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- Title
Tafenoquine at therapeutic concentrations does not prolong fridericia-corrected QT interval in healthy subjects.
- Authors
Green, Justin A.; Patel, Apurva K.; Patel, Bela R.; Hussaini, Azra; Harrell, Emma J.; McDonald, Mirna J.; Carter, Nick; Mohamed, Khadeeja; Duparc, Stephan; Miller, Ann K.
- Abstract
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.
- Subjects
CALIFORNIA; MARYLAND; DRUG therapy for malaria; ANALYSIS of covariance; ANTIMALARIALS; CONFIDENCE intervals; ELECTROCARDIOGRAPHY; HEART beat; RESEARCH funding; STATISTICAL sampling; RANDOMIZED controlled trials; DATA analysis software; PHARMACODYNAMICS
- Publication
Journal of Clinical Pharmacology, 2014, Vol 54, Issue 9, p995
- ISSN
0091-2700
- Publication type
Article
- DOI
10.1002/jcph.302