A. Kim,1 F. Jiang,1 S. Yoon,1 S. Yi,1 K. Yu,1 I. Jang,1 J. Chung2; 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea, Republic of, 2Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam-si, Korea, Republic of
BACKGROUND: This study aimed to evaluate the QTc prolongation potential of two frequently prescribed neuropsychiatric drugs, quetiapine and escitalopram, in healthy volunteers.
METHODS: A randomized, open-label, 4X4 crossover study with 4 single-dose treatments (placebo, moxifloxacin 400 mg as positive control, escitalopram 20 mg, and quetiapine 100 mg) was conducted in 40 healthy Korean subjects. Serial blood samples for pharmacokinetics (PK) and ECG data were collected up to 24 hours in each period. Individually RR corrected QTc intervals (QTcI) and the placebo-adjusted changes from baseline values of QTcI (ΔΔQTcI) were evaluated.
RESULTS: The maximum upper bound of 95% one-sided confidence interval (CI) for the ΔΔQTcI of quetiapine and escitalopram was 13.7 ms and 10.5 ms, respectively. The lower bound of the one-sided 95% CI for the ΔΔQTcI of moxifloxacin over 1-16 hours was >5 ms, confirming assay sensitivity. The plasma concentration-ΔΔQTcI relationships of quetiapine and escitalopram were relatively flat compared to moxifloxacin. Peak effects of moxifloxacin and quetiapine on ΔΔQTcI were observed around time to maximum concentration (Tmax), whereas that of escitalopram was observed at 3 hours after Tmax.
CONCLUSION: The QTc prolongation by quetiapine and escitalopram were defined as positive according to the ICH E14 guideline, although less than that of moxifloxacin. The concentration-response relationship for quetiapine and escitalopram were not apparent in contrast to that of moxifloxacin. Hysteresis of escitalorpam induced QTc prolongation warranted further evaluation.