학술논문
Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria.
Document Type
Academic Journal
Author
Mukaka M; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.; Onyamboko MA; Kinshasa School of Public Health, University of Kinshasa, Avenue Tombalbaye 68-78, Democratic Republic of Congo.; Olupot-Olupot P; Mbale Clinical Research Institute (MCRI), P.O. Box 1966, Mbale, Uganda; Busitema University, P.O. Box 1460, Mbale, Uganda.; Peerawaranun P; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand.; Suwannasin K; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand.; Pagornrat W; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand.; Kouhathong J; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand.; Madmanee W; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand.; Were W; Mbale Clinical Research Institute (MCRI), P.O. Box 1966, Mbale, Uganda.; Namayanja C; Mbale Clinical Research Institute (MCRI), P.O. Box 1966, Mbale, Uganda.; Onyas P; Mbale Clinical Research Institute (MCRI), P.O. Box 1966, Mbale, Uganda.; Titin H; Mbale Clinical Research Institute (MCRI), P.O. Box 1966, Mbale, Uganda.; Baseke J; Mbale Clinical Research Institute (MCRI), P.O. Box 1966, Mbale, Uganda.; Muhindo R; Mbale Clinical Research Institute (MCRI), P.O. Box 1966, Mbale, Uganda.; Kayembe DK; Kinshasa School of Public Health, University of Kinshasa, Avenue Tombalbaye 68-78, Democratic Republic of Congo.; Ndjowo PO; Kinshasa School of Public Health, University of Kinshasa, Avenue Tombalbaye 68-78, Democratic Republic of Congo.; Basara BB; Kinshasa School of Public Health, University of Kinshasa, Avenue Tombalbaye 68-78, Democratic Republic of Congo.; Bongo GS; Kinshasa School of Public Health, University of Kinshasa, Avenue Tombalbaye 68-78, Democratic Republic of Congo.; Okalebo CB; Mbale Clinical Research Institute (MCRI), P.O. Box 1966, Mbale, Uganda.; Abongo G; Mbale Clinical Research Institute (MCRI), P.O. Box 1966, Mbale, Uganda.; Uyoga S; KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.; Williams TN; KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya; Institute of Global Health Innovation, Department of Surgery and Cancer, Imperial College London, SW7 2AS, United Kingdom.; Taya C; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand.; Dhorda M; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.; Dondorp AM; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.; Waithira N; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.; Imwong M; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand; Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.; Maitland K; KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya; Institute of Global Health Innovation, Department of Surgery and Cancer, Imperial College London, SW7 2AS, United Kingdom.; Fanello C; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.; Day NPJ; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.; Tarning J; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.; White NJ; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom.; Taylor WRJ; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom. Electronic address: bob@tropmedres.ac.
Source
Publisher: Elsevier B.V Country of Publication: Netherlands NLM ID: 101647039 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2352-3964 (Electronic) Linking ISSN: 23523964 NLM ISO Abbreviation: EBioMedicine Subsets: MEDLINE
Subject
Language
English
Abstract
Background: There are no pharmacokinetic data of single low dose primaquine (SLDPQ) as transmission blocking in African children with acute Plasmodium falciparum and glucose-6-phosphate dehydrogenase deficiency (G6PDd).
Methods: Primaquine pharmacokinetics of age-dosed SLDPQ (shown previously to be gametocytocidal with similar tolerability as placebo) were characterised in falciparum-infected Ugandan and Congolese children aged 6 months to 11 years, treated on admission with standard 3-day dihydroartemisinin-piperaquine or artemether-lumefantrine plus SLDPQ: 6 m-<1 y: 1.25 mg, 1-5 y: 2.5 mg, 6-9 y: 5 mg, 10-11 y: 7.5 mg. LC-MS/MS-measured plasma primaquine and carboxyprimaquine (baseline, 1, 1.5, 2, 4, 8, 12, 24 h) were analysed by noncompartmental analysis. Multivariable linear regression modelled associations between covariates, including cytochrome-P450 2D6 metaboliser status, and outcomes.
Findings: 258 children (median age 5 [interquartile range (IQR) 3-7]) were sampled; 8 (3.1%) with early vomiting were excluded. Primaquine doses of 0.10-0.40 (median 0.21, IQR 0.16-0.25) mg base/kg resulted in primaquine maximum plasma concentrations (Cmax) of 2.3-447 (median 103.0, IQR 72.1-140.0) ng/mL between 1.0 and 8.0 (median 2) hours (Tmax ) and median areas under the drug concentration curves (AUC 0-last ) 730.2 (6 m-<1 y, n = 12), 582.8 (1-5 y, n = 126), 871.1 (6-9 y, n = 80), and 931.0 (10-11 y, n = 32) ng∗h/mL. Median elimination half-live (T½) was 4.7 (IQR 3.8-5.6) hours. Primaquine clearance/kg peaked at 18 months, plateauing at 4 y. Increasing CYP2D6 metaboliser activity score [poor (3/250), intermediate (52/250), normal (150/250), ultrarapid (5/250), indeterminate (40/250)] and baseline haemoglobin were significantly associated with a lower primaquine AUC 0-last ,which increased with increasing mg/kg dose and age but was independent of the artemisinin treatment used.
Interpretation: Age-dosed SLDPQ resulted in variable primaquine exposure that depended on bodyweight-adjusted dose, age, baseline haemoglobin and CYP2D6 metaboliser status, but not on dihydroartemisinin-piperaquine or artemether-lumefantrine. These data support age-dosed SLDPQ for transmission blocking in sub-Saharan Africa.
Funding: This work was cofunded by the UK Medical Research Council, Wellcome Trust, and UK Aid through the Global Health Trials (grant reference MR/P006973/1). The funders had no role in the study design, execution, and analysis and decisions regarding publication.
Competing Interests: Declaration of interests All authors declare that they have no competing interests.
(Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
Methods: Primaquine pharmacokinetics of age-dosed SLDPQ (shown previously to be gametocytocidal with similar tolerability as placebo) were characterised in falciparum-infected Ugandan and Congolese children aged 6 months to 11 years, treated on admission with standard 3-day dihydroartemisinin-piperaquine or artemether-lumefantrine plus SLDPQ: 6 m-<1 y: 1.25 mg, 1-5 y: 2.5 mg, 6-9 y: 5 mg, 10-11 y: 7.5 mg. LC-MS/MS-measured plasma primaquine and carboxyprimaquine (baseline, 1, 1.5, 2, 4, 8, 12, 24 h) were analysed by noncompartmental analysis. Multivariable linear regression modelled associations between covariates, including cytochrome-P450 2D6 metaboliser status, and outcomes.
Findings: 258 children (median age 5 [interquartile range (IQR) 3-7]) were sampled; 8 (3.1%) with early vomiting were excluded. Primaquine doses of 0.10-0.40 (median 0.21, IQR 0.16-0.25) mg base/kg resulted in primaquine maximum plasma concentrations (Cmax) of 2.3-447 (median 103.0, IQR 72.1-140.0) ng/mL between 1.0 and 8.0 (median 2) hours (T
Interpretation: Age-dosed SLDPQ resulted in variable primaquine exposure that depended on bodyweight-adjusted dose, age, baseline haemoglobin and CYP2D6 metaboliser status, but not on dihydroartemisinin-piperaquine or artemether-lumefantrine. These data support age-dosed SLDPQ for transmission blocking in sub-Saharan Africa.
Funding: This work was cofunded by the UK Medical Research Council, Wellcome Trust, and UK Aid through the Global Health Trials (grant reference MR/P006973/1). The funders had no role in the study design, execution, and analysis and decisions regarding publication.
Competing Interests: Declaration of interests All authors declare that they have no competing interests.
(Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)