Tafenoquine at therapeutic concentrations does not prolong Fridericia-corrected QT interval in healthy subjects.
Tafenoquine is being developed for relapse prevention in Plasmodium vivax malaria. This Phase I, single-blind, randomized, placebo- and active-controlled parallel group study investigated whether tafenoquine at supratherapeutic and therapeutic concentrations prolonged cardiac repolarization in healthy volunteers. Subjects aged 18-65 years were randomized to one of five treatment groups (n = 52 per group) to receive placebo, tafenoquine 300, 600, or 1200 mg, or moxifloxacin 400 mg (positive control). Lack of effect was demonstrated if the upper 90% CI of the change from baseline in QTcF following supratherapeutic tafenoquine 1200 mg versus placebo (ΔΔQTcF) was <10 milliseconds for all pre-defined time points. The maximum ΔΔQTcF with tafenoquine 1200 mg (n = 50) was 6.39 milliseconds (90% CI 2.85, 9.94) at 72 hours post-final dose; that is, lack of effect for prolongation of cardiac depolarization was demonstrated. Tafenoquine 300 mg (n = 48) or 600 mg (n = 52) had no effect on ΔΔQTcF. Pharmacokinetic/pharmacodynamic modeling of the tafenoquine-QTcF concentration-effect relationship demonstrated a shallow slope (0.5 ms/μg mL(-1) ) over a wide concentration range. For moxifloxacin (n = 51), maximum ΔΔQTcF was 8.52 milliseconds (90% CI 5.00, 12.04), demonstrating assay sensitivity. In this thorough QT/QTc study, tafenoquine did not have a clinically meaningful effect on cardiac repolarization.
Diseases of the Developing World Group, GlaxoSmithKline Research and Development, Stockley Park West, Uxbridge, Middlesex, UK.
Justin A
JA
Green
Apurva K
AK
Patel
Bela R
BR
Patel
Azra
A
Hussaini
Emma J
EJ
Harrell
Mirna J
MJ
McDonald
Nick
N
Carter
Khadeeja
K
Mohamed
Stephan
S
Duparc
Ann K
AK
Miller
D000293:Adolescent; D000328:Adult; D000368:Aged; D000634:Aminoquinolines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000962:Antimalarials / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D016037:Single-Blind Method; D055815:Young Adult
D000634:Aminoquinolines; D000962:Antimalarials; C055852:tafenoquine
QT; anti-malarial; cardiology; moxifloxacin; tafenoquine