Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum

Bridget E. Barber; Azrin N. Abd-Rahman; Rebecca Webster; Adam J. Potter; Stacey Llewellyn; Louise Marquart; Nischal Sahai; Indika Leelasena; Geoffrey W. Birrell; Michael D. Edstein; G. Dennis Shanks; David Wesche; Joerg J. Moehrle; James S. McCarthy

doi:10.1093/cid/ciad075

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Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum

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Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum

Bridget E. Barber, Azrin N. Abd-Rahman, Rebecca Webster, Adam J. Potter, Stacey Llewellyn, Louise Marquart, Nischal Sahai, Indika Leelasena, Geoffrey W. Birrell, Michael D. Edstein, …

Clinical Infectious Diseases, Vol.76(11), pp.1919-1927

2023

DOI: https://doi.org/10.1093/cid/ciad075

PMCID: PMC10249991

PMID: 36795050

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Abstract

Plasmodium falciparum

tafenoquine

blood stage

antimalarial

Background: The long-acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood-stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD)–deficient individuals. Methods: Healthy adults with normal levels of G6PD were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48 ± 2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. Results: Twelve participants were inoculated and administered 200 mg (n = 3), 300 mg (n = 4), 400 mg (n = 2), or 600 mg (n = 3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 hours and 4.2 hours, respectively) was faster than with 200 mg or 300 mg (11.8 hours and 9.6 hours, respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants) but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 106 and 109, respectively, in a 60-kg adult. Conclusions: Although a single dose of tafenoquine exhibits potent P. falciparum blood-stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency.

Details

Title: Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum
Authors: Bridget E. Barber (Corresponding Author) - QIMR Berghofer Medical Research Institute
Azrin N. Abd-Rahman (Author) - QIMR Berghofer Medical Research Institute
Rebecca Webster (Author) - QIMR Berghofer Medical Research Institute
Adam J. Potter (Author) - QIMR Berghofer Medical Research Institute
Stacey Llewellyn (Author) - QIMR Berghofer Medical Research Institute
Louise Marquart (Author) - QIMR Berghofer Medical Research Institute
Nischal Sahai (Author) - University of the Sunshine Coast, Queensland, UniSC Clinical Trials Centre
Indika Leelasena (Author) - University of the Sunshine Coast, Queensland, UniSC Clinical Trials Centre
Geoffrey W. Birrell (Author) - Australian Defence Force Malaria and Infectious Disease Institute (Australia)
Michael D. Edstein (Author) - Australian Defence Force Malaria and Infectious Disease Institute (Australia)
G. Dennis Shanks (Author) - Australian Defence Force Malaria and Infectious Disease Institute (Australia)
David Wesche (Author) - Certara (United States)
Joerg J. Moehrle (Author) - Medicines for Malaria Venture
James S. McCarthy (Author) - QIMR Berghofer Medical Research Institute
Publication details: Clinical Infectious Diseases, Vol.76(11), pp.1919-1927
Publisher: Oxford University Press
Date published: 2023
DOI: 10.1093/cid/ciad075
ISSN: 1537-6591
PMID: 36795050; PMC10249991
Copyright note: © The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons AttributionNonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
Grant note: Medicines for Malaria Venture INV-001965 / Bill and Melinda Gates Foundation
Organisation Unit: UniSC Clinical Trials Centre
Language: English
Record Identifier: 99716034002621
Output Type: Journal article

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