Comparison of dose-finding designs for narrow-therapeutic-index drugs: concentration-controlled vs. dose-controlled trials.

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.