title: Pharmacokinetic Interactions between Tafenoquine and Dihydroartemisinin-Piperaquine or Artemether-Lumefantrine in Healthy Adult Subjects.
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 Cmaxby 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.).
authors.affiliation: GlaxoSmithKline Research and Development, Stockley Park West, Uxbridge, Middlesex, United Kingdom justin.a.green@gsk.com.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Green
authors.affiliation: GlaxoSmithKline Research and Development, Stockley Park West, Uxbridge, Middlesex, United Kingdom.
authors.forename: Khadeeja
authors.initials: K
authors.lastname: Mohamed
authors.affiliation: GlaxoSmithKline, Upper Merion, King of Prussia, Pennsylvania, USA.
authors.forename: Navin
authors.initials: N
authors.lastname: Goyal
authors.affiliation: GlaxoSmithKline Research and Development, Stockley Park West, Uxbridge, Middlesex, United Kingdom.
authors.forename: Samia
authors.initials: S
authors.lastname: Bouhired
authors.affiliation: Parexel, Harbor Hospital, Baltimore, Baltimore, Maryland, USA.
authors.forename: Azra
authors.initials: A
authors.lastname: Hussaini
authors.affiliation: GlaxoSmithKline Research and Development, Stockley Park West, Uxbridge, Middlesex, United Kingdom.
authors.forename: Siôn W
authors.initials: SW
authors.lastname: Jones
authors.affiliation: GlaxoSmithKline Research and Development, Stockley Park West, Uxbridge, Middlesex, United Kingdom.
authors.forename: Gavin C K W
authors.initials: GC
authors.lastname: Koh
authors.affiliation: Parexel, Harbor Hospital, Baltimore, Baltimore, Maryland, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Kostov
authors.affiliation: GlaxoSmithKline Research and Development, Ware, Hertfordshire, United Kingdom.
authors.forename: Maxine
authors.initials: M
authors.lastname: Taylor
authors.affiliation: GlaxoSmithKline, Upper Providence, Collegeville, Pennsylvania, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Wolstenholm
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Duparc
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000634:Aminoquinolines / Q000009:adverse effects / Q000493:pharmacokinetics*; D000962:Antimalarials / Q000009:adverse effects / Q000493:pharmacokinetics*; D037621:Artemisinins / Q000009:adverse effects / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D005449:Fluorenes / Q000009:adverse effects / Q000493:pharmacokinetics*; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D000078102:Lumefantrine; D016780:Malaria, Vivax / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010966:Plasmodium vivax / Q000187:drug effects; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult; D010879:Piperazines
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D000078102:Lumefantrine; D011804:Quinolines; C055852:tafenoquine; C039060:artenimol; C031327:artemisinin; C034759:piperaquine; D010879:Piperazines