Chigutsa E, Long A J, Wallin J E
PKPD&Pharmacometrics, Eli Lilly, Indianapolis, Indiana, USA.
Eli Lilly Sweden, Solna, Sweden.
CPT Pharmacometrics Syst Pharmacol. 2017 Aug;6(8):560-568. doi: 10.1002/psp4.12209. Epub 2017 Jul 13.
We sought to describe the exposure-response relationship of necitumumab efficacy in squamous non-small cell lung cancer patients and evaluate intrinsic and extrinsic patient descriptors that may guide dosing. SQUIRE was a phase III study comparing necitumumab in combination with gemcitabine and cisplatin vs. gemcitabine and cisplatin alone in 1,014 patients. An integrated model for tumor size dynamics and overall survival was developed, where reduction in tumor size results in a decrease in survival hazard. The change in tumor size was characterized using linear growth and first-order shrinkage. Overall survival was described using a combination of a Weibull function and Gompertz function for the hazard, with dynamic tumor size being a predictor for the hazard. Although body weight resulted in higher clearance and lower exposure, simulations showed that an 800 mg flat dose provided optimal response regardless of body weight.
我们试图描述耐昔妥珠单抗在鳞状非小细胞肺癌患者中的疗效暴露-反应关系，并评估可能指导给药剂量的患者内在和外在特征。SQUIRE是一项III期研究，在1014例患者中比较了耐昔妥珠单抗联合吉西他滨和顺铂与单独使用吉西他滨和顺铂的疗效。建立了一个肿瘤大小动态变化和总生存的综合模型，其中肿瘤大小的减小会导致生存风险降低。使用线性生长和一阶收缩来表征肿瘤大小的变化。总生存采用威布尔函数和冈珀茨函数相结合来描述风险，动态肿瘤大小作为风险的预测指标。尽管体重会导致清除率升高和暴露量降低，但模拟结果显示，无论体重如何，800mg固定剂量均能提供最佳反应。
