Randomised dose controlled trials or concentration controlled trials when learning about drugs with narrow therapeutic index?
Rocío Lledó-García, Stefanie Hennig, Mats O. Karlsson
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
Objectives: Over the last two decades many comparisons between randomised dose controlled trials (DCT) and concentration controlled trials (CCT) have been made [1-3]. Interestingly, none of these has focused on the relative merits of CCT versus DCT for drugs with narrow therapeutic index, when considering the pharmacokinetic (PK) information in the exposure-response analysis for the DCT. This study aims at making such a comparison, for a more informative decision making assessing the possible gains and pitfalls of the trial designs.
Methods: A simulation-based study was performed using NONMEM VI and PsN, considering a hypothetical immunosuppressant agent with two clinical endpoints (rejections and infections). The PK-model was described by a one-compartment model at steady state and the pharmacodynamic relationship with two independent regression logistic models. Different scenarios were simulated and analysed: three designs were compared, a DCT and two CCT’s (a target equivalent (TCCT) and a variability equivalent (VCCT)). For each design two target levels (low and high dose (DCT) or exposure (CCT)) were considered. Different sizes of study and four different ranges of target levels were explored (both levels below or above the optimal exposure, both levels close on one side to the optimal exposure and one target level on either side of the optimal exposure). Considering the outcomes from the different scenarios the relative benefits of performing TDM versus a fixed dose regimen was assessed.
Results: The DCT showed to be superior over the CCT’s in all the following respects: (i) precision and bias in parameter estimates, (ii) precision and bias in the estimate of optimal exposure, (iii) bias in prediction of the therapeutic benefit at estimated optimal exposure, and (iv) bias in prediction of the therapeutic benefit of dose individualization over fixed dosing. This superiority was evident across all study sizes and target ranges explored.
Conclusions: A DCT design is a more informative design when describing the exposure-response relationship for drugs with narrow therapeutic index. It will improve information gained on the optimal dose and consequently improve prediction of the expectations of adverse events in the target population. The DCT thus can reach the same parameter precision with a lower number of subjects and with fewer adverse events in the dose-finding study.
 Sanathanan, L.P. and C.C. Peck, The randomized concentration-controlled trial: an evaluation of its sample size efficiency. Control Clin Trials, 1991. 12(6): p. 780-94.
 Endrenyi, L. and J. Zha, Comparative efficiencies of randomized concentration- and dose-controlled clinical trials. Clin Pharmacol Ther, 1994. 56(3): p. 331-8.
 Karlsson, K.E., et al., Randomized exposure-controlled trials; impact of randomization and analysis strategies. Br J Clin Pharmacol, 2007. 64(3): p. 266-77.