Abstract：
This study aimed to establish a population pharmacokinetic (PopPK) model using data from 2 clinical trials of zimberelimab, evaluate the pharmacokinetics (PKs) of zimberelimab, explore the feasibility of 360 mg once every 3 weeks (Q3W) and 480 mg once every 4 weeks (Q4W) as alternative dosage regimens, and analyze the exposure-response relationship of the efficacy and safety of zimberelimab for advanced tumors. The PKs of zimberelimab were described using the 2-compartment model with time-dependent nonlinear elimination. The prediction-corrected visual predictive check was used to evaluate the model\'s predictive value on blood drug concentrations. In total, 2165 PK observations from 321 participants were included. The PopPK model demonstrated a high level of concordance between the observed data and the predicted values, indicative of a robust fit to the PK data of zimberelimab. The PK variables were similar for the 240 mg once every 2 weeks, 360 mg Q3W, and 480 mg Q4W regimens. No covariates significantly affecting the PK variables in the final model were found. The exposure variables of zimberelimab have no obvious correlations with efficacy and safety, and 360 mg Q3W and 480 mg Q4W are worthy of further study. This study establishes a PopPK model and analyzes the exposure-response relationship of zimberelimab, which helps to explore the potential for alternative dosing regimens and offers a foundation for optimizing therapeutic strategies for advanced cancer patients through simulation-based methods.
摘要：
本研究旨在建立群体药代动力学（PopPK）模型，使用来自2项临床试验的数据，评估齐姆贝雷利马的药代动力学（PKs），探讨360毫克每3周一次（Q3W）和480毫克每4周一次（Q4W）作为替代剂量方案的可行性，并分析齐姆贝瑞利马治疗晚期肿瘤的疗效和安全性的暴露-反应关系。使用具有时间依赖性非线性消除的2室模型描述了zimberelimab的PKs。预测校正的视觉预测检查用于评估模型对血药浓度的预测价值。总的来说,包括来自321名参与者的2165个PK观察。PopPK模型显示了观测数据与预测值之间的高度一致性，表明与zimbererelimab的PK数据有很强的拟合。PK变量是相似的240毫克每2周一次，360毫克Q3W，和480毫克Q4W方案。在最终模型中没有发现显著影响PK变量的协变量。不同暴露变量的齐姆贝雷利玛与疗效和安全性无明显相关性,360mgQ3W和480mgQ4W值得进一步研究。本研究建立了PopPK模型，分析了zimberelimab的暴露-反应关系，这有助于探索替代给药方案的潜力，并为通过基于模拟的方法优化晚期癌症患者的治疗策略奠定了基础。
