Investigation of potential mechanisms of sex differences in quinidine-induced torsade de pointes risk

Jose Vicente; Jacob Simlund; Lars Johannesen; Frida Sundh; Jeffry Florian; Martin Ugander; Galen S Wagner; Raymond L Woosley; David G Strauss

doi:10.1016/j.jelectrocard.2015.03.011

Investigation of potential mechanisms of sex differences in quinidine-induced torsade de pointes risk

J Electrocardiol. 2015 Jul-Aug;48(4):533-8. doi: 10.1016/j.jelectrocard.2015.03.011. Epub 2015 Mar 12.

Authors

Jose Vicente¹, Jacob Simlund², Lars Johannesen³, Frida Sundh², Jeffry Florian⁴, Martin Ugander⁵, Galen S Wagner⁶, Raymond L Woosley⁷, David G Strauss⁸

Affiliations

¹ Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Device and Radiological Health, US Food and Drug Administration, Silver Spring, MD, USA; Division of Cardiovascular and Renal Products, Office of New Drugs, Center of Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA; BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Spain.
² Duke Clinical Research Institute, Durham, NC, USA; Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
³ Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Device and Radiological Health, US Food and Drug Administration, Silver Spring, MD, USA; Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center of Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
⁴ Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center of Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
⁵ Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
⁶ Duke Clinical Research Institute, Durham, NC, USA.
⁷ AZCERT, Inc., Oro Valley, AZ, USA.
⁸ Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Device and Radiological Health, US Food and Drug Administration, Silver Spring, MD, USA; Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. Electronic address: david.strauss@fda.hhs.gov.

PMID: 25796102
DOI: 10.1016/j.jelectrocard.2015.03.011

Abstract

Introduction: The electrocardiographic index Tpeak-Tend has been proposed as a marker of dispersion of repolarization and may be a stronger predictor of torsade de pointes risk than QTc prolongation.

Methods and results: We assessed whether quinidine-induced Tpeak-Tend prolongation is greater in women than men. The relationship between QTc prolongation and quinidine concentration was greater in women than men (38 ± 10 vs. 28 ± 9 ms/μg/ml, p=0.02), but there was no difference for Tpeak-Tend prolongation (39 ± 13 vs. 32 ± 13 ms/μg/ml, p=0.21). There was a delay (hysteresis) between peak concentration and both maximum QTc and Tpeak-Tend prolongation and a trend toward higher serum quinidine concentration in men than women. Analysis controlling for hysteresis showed no sex difference for QTc (55 ± 18 vs. 43 ± 19 ms/μg/ml, p=0.14), without changing the lack of sex difference with Tpeak-Tend (61 ± 22 vs. 55 ± 21 ms/μg/ml, p=0.49).

Conclusions: Women do not have a greater quinidine-induced Tpeak-Tend prolongation than men. Sex differences in hysteresis and serum quinidine concentration in this study may have contributed to sex differences in quinidine-induced QTc prolongation.

Keywords: QTc prolongation; Quinidine; Sex differences; T wave notching; Torsade de pointes.

Published by Elsevier Inc.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adolescent
Adult
Anti-Arrhythmia Agents / administration & dosage
Anti-Arrhythmia Agents / adverse effects
Anti-Arrhythmia Agents / pharmacokinetics
Dose-Response Relationship, Drug
Electrocardiography / drug effects*
Feasibility Studies
Female
Humans
Male
Quinidine / administration & dosage
Quinidine / adverse effects*
Quinidine / blood*
Reproducibility of Results
Risk Assessment / methods
Sensitivity and Specificity
Sex Factors
Single-Blind Method
Torsades de Pointes / blood*
Torsades de Pointes / chemically induced*
Torsades de Pointes / diagnosis
Young Adult

Substances

Anti-Arrhythmia Agents
Quinidine