Lledó-García R, Hennig S, Karlsson M O
Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Clin Pharmacol Ther. 2009 Jul;86(1):62-9. doi: 10.1038/clpt.2009.23. Epub 2009 Apr 1.
This study compared the performances of randomized dose-controlled trials (DCTs) with those of concentration-controlled trials (CCTs) in dose finding for drugs with narrow therapeutic indexes. A simulation-based study was performed for a hypothetical immunosuppressant agent with two clinical end points. Different scenarios were simulated and analyzed, and three designs were compared: one DCT and two CCTs (a target-equivalent CCT and a variability-equivalent CCT). The DCT was consistently superior to the CCTs in the following aspects: (i) precision and bias reduction in parameter estimates, (ii) precision and bias reduction in the estimate of optimal exposure, (iii) bias reduction in prediction of the estimated therapeutic benefit at estimated optimal exposure, and (iv) bias reduction in prediction of the estimated benefit of therapeutic drug monitoring as compared with fixed dosing. DCT designs are more informative when describing the exposure-response relationship for drugs with narrow therapeutic indexes and provide a better basis for decision making with regard to dosing strategy.
本研究比较了随机剂量对照试验（DCT）与浓度对照试验（CCT）在确定窄治疗指数药物剂量方面的表现。针对一种具有两个临床终点的假设性免疫抑制剂进行了一项基于模拟的研究。模拟并分析了不同的场景，比较了三种设计：一种DCT和两种CCT（一种目标等效CCT和一种变异等效CCT）。DCT在以下方面始终优于CCT：（i）参数估计的精度和偏差降低；（ii）最佳暴露估计的精度和偏差降低；（iii）在估计的最佳暴露水平下估计治疗益处预测的偏差降低；（iv）与固定给药相比，治疗药物监测估计益处预测的偏差降低。在描述窄治疗指数药物的暴露-反应关系时，DCT设计提供了更多信息，并为给药策略的决策提供了更好的依据。
