌 (NSCLC) 和其他肿瘤。 TROPION-PanTumor01 I 期剂量扩展和递增研究收集了 NSCLC 中的药代动力学 (PK)、疗效和安全性数据，剂量范围广泛，每 3 周给药 0.27-10 mg/kg。在三个数据截止点迭代进行群体 PK 和暴露反应分析，以告知剂量选择。通过第二次数据截止分析确定6mg/kg剂量为最佳剂量，并通过随后的第三次数据截止分析确认。 6mg/kg 剂量比 MTD (8mg/kg) 更耐受（即间质性肺疾病、口腔炎和粘膜炎症的发生率较低），并且比 4mg/kg 更有效（模拟平均客观缓解率： 23.8% vs. 18.6%；无进展生存的平均风险比：0.74）——研究的候选剂量略低于 6mg/kg。因此，6mg/kg剂量被认为能够提供最佳的利益-风险平衡。本案例研究展示了 MIDD 方法在剂量优化和剂量选择方面的实用性。© 2023 Daiichi Sankyo, Inc. CPT：药理学

To replace the conventional maximum tolerated dose (MTD) approach, a paradigm for dose optimization and dose selection that relies on model-informed drug development (MIDD) approaches has been proposed in oncology. Here, we report our application of an MIDD approach during phase I to inform dose selection for the late-stage development of datopotamab deruxtecan (Dato-DXd). Dato-DXd is a TROP2-directed antibody-drug conjugate being developed for advanced/metastatic non-small cell lung cancer (NSCLC) and other tumors. Data on pharmacokinetics (PKs), efficacy, and safety in NSCLC were collected in the TROPION-PanTumor01 phase I dose-expansion and -escalation study over a wide dose range of 0.27-10 mg/kg administered every 3 weeks. Population PK and exposure-response analyses were performed iteratively at three data cutoffs to inform dose selection. The 6 mg/kg dose was identified as the optimal dose by the second data cutoff analysis and confirmed by the subsequent third data cutoff analysis. The 6 mg/kg dose was more tolerable (i.e., lower rates of interstitial lung disease, stomatitis, and mucosal inflammation) than the MTD (8 mg/kg) and was more efficacious than 4 mg/kg (simulated mean objective response rate: 23.8% vs. 18.6%; mean hazard ratio of progression-free survival: 0.74) - a candidate dose studied just below 6 mg/kg. Therefore, the 6 mg/kg dose was judged to afford the optimal benefit-risk balance. This case study demonstrated the utility of an MIDD approach for dose optimization and dose selection.© 2023 Daiichi Sankyo, Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.