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Published VersionCC BY V4.0, Open Access
Journal article
Characterizing the blood stage antimalarial activity of pyronaridine in healthy volunteers experimentally infected with Plasmodium falciparum
International Journal of Antimicrobial Agents, Vol.64(1), pp.1-8
2024
PMID: 38734217
Abstract
With the spread of artemisinin resistance throughout Southeast Asia and now in Africa, the antimalarial drug pyronaridine is likely to become an increasingly important component of new antimalarial drug regimens. However, the antimalarial activity of pyronaridine in humans has not been completely characterised. This volunteer infection study aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of pyronaridine in malaria naïve adults. Volunteers were inoculated with Plasmodium falciparum-infected erythrocytes on day 0 and administered different single oral doses of pyronaridine on day 8. Parasitaemia and concentrations of pyronaridine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 47 ± 2. Outcomes were parasite clearance kinetics, PK and PK/PD parameters from modelling. Ten participants were inoculated and administered 360 mg (n = 4), 540 mg (n = 4) or 720 mg (n = 1) pyronaridine. One participant was withdrawn without receiving pyronaridine. The time to maximum pyronaridine concentration was 1–2 h, the elimination half-life was 8–9 d, and the parasite clearance half-life was approximately 5 h. Parasite regrowth occurred with 360 mg (4/4 participants) and 540 mg (2/4 participants). Key efficacy parameters including the minimum inhibitory concentration (5.5 ng/mL) and minimum parasiticidal concentration leading to 90% of maximum effect (MPC90: 8 ng/mL) were derived from the PK/PD model. Adverse events considered related to pyronaridine were predominantly mild to moderate gastrointestinal symptoms. There were no serious adverse events. Data obtained in this study will support the use of pyronaridine in new antimalarial combination therapies by informing partner drug selection and dosing considerations.
Details
- Title
- Characterizing the blood stage antimalarial activity of pyronaridine in healthy volunteers experimentally infected with Plasmodium falciparum
- Authors
- Bridget E Barber - QIMR Berghofer Medical Research InstituteRebecca Webster - QIMR Berghofer Medical Research InstituteAdam J Potter - QIMR Berghofer Medical Research InstituteStacey Llewellyn - QIMR Berghofer Medical Research InstituteNischal Sahai - University of the Sunshine Coast, Queensland, UniSC Clinical Trials CentreIndika Leelasena - University of the Sunshine Coast, Queensland, UniSC Clinical Trials CentreSusan Mathison - University of the Sunshine Coast, Queensland, UniSC Clinical Trials CentreKarsten Kuritz - IntiQuan GmbH (Switzerland)Julia Flynn - Medicines for Malaria VentureStephan Chalon - Medicines for Malaria VentureAnne Claire Marrast - Medicines for Malaria VentureNathalie Gobeau - Medicines for Malaria VentureJoerg J Moehrle (Corresponding Author) - Medicines for Malaria Venture
- Publication details
- International Journal of Antimicrobial Agents, Vol.64(1), pp.1-8
- Publisher
- Elsevier BV
- Date published
- 2024
- DOI
- 10.1016/j.ijantimicag.2024.107196
- ISSN
- 1872-7913; 0924-8579
- PMID
- 38734217
- Copyright note
- © 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
- Grant note
- This study was funded by a grant from the Bill and Melinda Gates Foundation (INV-007155) and by a grant from the Australian Department of Foreign Affairs and Trade (74339) awarded to Medicines for Malaria Venture (MMV).
- Organisation Unit
- UniSC Clinical Trials Centre
- Language
- English
- Record Identifier
- 991036398702621
- Output Type
- Journal article
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