The effect of tafamidis on the QTc interval in healthy subjects

摘要

Aims The transthyretin (TTR) stabilizer, tafamidis, has demonstrated efficacy and safety in the treatment of TTR familial amyloid polyneuropathy (20 mg day?1). Tafamidis use in TTR cardiomyopathy led to the study of the potential effect of tafamidis on the QT_c interval in healthy subjects. Methods This randomized, three treatment, three period, six sequence crossover study with placebo, a positive control (moxifloxacin 400 mg) and tafamidis (400 mg, to achieve a supra-therapeutic C _max of ~20 μg ml?1) was conducted in healthy volunteers at three clinical research units. Oral dosing in each of the three treatment periods was separated by a washout period of ?≥?14 days. Serial triplicate 12-lead electrocardiograms were performed. QT_c intervals were derived using the Fridericia correction method. Safety and tolerability were assessed by physical examination, vital signs measurement, laboratory analyses and monitoring of adverse events (AEs). Results A total of 42 subjects completed the study. The upper limit of the two-sided 90% confidence intervals (CIs) for the difference in baseline-adjusted QT_cF between tafamidis 400 mg and placebo was max of 3 h post-dose, confirming assay sensitivity. C _max and AUC(0,24 h) for tafamidis were 20.36 μg ml?1 and 305.4 μg ml?1 h, respectively. There were no serious/severe AEs or treatment discontinuations due to AEs. Conclusions This thorough QT_c study suggests that a supra-therapeutic single 400 mg oral dose of tafamidis does not prolong the QT_c interval and is well-tolerated in healthy volunteers.