The effect of tafamidis on the QT c interval in healthy subjects

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 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 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.