Tafenoquine at therapeutic concentrations does not prolong Fridericia-corrected QT interval in healthy subjects.

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.

• Authors: Justin A Green, Apurva K Patel, Bela R Patel, Azra Hussaini, Emma J Harrell, Mirna J McDonald, Nick Carter, Khadeeja Mohamed, Stephan Duparc, Ann K Miller
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 54 Issue 9 Pg. 995-1005 (Sep 2014) ISSN: 1552-4604 [Electronic] England
• PMID: 24700490 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2014, The American College of Clinical Pharmacology.

Chemical References

• Aminoquinolines
• Antimalarials
• tafenoquine

Topics

• Adolescent
• Adult
• Aged
• Aminoquinolines (adverse effects, blood, pharmacokinetics, pharmacology)
• Antimalarials (adverse effects, blood, pharmacokinetics, pharmacology)
• Electrocardiography (drug effects)
• Female
• Healthy Volunteers
• Heart Rate (drug effects)
• Humans
• Male
• Middle Aged
• Models, Biological
• Single-Blind Method
• Young Adult