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Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum678.69 kB
Published VersionCC BY-NC-ND V4.0, Open Access
Journal article
Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum
Clinical Infectious Diseases, Vol.76(11), pp.1919-1927
2023
PMID: 36795050
Abstract
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 InstituteAzrin N. Abd-Rahman (Author) - QIMR Berghofer Medical Research InstituteRebecca Webster (Author) - QIMR Berghofer Medical Research InstituteAdam J. Potter (Author) - QIMR Berghofer Medical Research InstituteStacey Llewellyn (Author) - QIMR Berghofer Medical Research InstituteLouise Marquart (Author) - QIMR Berghofer Medical Research InstituteNischal Sahai (Author) - University of the Sunshine Coast, Queensland, UniSC Clinical Trials CentreIndika Leelasena (Author) - University of the Sunshine Coast, Queensland, UniSC Clinical Trials CentreGeoffrey W. Birrell (Author) - Australian Defence Force Malaria and Infectious Disease InstituteMichael D. Edstein (Author) - Australian Defence Force Malaria and Infectious Disease InstituteG. Dennis Shanks (Author) - Australian Defence Force Malaria and Infectious Disease InstituteDavid Wesche (Author) - CertaraJoerg J. Moehrle (Author) - Medicines for Malaria VentureJames 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; 1058-4838
- PMID
- 36795050
- 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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