Randomized dose controlled trials or concentration controlled trials when learning about drugs with narrow therapeutic index?

(2008). Randomized dose controlled trials or concentration controlled trials when learning about drugs with narrow therapeutic index?. In: PAGE 2008, Marseille, France, (). 18-20 June 2008.


Title of paper Randomized dose controlled trials or concentration controlled trials when learning about drugs with narrow therapeutic index?
Conference name PAGE 2008
Conference location Marseille, France
Conference dates 18-20 June 2008
Publication Year 2008
Sub-type Poster
Language eng
Abstract/Summary 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.
Q-Index Code EX
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Conference Paper
Collection: School of Pharmacy Publications
 
Versions
Version Filter Type
Citation counts: Google Scholar Search Google Scholar
Created: Wed, 23 Mar 2011, 10:58:06 EST by Dr Stefanie Hennig on behalf of School of Pharmacy