Tafenoquine at therapeutic concentrations does not prolong fridericia-corrected QT interval in healthy subjects
Version of Record online: 9 APR 2014
© 2014 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
The Journal of Clinical Pharmacology
Volume 54, Issue 9, pages 995–1005, September 2014
How to Cite
Green, J. A., Patel, A. K., Patel, B. R., Hussaini, A., Harrell, E. J., McDonald, M. J., Carter, N., Mohamed, K., Duparc, S. and Miller, A. K. (2014), Tafenoquine at therapeutic concentrations does not prolong fridericia-corrected QT interval in healthy subjects. Journal of Clinical Pharma, 54: 995–1005. doi: 10.1002/jcph.302
[The copyright line for this article was changed on 28 October 2014 after original online publication.]
Author contributions: JAG, AKP, EJH, AKM, NC, KM and SD developed the protocol. JAG, AH and AKP oversaw the clinical study. AH and MJMcD were involved in data acquisition. AKM and BRP conducted the pharmacokinetic analysis and the pharmacokinetic/pharmacodynamic modelling. NC, MJMcD and KM provided statistical input into data analysis. All authors contributed to this manuscript and approved the final version for submission.
- Issue online: 5 AUG 2014
- Version of Record online: 9 APR 2014
- Accepted manuscript online: 3 APR 2014 04:27AM EST
- Manuscript Accepted: 1 APR 2014
- Manuscript Received: 5 FEB 2014
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.