title: Investigation of potential mechanisms of sex differences in quinidine-induced torsade de pointes risk.
abstract: BACKGROUND
  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.
  
  
  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.
authors: 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.
authors: Jose
authors: J
authors: Vicente
authors: Duke Clinical Research Institute, Durham, NC, USA; Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors: Jacob
authors: J
authors: Simlund
authors: 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.
authors: Lars
authors: L
authors: Johannesen
authors: Duke Clinical Research Institute, Durham, NC, USA; Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors: Frida
authors: F
authors: Sundh
authors: 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.
authors: Jeffry
authors: J
authors: Florian
authors: Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors: Martin
authors: M
authors: Ugander
authors: Duke Clinical Research Institute, Durham, NC, USA.
authors: Galen S
authors: GS
authors: Wagner
authors: AZCERT, Inc., Oro Valley, AZ, USA.
authors: Raymond L
authors: RL
authors: Woosley
authors: 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.
authors: David G
authors: DG
authors: Strauss
mesh_terms: D000293:Adolescent; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D011802:Quinidine / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood*; D015203:Reproducibility of Results; D018570:Risk Assessment / Q000379:methods; D012680:Sensitivity and Specificity; D012737:Sex Factors; D016037:Single-Blind Method; D016171:Torsades de Pointes / Q000097:blood* / Q000139:chemically induced* / Q000175:diagnosis; D055815:Young Adult
chemical_list: D000889:Anti-Arrhythmia Agents; D011802:Quinidine
keywords: QTc prolongation; Quinidine; Sex differences; T wave notching; Torsade de pointes