The effect of tafamidis on the QTc interval in healthy subjects.

AimsThe 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. MethodsThis 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 similar to 20 mu g 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). ResultsA 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(c)F between tafamidis 400 mg and placebo was <10 ms (non-inferiority criterion) for all time points. The lower limit of the two-sided 90% CI between moxifloxacin 400 mg and placebo exceeded 5 ms at the pre-specified moxifloxacin t(max) of 3 h post-dose, confirming assay sensitivity. C-max and AUC(0,24 h) for tafamidis were 20.36 mu g ml(-1) and 305.4 mu g ml(-1) h, respectively. There were no serious/severe AEs or treatment discontinuations due to AEs. ConclusionsThis 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.