Genentech, Inc., South San Francisco, California, USA.
Certara, Menlo Park, California, USA.
CPT Pharmacometrics Syst Pharmacol. 2019 Apr;8(4):240-248. doi: 10.1002/psp4.12394. Epub 2019 Mar 6.
The aims of this work were to characterize ipatasertib exposure-response (E-R) relationships in a phase II study and to quantitatively assess benefit-risk using a clinical utility index approach to support ipatasertib phase III dose selection in patients with metastatic castration-resistant prostate cancer. Logistic regression and Cox proportional-hazards models characterized E-R relationships for safety and efficacy endpoints, respectively. Exposure metrics with and without considering dose interruptions/reductions (modifications) were tested in the E-R models. Despite a steeper E-R relationship when accounting for dose modifications, similar dose-response projections were generated. The clinical utility index analysis assessed important attributes, weights, and clinically meaningful cutoff/tradeoff values based on predefined minimal, target, and optimistic product profiles. Ipatasertib 400 mg daily, showing the highest probability of achieving the minimal product profiles and better benefit-risk balance than other doses (200-500 mg daily), was selected for further development in metastatic castration-resistant prostate cancer.
本研究旨在通过 II 期研究描述伊帕替斯巴（ipatasertib）的暴露-反应（E-R）关系，并采用临床实用指数方法定量评估获益-风险，以支持转移性去势抵抗性前列腺癌患者中伊帕替斯巴的 III 期剂量选择。逻辑回归和 Cox 比例风险模型分别对安全性和有效性终点的 E-R 关系进行了描述。在 E-R 模型中，测试了考虑和不考虑剂量中断/减少（修改）的暴露指标。尽管在考虑剂量修改时 E-R 关系更为陡峭，但仍得出了相似的剂量反应预测。临床实用指数分析根据预设的最小、目标和乐观产品特征，评估了重要属性、权重和有临床意义的临界值/权衡值。选择每日 400mg 的伊帕替斯巴（ipatasertib），因其具有最高的达到最小产品特征的概率，且与其他剂量（每日 200-500mg）相比具有更好的获益-风险平衡，因此被进一步开发用于转移性去势抵抗性前列腺癌。
