The effect of tafamidis on the QTc interval in healthy subjects

Abstract

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 QTc 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 Cmax 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. QTc 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 QTc 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 tmax of 3 h post-dose, confirming assay sensitivity. Cmax 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 QTc study suggests that a supra-therapeutic single 400 mg oral dose of tafamidis does not prolong the QTc interval and is well-tolerated in healthy volunteers.

Trial registration: ClinicalTrials.gov NCT01775761.

Keywords: QTc prolongation; cardiomyopathy; familial amyloid polyneuropathy; tafamidis; transthyretin amyloidosis.

© 2015 The British Pharmacological Society.

Figures

Figure 1

Time-matched baseline adjusted least squares mean differences between tafamidis 400 mg and placebo, and moxifloxacin 400 mg and placebo for QTcF. , tafamidis 400 mg; , moxifloxacin 400 mg. Circles and squares represent the baseline adjusted mean differences and vertical lines represent 90% confidence intervals obtained from mixed effect model. Mean of triplicate collections at each time point was used in the analysis

Figure 2

Plasma tafamidis concentration−time profile following single oral doses of tafamidis 400 mg (linear and log scales for median plasma concentrations of tafamidis). , tafamidis 400 mg. The lower limit of quantification for the measurement of tafamidis concentrations was 3.0 ng ml−1