The power of the food effect on QTc to show assay sensitivity

Abstract

Event Abstract Back to Event The power of the food effect on QTc to show assay sensitivity Jörg Täubel1, 2*, Sara Fernandes1 and Georg Ferber3 1 Richmond Pharmacology Ltd., UK 2 St George's University of London, Cardiovascular and Cell Sciences Research Institute, UK 3 Statistik Georg Ferber GmbH, Switzerland Background: Validation of exposure-QTc relationship studies still raises concern. The sensitivity of Phase I studies to detect small changes in the QTc interval has been confirmed by demonstrating a significant shortening of QTcF after a standardised meal1,2. The effect was shown to be stable and reproducible3. Methods: This simulation work was based on data from studies in where standardised meals have been served either before or after study drug administration. Drug plasma concentration and corresponding QTcF data were selected and a concentrationeffect model was used to assess the effect of the meal. Simulations were performed and the Hochberg procedure was applied. Results: This simulation indicated that with 18 subjects, assay sensitivity can be shown reliably if the Hochberg procedure is used. The power was not affected by the size of the drug effect. The performance of studies where only pre-dose baseline was possible was compared with different pre-meal baseline options in studies were meal was given after dose. The results indicated that the change from pre-dose is larger than that from the immediate pre-prandial time points as there appears to be shortening post-dose and pre-meal that is not provoked by the meal. Conclusion: This simulation confirmed that the effect of food on QTc can be reliably used to prove assay sensitivity with a small sample size. The various challenges when food is given after dosing will be discussed. Based on the results presented, rules for baseline selection, calculation of effect and validation to appropriately declare assay sensitivity will be proposed.