Cardiovascular Effects of Duloxetine: Preclinical and Clinical Findings

Abstract

Background We summarize cardiac effects of duloxetine based on in vitro and animal studies, and human trials including higher doses and chronic treatment. Methods The affinity of duloxetine for cardiac ion channels was determined in vitro in a stably expressed human cell line. Cardiovascular parameters were evaluated in single- and repeat-dose studies in rats and dogs. In humans, cardiovascular safety was analyzed in (1) healthy volunteers receiving duloxetine up to 400 mg/d; (2) 8 placebo-controlled MDD trials of duloxetine (40-120 mg/d) for 8-9 weeks, compared with paroxetine or fluoxetine in 6 trials; (3) 52-week, open-label duloxetine study (80-120 mg/d); (4) 12-week MDD study of duloxetine versus venlafaxine. Results Duloxetine, at the maximum unbound plasma concentration observed clinically, had no adverse effect on the human cardiac ion channels tested in vitro. Blood pressure (BP) and heart rate (HR) were not significantly altered in conscious animals following single oral doses of 7 or 20 mg/kg in rats and 10 mg/kg in dogs. Cardiac rhythm, conduction, and HR were unaffected in dogs by up to 1 year of treatment with 3, 10, or 30 mg/kg. In healthy volunteers, duloxetine had a modest effect on BP and HR elevation with no prolongation of QTc interval. In patients with MDD, small increases in HR and BP were observed. Although there were statistically significant differences in HR from baseline to endpoint between duloxetine versus fluoxetine or paroxetine, changes were clinically insignificant. In the study of duloxetine (60-120 mg/day) and venlafaxine (75-225 mg/day) in MDD, no statistically significant differences occurred in elevated HR and BP except for significantly more venlafaxine patients with sustained systolic BP during the first 6 weeks. Discussion Consistent with the lack of effect on human cardiac ion channel binding in vitro, and the lack of effect on conduction parameters in repeat-dose dog studies, no QTc prolongation was seen in humans. Consistent with the HR and BP findings in animals, humans had a few small effects with these measures. In summary, duloxetine has a good cardiovascular safety profile, possibly due to its lack of affinity for crucial cardiac ion channels and/or other unknown factors. Funding provided by Eli Lilly and Company.