Sensitivity of pharmacokinetic-pharmacodynamic analysis for detecting small magnitudes of QTc prolongation in preclinical safety testing.

Abstract

Preclinical concentration-effect (pharmacokinetic-pharmacodynamic, PKPD) modeling has successfully quantified QT effects of several drugs known for significant QT prolongation. This study investigated its sensitivity for detecting small magnitudes of QT-prolongation in a typical preclinical cardiovascular (CV) safety study in the conscious telemetered dog (crossover study in 4-8 animals receiving a vehicle and three dose levels). Results were compared with conventional statistical analysis (analysis of covariance, ANCOVA). A PKPD model predicting individual QTc was first developed from vehicle arms of 28 typical CV studies and one positive control study (sotalol). The model quantified between-animal, inter-occasion and within-animal variability and described QTc over 24h as a function of circadian variation and drug concentration. This "true" model was used to repeatedly (n = 500) simulate studies with typical drug-induced QTc prolongation (∆QTc) of 1 to 12 ms at high-dose peak concentrations. Simulated studies were re-analyzed by both PKPD analysis (with varying complexity) and ANCOVA. Sensitivity (power) was calculated as the percentage of studies in which a significant (α = 0.05) drug effect was found. One simulation scenario did not include a concentration-effect relationship and served to investigate false-positive rates. Exposure-effect relationships were derived from both PKPD analysis (linear concentration-effect) and ANCOVA (linear trend test for dose) and compared. PKPD analysis/ANCOVA had a sensitivity of 80% to detect the effects of 7/13 ms (n = 4), 5/10 ms (n = 6) and 4.5/8 ms (n = 8), respectively. The false-positive rate was much higher using ANCOVA (40%) compared to PKPD analysis (1%). Typical drug effects were more precisely predicted using estimated concentration-effect slopes (± 1.5-2.8 ms) than dose-effect slopes (± 3.3-3.7 ms). Preclinical PKPD analysis can increase the confidence in the quantification of small QTc effects and potentially allow reducing the number of animals while maintaining the required study sensitivity. This underscores the value of PKPD modeling in preclinical safety testing.