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

Author:

Green Justin A.1,Mohamed Khadeeja1,Goyal Navin2,Bouhired Samia1,Hussaini Azra3,Jones Siôn W.1,Koh Gavin C. K. W.1,Kostov Ivan3,Taylor Maxine4,Wolstenholm Allen5,Duparc Stephan6

Affiliation:

1. GlaxoSmithKline Research and Development, Stockley Park West, Uxbridge, Middlesex, United Kingdom

2. GlaxoSmithKline, Upper Merion, King of Prussia, Pennsylvania, USA

3. Parexel, Harbor Hospital, Baltimore, Baltimore, Maryland, USA

4. GlaxoSmithKline Research and Development, Ware, Hertfordshire, United Kingdom

5. GlaxoSmithKline, Upper Providence, Collegeville, Pennsylvania, USA

6. Medicines for Malaria Venture, Geneva, Switzerland

Abstract

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

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

Reference29 articles.

1. World Health Organization. 2015. World malaria report. WHO, Geneva, Switzerland. http://apps.who.int/iris/bitstream/10665/200018/1/9789241565158_eng.pdf. Accessed 11 February 2016.

2. World Health Organization. 2015. Guidelines for the treatment of malaria, 3rd ed. WHO, Geneva, Switzerland. http://www.who.int/malaria/publications/atoz/9789241549127/en/. Accessed 7 April 2016.

3. Primaquine radical cure of Plasmodium vivax: a critical review of the literature

4. Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study

5. The Hemolytic Effect of Primaquine and Related Compounds: a Review

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