Importance of QT/RR hysteresis correction in studies of drug-induced QTc interval changes

Marek Malik,Jose Vicente,Christine Garnett,Katerina Hnatkova,Norman Stockbridge,Lars Johannesen

doi:10.1007/s10928-018-9587-8

Abstract

QT/RR hysteresis and QT/RR adaptation are interlinked but separate physiological processes signifying how quickly and how much QT interval changes when heart rate changes, respectively. While QT interval duration is, as a rule, corrected for heart rate in terms of the QT/RR adaptation, the correction for QT/RR hysteresis is frequently omitted in studies of drug-induced QTc changes. This study used data from previously conducted thorough QT studies to investigate the extent of QTc errors caused by omitting the correction for QT/RR hysteresis, particularly in small clinical investigations. Statistical modeling approach was used to generate 11,000 simulated samples of 10-subject studies in which mixed effect PK/PD models were used to estimate drug-induced QTc changes at mean maximum plasma concentration of investigated compounds. Calculations of QTc intervals involving and omitting QT/RR hysteresis correction were compared. These comparisons showed that ignoring QT/RR hysteresis has two undesirable effects: (A) In the design of subject-specific heart rate corrections (needed in studies of drugs that change heart rate) omission of QT/RR hysteresis may lead to signals of QTc prolongation of more than 10 ms to be missed. (B) Irrespective of whether the investigated drug changes heart rate, omission of QT/RR hysteresis causes the widths of the confidence intervals of the PK/PD predicted QTc interval changes to be increased by 20–30% on average (exceeding 50% in some cases). This may lead to a failure of excluding meaningful QTc prolongation which would be excluded if using hysteresis correction. The study concludes that correction for QT/RR hysteresis should be incorporated into future studies of drug-induced QTc changes. Subject-specific heart rate corrections that omit hysteresis correction may lead to erroneously biased conclusions. Even when using universal (e.g. Fridericia) heart rate correction, hysteresis correction decreases the confidence intervals of QTc changes and thus helps avoiding false positive outcomes.

Highlights

The principles and implications of the E14 regulatory guidance [1] have repeatedly been described and discussed [2, 3]
Calculations of QTc intervals involving and omitting QT/RR hysteresis correction were compared. These comparisons showed that ignoring QT/RR hysteresis has two undesirable effects: (A) In the design of subject-specific heart rate corrections omission of QT/RR hysteresis may lead to signals of QTc prolongation of more than 10 ms to be missed. (B) Irrespective of whether the investigated drug changes heart rate, omission of QT/RR hysteresis causes the widths of the confidence intervals of the PK/PD predicted QTc interval changes to be increased by 20–30% on average
As previously published [17], we used a universal model corresponding to the 95% adaptation of QT interval duration achieved in 2 min after an abrupt heart rate change. (See the Appendix for details.) To model the approaches of ignoring the QT/RR hysteresis, we considered two further options: (C) Correcting the QT interval measurements for the RR interval obtained as the average of RR intervals in a 10 s window preceding the QT measurement, and

Summary

Introduction

The principles and implications of the E14 regulatory guidance [1] have repeatedly been described and discussed [2, 3]. The concept of investigating drug-induced QTc interval changes by means of PK/PD modeling in early clinical studies [4] has obvious practical attraction [5] but, compared to the ‘‘standard’’ thorough QT (TQT) studies, it brings challenges. One of the most obvious is the necessity of measuring the QTc values with high fidelity precision. This is because the regulatory review of the predicted QTc change at the mean maximum plasma concentration of the investigated drug needs to be based on the upper confidence interval of such a prediction. Since, compared to ‘‘standard’’ TQT studies, usual early clinical investigations involve fewer subjects per drug dose, it is impractical if not impossible to offset the effect of QTc inaccuracies by an increased number of subjects [2]

Methods

Results

Discussion

Conclusion