Importance of QT/RR hysteresis correction in studies of drug-induced QTc interval changes
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2018-06-01
Date Acceptance
2018-04-04
Citation
Journal of Pharmacokinetics and Pharmacodynamics, 2018, 45 (3), pp.491-503
ISSN
1567-567X
Publisher
Springer Verlag
Start Page
491
End Page
503
Journal / Book Title
Journal of Pharmacokinetics and Pharmacodynamics
Volume
45
Issue
3
Copyright Statement
© The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Sponsor
British Heart Foundation
Grant Number
NH/16/2/32499
Subjects
Science & Technology
Life Sciences & Biomedicine
Pharmacology & Pharmacy
QT/RR adaptation
QT/RR hysteresis
QTc interval
Heart rate correction
PK/PD modeling
Statistical simulation
HEART-RATE CORRECTION
THOROUGH QT/QTC
CARDIAC SAFETY
HEALTHY-SUBJECTS
PROLONGATION
PRECISION
RISK
1115 Pharmacology And Pharmaceutical Sciences
Publication Status
Published
Date Publish Online
2018-04-12