RESUMO
Determining the efficacy contribution of an investigational drug as part of a novel combination regimen that also includes a previously untested dose of a standard treatment is challenging, particularly when "placebo control" data (combination regimen minus the investigational drug) is not available for comparison. This situation was encountered in a phase III trial that tested the combination of the investigational drug everolimus with a dose of tacrolimus lower than used in standard liver transplantation therapy. The challenge was addressed by predicting the efficacy of the placebo control from the study data using a pharmacometric-based exposure-response analysis, selected to account for features specific to the transplant setting: systematic change in drug exposure over time and sparse pharmacokinetic sampling. The efficacy contribution of everolimus was then demonstrated by comparing this prediction to the efficacy of the combination regimen. This pharmacometrics-based approach may contribute to characterization of therapeutic agents in real-world settings.