Within-host modeling of primaquine-induced hemolysis in hemizygote glucose-6-phosphate dehydrogenase deficient healthy volunteers
Primaquine is the only widely available drug to prevent relapses of <i>Plasmodium vivax</i> malaria. Primaquine is underused because of concerns over oxidant hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficiency. A pharmacometric trial showed that ascending-dose radical cure primaquine regimens causing 'slow burn' hemolysis were safe in G6PD-deficient Thai and Burmese male volunteers. We developed and calibrated a within-host model of primaquine hemolysis in G6PD deficiency, using detailed serial hemoglobin and reticulocyte count data from 23 hemizygote deficient volunteers given ascending-dose primaquine (1,523 individual measurements over 656 unique time points). We estimate that primaquine doses of ~0.75 mg base/kg reduce the circulating lifespan of deficient erythrocytes by ~30 days in individuals with common Southeast Asian <i>G6PD</i> variants. We predict that 5 mg/kg primaquine total dose can be administered safely to G6PD-deficient individuals over 14 days with expected hemoglobin drops of 18 to 43% (2.7 to 6.5 g/dL drop from a baseline of 15 g/dL).CLINICAL TRIALSThis study is registered with the Thai Clinical Trials Registry (TCTR) as TCTR20170830002 and TCTR20220317004.
Authors
- Sasithon Pukrittayakamee (ORCID: https://orcid.org/0000-0003-2573-3967)
- Pawanrat Leungsinsiri
- Borimas Hanboonkunupakarn (ORCID: https://orcid.org/0000-0001-8729-1442)
- S Dini (ORCID: https://orcid.org/0000-0002-4613-3672)
- Podjanee Jittamala (ORCID: https://orcid.org/0000-0002-1020-2760)
- Nicholas Day (ORCID: https://orcid.org/0000-0003-2309-1171)
- Parinaz Mehdipour (ORCID: https://orcid.org/0000-0002-1608-8487)
- Walter Taylor (ORCID: https://orcid.org/0000-0001-6236-0464)
- Germana Bancone (ORCID: https://orcid.org/0000-0003-4550-0431)
- James A Watson (ORCID: https://orcid.org/0000-0001-5524-0325)
- Julie Anne Simpson (ORCID: https://orcid.org/0000-0002-2660-2013)
- Kesinee Chotivanich (ORCID: https://orcid.org/0000-0002-6533-6811)
- Kittiyod Poovorawan (ORCID: https://orcid.org/0000-0001-7016-7605)
- Robert Moss (ORCID: https://orcid.org/0000-0002-4568-2012)
- Nicholas John White (ORCID: https://orcid.org/0000-0002-1897-1978)
- Sophie Zaloumis (ORCID: https://orcid.org/0000-0002-8253-8896)
- Robert J. Commons (ORCID: https://orcid.org/0000-0002-3359-5632)
- David J. Price (ORCID: https://orcid.org/0000-0003-0076-3123)
Institutions
- The University of Melbourne (AU)
- Mahidol University (TH)
- Angkor Hospital for Children (KH)
- Charles Darwin University (AU)
- University of Oxford (GB)
- Menzies School of Health Research (AU)
- Shoklo Malaria Research Unit (TH)
- Peter Doherty Institute (AU)
- Ballarat Health Services (AU)
- Mahidol Oxford Tropical Medicine Research Unit (TH)
- Infectious Diseases Data Observatory (GB)
- Grampians Health
Publication Details
- Journal
- Antimicrobial Agents and Chemotherapy
- Published
- 2025-02-24
- DOI
- https://doi.org/10.1128/aac.01549-24
- Primary Topic
- Neonatal Health and Biochemistry
- Type
- article
- Field-Weighted Citation Impact
- 0.00