A thorough QT study to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine and escitalopram, in healthy volunteers

作者：Kim Anhye; Lim Kyoung Soo; Lee Howard; Chung Hyewon; Yoon Seo Hyun; Yu Kyung Sang; Cho Joo Youn; Jang In Jin; Chung Jae Yong^*

来源：International Clinical Psychopharmacology, 2016, 31(4): 210-217.

DOI：10.1097/YIC.0000000000000124

• escitalopram
• healthy volunteer
• moxifloxacin
• pharmacodynamic
• pharmacokinetic
• quetiapine
• QT interval

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, 4x4 Williams crossover study, with four single-dose treatments [placebo, 400mg 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 (Delta Delta QTcI) were evaluated. Lower-bound values of the one-sided 95% confidence interval for Delta Delta QTcI of moxifloxacin with more than 5 ms confirmed the sensitivity of the assay. The maximum upper bound 95% confidence interval for the Delta Delta QTcI 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 Delta Delta QTcI were observed at approximately time to maximum concentration (T-max), whereas that of escitalopram was observed 3 h after T-max. The concentration-Delta Delta QTcI 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.

• 出版日期2016-7