Sex differences in drug-induced changes in ventricular repolarization.
BACKGROUND
Heart rate corrected QT (QTc) interval prolongation is a predictor of drug-induced torsade de pointes, a potentially fatal ventricular arrhythmia that disproportionately affects women. This study assesses whether there are sex differences in the ECG changes induced by four different hERG potassium channel blocking drugs.


RESULTS
Twenty-two healthy subjects (11 women) received a single oral dose of dofetilide, quinidine, ranolazine, verapamil and placebo in a double-blind 5-period crossover study. ECGs and plasma drug concentrations were obtained at pre-dose and at 15 time-points post-dose. Dofetilide, quinidine and ranolazine prolonged QTc. There were no sex differences in QTc prolongation for any drug, after accounting for differences in exposure. Sex differences in any ECG biomarker were observed only with dofetilide, which caused greater J-Tpeakc prolongation (p=0.045) but lesser Tpeak-Tend prolongation (p=0.006) and lesser decrease of T wave amplitude (p=0.003) in women compared to men.


CONCLUSIONS
There were no sex differences in QTc prolongation for any of the studied drugs. Moreover, no systematic sex differences in other drug-induced ECG biomarker changes were observed in this study. This study suggests that the higher torsade risk in women compared to men is not due to a larger concentration-dependent QTc prolongation.
Office of Science and Engineering Laboratories, CDRH, US FDA, Silver Spring, MD, USA; Division of Cardiovascular and Renal Products, Office of New Drugs, CDER, US FDA, Silver Spring, MD, USA; BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Spain. Electronic address: jose.vicente@fda.hhs.gov.
Jose
J
Vicente
Office of Science and Engineering Laboratories, CDRH, US FDA, Silver Spring, MD, USA; Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
Lars
L
Johannesen
Spaulding Clinical Research, West Bend, WI, USA.
Jay W
JW
Mason
Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain; BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Spain.
Esther
E
Pueyo
Division of Cardiovascular and Renal Products, Office of New Drugs, CDER, US FDA, Silver Spring, MD, USA.
Norman
N
Stockbridge
Office of Science and Engineering Laboratories, CDRH, US FDA, Silver Spring, MD, USA.
David G
DG
Strauss
D000328:Adult; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D012737:Sex Factors; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000175:diagnosis*
D026902:Potassium Channel Blockers
Drugs; QTc prolongation; Sex differences; T wave morphology; Torsade de pointes; hERG block