title: A thorough QT study to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine and escitalopram, in healthy volunteers.
abstract: Prolongation of the QT interval on an ECG is a surrogate marker for predicting the proarrhythmic potential of a drug under development. The aim of this study was to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine immediate release (IR) and escitalopram, in healthy individuals. This was a randomized, open-label, 4×4 Williams crossover study, with four single-dose treatments [placebo, 400 mg moxifloxacin (positive control), 20 mg escitalopram, and 100 mg quetiapine IR], conducted in 40 healthy volunteers. Serial blood samples for pharmacokinetics and ECG were collected. Individually, RR-corrected QTc intervals (QTcI) and placebo-adjusted changes from baseline values of QTcI (ΔΔQTcI) were evaluated. Lower-bound values of the one-sided 95% confidence interval for ΔΔQTcI of moxifloxacin with more than 5 ms confirmed the sensitivity of the assay. The maximum upper bound 95% confidence interval for the ΔΔQTcI of quetiapine IR and escitalopram was 13.7 and 10.5 ms, with mean estimates of 10.2 and 6.9 ms, respectively. Peak effects of moxifloxacin and quetiapine IR on ΔΔQTcI were observed at approximately time to maximum concentration (Tmax), whereas that of escitalopram was observed 3 h after Tmax. The concentration-ΔΔQTcI relationships of quetiapine IR and escitalopram were relatively flat, as compared with that of moxifloxacin. The results demonstrated the validity of trial methodology and that quetiapine IR and escitalopram caused QT prolongation in healthy individuals. In addition, hysteresis of escitalopram-induced QTc prolongation. These results indicate that higher doses of these drugs could lead to greater QT prolongation in a dose-response manner.
authors.affiliation: aDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital bDepartment of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul cDepartment of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center dDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea.
authors.forename: Anhye
authors.initials: A
authors.lastname: Kim
authors.forename: Kyoung Soo
authors.initials: KS
authors.lastname: Lim
authors.forename: Howard
authors.initials: H
authors.lastname: Lee
authors.forename: Hyewon
authors.initials: H
authors.lastname: Chung
authors.forename: Seo Hyun
authors.initials: SH
authors.lastname: Yoon
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Chung
mesh_terms: D014150:Antipsychotic Agents / Q000097:blood / Q000494:pharmacology*; D015283:Citalopram / Q000097:blood / Q000494:pharmacology*; D018592:Cross-Over Studies; D004562:Electrocardiography / Q000187:drug effects* / Q000379:methods; D005260:Female; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D000069348:Quetiapine Fumarate / Q000097:blood / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D015283:Citalopram; D000069348:Quetiapine Fumarate; D017367:Selective Serotonin Reuptake Inhibitors