Concentration-QTc analysis with two or more correlated baselines.

Abstract

The relationship between drug concentration and QTc interval is typically evaluated by applying the standard analysis model proposed in a scientific whitepaper by Garnett et al. ( https://doi.org/10.1007/s10928-017-9558-5 ). The model is a mixed effects model in which a baseline QTc interval is included as a covariate. Two or more baseline QTc intervals are sometimes observed for a study participant, such as time-matched baselines on a baseline day in parallel studies, or pre-dose baselines in each period in crossover studies. In such situations, the baseline adjustments are not straightforward because these baselines correlate with not only the corresponding QTc intervals after drug administration, but also other QTc intervals at different timepoints for parallel studies, or those in different periods for crossover studies. In this study, we compared three analysis models through simulations and clinical study examples in settings in which two or more baselines were observed for a subject. We compared a model without baseline adjustment, a model with baseline adjustment, and a model in which baseline and baseline mean were included as covariates. In the simulations and clinical study examples, the model with baseline and baseline mean as covariates demonstrated higher accuracy and power than the other models. This model assumed a specific covariance structure in QTc intervals, which well approximated the correlations between QTc intervals within and between days. When there are two or more baselines in concentration-QTc analyses, the baseline mean should be included as a covariate in addition to the corresponding baseline.