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

MedStar author(s):
Citation: Antimicrobial Agents & Chemotherapy. 60(12):7321-7332, 2016 DecPMID: 27697758Institution: MedStar Harbor HospitalDepartment: PAREXEL Early Phase Clinical UnitForm of publication: Journal ArticleMedline article type(s): Journal Article | Randomized Controlled TrialSubject headings: *Aminoquinolines/pk [Pharmacokinetics] | *Antimalarials/pk [Pharmacokinetics] | *Artemisinins/pk [Pharmacokinetics] | *Ethanolamines/pk [Pharmacokinetics] | *Fluorenes/pk [Pharmacokinetics] | *Malaria, Vivax/dt [Drug Therapy] | *Quinolines/pk [Pharmacokinetics] | Adolescent | Adult | Aged | Aminoquinolines/ae [Adverse Effects] | Antimalarials/ae [Adverse Effects] | Artemisinins/ae [Adverse Effects] | Drug Interactions | Drug Therapy, Combination | Ethanolamines/ae [Adverse Effects] | Female | Fluorenes/ae [Adverse Effects] | Half-Life | Healthy Volunteers | Humans | Male | Middle Aged | Plasmodium vivax/de [Drug Effects] | Quinolines/ae [Adverse Effects] | Young AdultYear: 2016Local holdings: Available online from MWHC library: 1972 - present (after 4 months), Available in print through MWHC library: July 1996 - 2006ISSN:
  • 0066-4804
Name of journal: Antimicrobial agents and chemotherapyAbstract: 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 (C<sub>max</sub>) 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 C<sub>max</sub> by 38% (90% confidence interval, 25 to 52%), the AUC from time zero to infinity (AUC<sub>0-</sub>) by 12% (1 to 26%), and the half-life (t<sub>1/2</sub>) by 29% (19 to 40%), with no effect on the AUC from time zero to the time of the last nonzero concentration (AUC<sub>0-last</sub>). 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 (c) 2016 Green et al.All authors: Bouhired S, Duparc S, Goyal N, Green JA, Hussaini A, Jones SW, Koh GC, Kostov I, Mohamed K, Taylor M, Wolstenholm AFiscal year: FY2017Digital Object Identifier: Date added to catalog: 2017-10-16
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Item type Current library Collection Call number Status Date due Barcode
Journal Article MedStar Authors Catalog Article 27697758 Available 27697758

Available online from MWHC library: 1972 - present (after 4 months), Available in print through MWHC library: July 1996 - 2006

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 (C<sub>max</sub>) 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 C<sub>max</sub> by 38% (90% confidence interval, 25 to 52%), the AUC from time zero to infinity (AUC<sub>0-</sub>) by 12% (1 to 26%), and the half-life (t<sub>1/2</sub>) by 29% (19 to 40%), with no effect on the AUC from time zero to the time of the last nonzero concentration (AUC<sub>0-last</sub>). 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 (c) 2016 Green et al.

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