Pharmacokinetic Interactions between Tafenoquine and Dihydroartemisinin-Piperaquine or Artemether-Lumefantrine in Healthy Adult Subjects

Justin A Green, Khadeeja Mohamed, Navin Goyal, Samia Bouhired, Azra Hussaini, Siôn W Jones, Gavin C K W Koh, Ivan Kostov, Maxine Taylor, Allen Wolstenholm, Stephan Duparc, Justin A Green, Khadeeja Mohamed, Navin Goyal, Samia Bouhired, Azra Hussaini, Siôn W Jones, Gavin C K W Koh, Ivan Kostov, Maxine Taylor, Allen Wolstenholm, Stephan Duparc

Abstract

Tafenoquine is in development as a single-dose treatment for relapse prevention in individuals with Plasmodium vivax malaria. Tafenoquine must be coadministered with a blood schizonticide, either chloroquine or artemisinin-based combination therapy (ACT). This open-label, randomized, parallel-group study evaluated potential drug interactions between tafenoquine and two ACTs: dihydroartemisinin-piperaquine and artemether-lumefantrine. Healthy volunteers of either sex aged 18 to 65 years without glucose-6-phosphate dehydrogenase deficiency were randomized into five cohorts (n = 24 per cohort) to receive tafenoquine on day 1 (300 mg) plus once-daily dihydroartemisinin-piperaquine on days 1, 2, and 3 (120 mg/960 mg for 36 to <75 kg of body weight and 160 mg/1,280 mg for ≥75 to 100 kg of body weight), or plus artemether-lumefantrine (80 mg/480 mg) in two doses 8 h apart on day 1 and then twice daily on days 2 and 3, or each drug alone. The pharmacokinetic parameters of tafenoquine, piperaquine, lumefantrine, artemether, and dihydroartemisinin were determined by using noncompartmental methods. Point estimates and 90% confidence intervals were calculated for area under the concentration-time curve (AUC) and maximum observed plasma concentration (Cmax) comparisons of tafenoquine plus ACT versus tafenoquine or ACT. All subjects receiving dihydroartemisinin-piperaquine experienced QTc prolongation (a known risk with this drug), but tafenoquine coadministration had no clinically relevant additional effect. Tafenoquine coadministration had no clinically relevant effects on dihydroartemisinin, piperaquine, artemether, or lumefantrine pharmacokinetics. Dihydroartemisinin-piperaquine coadministration increased the tafenoquine Cmax by 38% (90% confidence interval, 25 to 52%), the AUC from time zero to infinity (AUC0-∞) by 12% (1 to 26%), and the half-life (t1/2) by 29% (19 to 40%), with no effect on the AUC from time zero to the time of the last nonzero concentration (AUC0-last). Artemether-lumefantrine coadministration had no effect on tafenoquine pharmacokinetics. Tafenoquine can be coadministered with dihydroartemisinin-piperaquine or artemether-lumefantrine without dose adjustment for any of these compounds. (This study has been registered at ClinicalTrials.gov under registration no. NCT02184637.).

Copyright © 2016 Green et al.

Figures

FIG 1
FIG 1
Study design and drug dosing. TQ, tafenoquine; DHA-PQP, dihydroartemisinin-piperaquine; AL, artemether-lumefantrine; AE adverse event; SAE, serious adverse event.
FIG 2
FIG 2
Mean methemoglobin levels as a percentage of hemoglobin (± standard deviations) (A) and mean hemoglobin levels (± standard deviations) (B) following dosing with tafenoquine (TQ), artemether-lumefantrine (AL), dihydroartemisinin-piperaquine (DHA-PQP), artemether-lumefantrine plus tafenoquine, or dihydroartemisinin-piperaquine plus tafenoquine.
FIG 3
FIG 3
(A) Adjusted mean change (90% CI) in QTcF from baseline following administration of artemether-lumefantrine (AL), artemether-lumefantrine plus tafenoquine (TQ), or tafenoquine alone. (B) Adjusted mean change (90% CI) in QTcF from baseline following administration of dihydroartemisinin-piperaquine (DHA-PQP), dihydroartemisinin-piperaquine plus tafenoquine, or tafenoquine alone. (C) Mean absolute QTcF (and standard deviations) following administration of dihydroartemisinin-piperaquine, dihydroartemisinin-piperaquine plus tafenoquine, or tafenoquine alone. (D) Mean heart rate following administration of dihydroartemisinin-piperaquine, dihydroartemisinin-piperaquine plus tafenoquine, or tafenoquine alone.
FIG 4
FIG 4
Concentration-time profiles for tafenoquine (TQ), lumefantrine, piperaquine, artesunate, and dihydroartemisinin (directly dosed or as a metabolite as artemether) dosed as tafenoquine plus dihydroartemisinin-piperaquine (DHA-PQP); tafenoquine plus artemether-lumefantrine (AL); or tafenoquine, dihydroartemisinin-piperaquine, or artemether-lumefantrine alone.

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Source: PubMed

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