Tafenoquine is in development as a single-dose treatment for relapse prevention in Plasmodium vivax malaria. Tafenoquine must be co-administered 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 or artemether-lumefantrine. Healthy volunteers of either sex, aged 18–65 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 (120:960 mg for 36–<75 kg bodyweight; 160:1280 mg for ≥75–100 kg bodyweight); or artemether-lumefantrine (80:480 mg) two doses 8 h apart on day 1, then twice daily on days 2 and 3; or each drug given alone. The pharmacokinetic parameters of tafenoquine, piperaquine, lumefantrine, artemether, and dihydroartemisinin were determined using non-compartmental methods. Point estimates and 90% confidence intervals were calculated for AUC and Cmax comparisons of tafenoquine plus ACT versus tafenoquine or ACT. All subjects receiving dihydroartemisinin-piperaquine experienced QTc prolongation (a known risk for this drug), but tafenoquine co-administration had no clinically relevant additional effect. Tafenoquine co-administration had no clinically relevant effects on dihydroartemisinin, piperaquine, artemether or lumefantrine pharmacokinetics. Dihydroartemisinin-piperaquine co-administration increased tafenoquine Cmax by 38% (90% confidence interval: 25 to 52%), AUC0–∞ by 12% (1 to 26%) and t1/2 by 29% (19 to 40%); with no effect on AUC0–last. Artemether-lumefantrine co-administration had no effect on tafenoquine pharmacokinetics. Tafenoquine can be co-administered with dihydroartemisinin-piperaquine or artemether-lumefantrine without dose adjustment for any of these compounds. (This clinical trial is registered at ClinicalTrials.gov with the study identifier NCT02184637).
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