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.)
Highlights
GlaxoSmithKline Research and Development, Stockley Park West, Uxbridge, Middlesex, United Kingdoma; GlaxoSmithKline, Upper Merion, King of Prussia, Pennsylvania, USAb; Parexel, Harbor Hospital, Baltimore, Baltimore, Maryland, USAc; GlaxoSmithKline Research and Development, Ware, Hertfordshire, United Kingdomd; GlaxoSmithKline, Upper Providence, Collegeville, Pennsylvania, USAe; Medicines for Malaria Venture, Geneva, Switzerlandf
There was no apparent effect of the addition of tafenoquine on the number of patients experiencing adverse events of any cause compared with artemisinin-based combination therapy (ACT) alone: 58.3% (14/24) for dihydroartemisinin-piperaquine versus 37.5% (9/24) for tafenoquine plus dihydroartemisininpiperaquine and 54.2% (13/24) for artemether-lumefantrine versus 33.3% (8/24) for tafenoquine plus artemether-lumefantrine, compared with 12.5% (3/24) for tafenoquine alone
Except for a possible increase in the incidence of headache with tafenoquine plus artemether-lumefantrine (4/24) versus artemether-lumefantrine (1/24), there was no discernible effect of the addition of tafenoquine on the nature of the adverse events experienced compared with ACTs alone (Table 2)
Summary
GlaxoSmithKline Research and Development, Stockley Park West, Uxbridge, Middlesex, United Kingdoma; GlaxoSmithKline, Upper Merion, King of Prussia, Pennsylvania, USAb; Parexel, Harbor Hospital, Baltimore, Baltimore, Maryland, USAc; GlaxoSmithKline Research and Development, Ware, Hertfordshire, United Kingdomd; GlaxoSmithKline, Upper Providence, Collegeville, Pennsylvania, USAe; Medicines for Malaria Venture, Geneva, Switzerlandf. 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. Tafenoquine coadministration had no clinically relevant effects on dihydroartemisinin, piperaquine, artemether, or lumefantrine pharmacokinetics. In phase II studies, 89% (95% confidence interval [CI], 77 to 95%) of patients receiving a single 300-mg dose of tafenoquine in combination with standard 3-day chloroquine treatment were relapse-free at 6 months, compared with 77% (63 to 87%) of those receiving 15 mg/day primaquine for 14 days plus chloroquine and 38% (23 to 52%) of those who received chloroquine alone [4]
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