Abstract
IntroductionUniversal QT correction formulas are potentially problematic in corrected QT (QTc) interval comparisons at different heart rates. Instead of individual-specific corrections, population-specific corrections are occasionally used based on QT/RR data pooled from all study subjects.ObjectiveTo investigate the performance of individual-specific and population-specific corrections, a statistical modeling study was performed using QT/RR data of 523 healthy subjects.MethodsIn each subject, full drug-free QT/RR profiles were available, characterized using non-linear regression models. In each subject, 50 baseline QT/RR readings represented baseline data of standard QT studies. Using these data, linear and log-linear heart rate corrections were optimized for each subject and for different groups of ten and 50 subjects. These corrections were applied in random combinations of heart rate changes between − 10 and + 25 beats per minute (bpm) and known QTc interval changes between − 25 and + 25 ms.ResultsBoth the subject-specific and population-specific corrections based on the 50 baseline QT/RR readings tended to underestimate/overestimate the QTc interval changes when heart rate was increasing/decreasing, respectively. The result spread was much wider with population-specific corrections, making the estimates of QTc interval changes practically unpredictable.ConclusionSubject-specific heart rate corrections based on limited baseline drug-free data may lead to inconsistent results and, in the presence of underlying heart rate changes, may potentially underestimate or overestimate QTc interval changes. The population-specific corrections lead to results that are much more influenced by the combination of individual QT/RR patterns than by the actual QTc interval changes. Subject-specific heart rate corrections based on full profiles derived from drug-free baseline recordings with wide QT/RR distribution should be used when studying drugs expected to cause heart rate changes.Electronic supplementary materialThe online version of this article (10.1007/s40264-018-0736-1) contains supplementary material, which is available to authorized users.
Highlights
Universal QT correction formulas are potentially problematic in corrected QT (QTc) interval comparisons at different heart rates
Identical comparisons between subject-specific and population-specific corrections were observed with the experiments of the second type
When we performed limited series of experiments with mixed-effects pharmacokinetic/ pharmacodynamic (PK/PD) models, the comparisons of the individual-specific and population-specific corrections were practically the same as the results that we presented with the same wide spread and uncertainty of the of ΔΔQTc values provided by the population corrections
Summary
Universal QT correction formulas are potentially problematic in corrected QT (QTc) interval comparisons at different heart rates. Results Both the subject-specific and population-specific corrections based on the 50 baseline QT/RR readings tended to underestimate/overestimate the QTc interval changes when heart rate was increasing/decreasing, respectively. Conclusion Subject-specific heart rate corrections based on limited baseline drug-free data may lead to inconsistent results and, in the presence of underlying heart rate changes, may potentially underestimate or overestimate QTc interval changes. The document suggests that the appropriateness of subject-specific heart rate corrections depends on the wide range of drug-free QT and RR measurements in each individual. Collecting such a wide range of drug-free QT/RR pairs brings challenges to the study design, e.g., when incorporating the assessment of QTc interval changes into early clinical studies [3]. It is especially challenging obtaining QT/RR pairs at low heart rates, e.g., in QT studies assessing a drug that is expected to reduce the heart rate
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