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

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, 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

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.

Keywords: QT; anti-malarial; cardiology; moxifloxacin; tafenoquine.

© 2014, The American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Primary outcome: Least squares (LS) mean of treatment differences from placebo for QTcF change from baseline (ΔΔQTcF) and 90% confidence intervals show lack of effect for tafenoquine: upper 90% CI

Figure 2

Visual predictive check for QTcF…

Figure 2

Visual predictive check for QTcF interval (milliseconds) versus time profiles following administration of…

Figure 2
Visual predictive check for QTcF interval (milliseconds) versus time profiles following administration of placebo, 300, 600, and 1200 mg tafenoquine, and 400 mg moxifloxacin. The shaded area indicates the 90% prediction intervals of the simulated QTcF values.
Figure 2
Figure 2
Visual predictive check for QTcF interval (milliseconds) versus time profiles following administration of placebo, 300, 600, and 1200 mg tafenoquine, and 400 mg moxifloxacin. The shaded area indicates the 90% prediction intervals of the simulated QTcF values.

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Source: PubMed

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