The effect of tafamidis on the QTc interval in healthy subjects. (June 2015)

• Record Type: Journal Article
• Authors: Klamerus, Karen J.; Watsky, Eric; Moller, Robert; Wang, Ronnie; Riley, Steve
• Is Part Of: British journal of clinical pharmacology. Volume 79:Number 6(2015:Jun.)
• Page Start: 918
• Page End: 925
• Publication Date: 2015-06
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12561
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12561-sec-0001" sec-type="section"> <title>Aims</title> <p>The transthyretin (TTR) stabilizer, tafamidis, has demonstrated efficacy and safety in the treatment of TTR familial amyloid polyneuropathy (20 mg day<sup>−1</sup>). Tafamidis use in TTR cardiomyopathy led to the study of the potential effect of tafamidis on the QT<sub>c</sub> interval in healthy subjects.</p> </sec> <sec id="bcp12561-sec-0002" sec-type="section"> <title>Methods</title> <p>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 <italic>C</italic><sub>max</sub> of ~20 µg ml<sup>−1</sup>) 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<sub>c</sub> 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).</p> </sec> <sec id="bcp12561-sec-0003" sec-type="section"> <title>Results</title> <p>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<sub>c</sub>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 <italic>t</italic><sub>max</sub> of 3 h post‐dose, confirming assay sensitivity. <italic>C</italic><sub>max</sub> and AUC(0, 24 h) for tafamidis were 20.36 µg ml<sup>−1</sup> and 305.4 µg ml<sup>−1</sup> h, respectively. There were no serious/severe AEs or treatment discontinuations due to AEs.</p> </sec> <sec id="bcp12561-sec-0004" sec-type="section"> <title>Conclusions</title> <p>This thorough QT<sub>c</sub> study suggests that a supra‐therapeutic single 400 mg oral dose of tafamidis does not prolong the QT<sub>c</sub> interval and is well‐tolerated in healthy volunteers.</p> </sec> </abstract>