A Placebo- and Active-Controlled Assessment of 6- and 50-mg Oral Doxepin on Cardiac Repolarization in Healthy Volunteers: A Thorough QT Evaluation

Background: Doxepin tablets have recently been approved in the United States in doses of 3 and 6 mg for the treatment of insomnia characterized by difficulty with sleep maintenance. Objective: Because no previous thorough QT evaluation of doxepin has been conducted, the primary objective of this study was to assess the highest recommended dose (6 mg) and a supratherapeutic amount (50 mg) of doxepin on cardiac repolarization under steady-state conditions in healthy adult subjects. Methods: Male and female volunteers aged 18 to 45 years were randomized to receive double-blind doxepin or placebo for 7 days, or 6 days of double-blind placebo before one open-label administration of 400-mg moxifloxacin on day 7. Holter electrocardiograms were collected at baseline and on day 7 for up to 23.5 hours after dosing; the results were read at a central facility. The primary outcome measure was the time-matched change from baseline in individually corrected QT (QTcI) intervals. Additional outcome measures were used to evaluate outlying QTc values and the relationship of QTcI to plasma concentrations of doxepin and its primary demethylated metabolite, nordoxepin. Results: A total of 206 healthy subjects (108 women, 98 men) were randomized to a study group; 192 subjects (93.2%) received all scheduled administrations of study drug, and 190 subjects (92.2%) completed the study. The study population was 47.6% male and 52.4% female, and the mean age was 30.3 years. Neither amount of administered doxepin increased QTcI, nor did the upper bound of the 95% CIs for the point estimates exceed 10 milliseconds at any time point. The results for moxifloxacin met the assay sensitivity criteria for a positive control. The predicted placebo-corrected change in QTcI at the mean doxepin C-max values for both administered amounts (6 mg: -0.88 millisecond [upper CI: 0.37 millisecond]; 50 mg, 2.38 milliseconds [upper CI: 4.00 milliseconds]) did not suggest an effect on cardiac repolarization, and no doxepin-treated subject met specific criteria for outlying QTc values. Conclusion: This thorough QT study revealed no effects of doxepin on QTcI up to 50 mg, suggesting that doxepin therapy for insomnia is unlikely to increase QTc intervals. (Clin Ther. 2011;33:851-862) (C) 2011 Elsevier HS Journals, Inc. All rights reserved.