Clinical Pharmacology and Modeling & Simulation, Amgen Inc., Thousand Oaks, California, USA.
Clinical Pharmacology and Pharmacometrics, Janssen Research and Development, Beerse, Belgium.
CPT Pharmacometrics Syst Pharmacol. 2018 Nov;7(11):771-779. doi: 10.1002/psp4.12354. Epub 2018 Oct 15.
Optimal dose selection in clinical trials is problematic when efficacious and toxic concentrations are close. A novel quantitative approach follows for optimizing dose titration in clinical trials. A system of pharmacokinetics (PK), pharmacodynamics, efficacy, and toxicity was simulated for scenarios characterized by varying degrees of different types of variability. Receiver operating characteristic (ROC) and clinical trial simulation (CTS) were used to optimize drug titration by maximizing efficacy/safety. The scenarios included were a low-variability base scenario, and high residual (20%), interoccasion (20%), interindividual (40%), and residual plus interindividual variability scenarios, and finally a shallow toxicity slope scenario. The percentage of subjects having toxicity was reduced by 87.4% to 93.5%, and those having efficacy was increased by 52.7% to 243%. Interindividual PK variability may have less impact on optimal cutoff values than other sources of variability. ROC/CTS methods for optimizing dose titration offer an individualized approach that leverages exposure-response relationships.
当有效浓度和毒性浓度接近时，临床试验中的最佳剂量选择会成为问题。本研究提出了一种优化临床试验剂量滴定的新定量方法。针对具有不同程度的不同类型变异性的情况，建立了药代动力学（PK）、药效学、疗效和毒性系统模型。通过最大程度地提高疗效/安全性，使用接收者操作特征（ROC）和临床试验模拟（CTS）来优化药物滴定。所包括的方案包括低变异性基础方案、高残留（20%）、间发性（20%）、个体间（40%）和残留加个体间变异性方案，最后是浅毒性斜率方案。具有毒性的受试者比例从 87.4%降低到 93.5%，具有疗效的受试者比例从 52.7%增加到 243%。个体间 PK 变异性对最佳截止值的影响可能小于其他变异性来源。用于优化剂量滴定的 ROC/CTS 方法提供了一种个体化方法，利用了暴露-反应关系。
