Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria – a proposed model-derived age-based regimen for sub-Saharan Africa
Abstract Background In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients...
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2018-01-01
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Online Access: | http://link.springer.com/article/10.1186/s12916-017-0990-6 |
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author |
W. Robert Taylor Htee Khu Naw Kathryn Maitland Thomas N. Williams Melissa Kapulu Umberto D’Alessandro James A. Berkley Philip Bejon Joseph Okebe Jane Achan Alfred Ngwa Amambua Muna Affara Davis Nwakanma Jean-Pierre van Geertruyden Muhindo Mavoko Pascal Lutumba Junior Matangila Philipe Brasseur Patrice Piola Rindra Randremanana Estrella Lasry Caterina Fanello Marie Onyamboko Birgit Schramm Zolia Yah Joel Jones Rick M. Fairhurst Mahamadou Diakite Grace Malenga Malcolm Molyneux Claude Rwagacondo Charles Obonyo Endalamaw Gadisa Abraham Aseffa Mores Loolpapit Marie-Claire Henry Grant Dorsey Chandy John Sodiomon B. Sirima Karen I. Barnes Peter Kremsner Nicholas P. Day Nicholas J. White Mavuto Mukaka |
spellingShingle |
W. Robert Taylor Htee Khu Naw Kathryn Maitland Thomas N. Williams Melissa Kapulu Umberto D’Alessandro James A. Berkley Philip Bejon Joseph Okebe Jane Achan Alfred Ngwa Amambua Muna Affara Davis Nwakanma Jean-Pierre van Geertruyden Muhindo Mavoko Pascal Lutumba Junior Matangila Philipe Brasseur Patrice Piola Rindra Randremanana Estrella Lasry Caterina Fanello Marie Onyamboko Birgit Schramm Zolia Yah Joel Jones Rick M. Fairhurst Mahamadou Diakite Grace Malenga Malcolm Molyneux Claude Rwagacondo Charles Obonyo Endalamaw Gadisa Abraham Aseffa Mores Loolpapit Marie-Claire Henry Grant Dorsey Chandy John Sodiomon B. Sirima Karen I. Barnes Peter Kremsner Nicholas P. Day Nicholas J. White Mavuto Mukaka Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria – a proposed model-derived age-based regimen for sub-Saharan Africa BMC Medicine Primaquine Age-based dosing Plasmodium falciparum Malaria Transmission blocking |
author_facet |
W. Robert Taylor Htee Khu Naw Kathryn Maitland Thomas N. Williams Melissa Kapulu Umberto D’Alessandro James A. Berkley Philip Bejon Joseph Okebe Jane Achan Alfred Ngwa Amambua Muna Affara Davis Nwakanma Jean-Pierre van Geertruyden Muhindo Mavoko Pascal Lutumba Junior Matangila Philipe Brasseur Patrice Piola Rindra Randremanana Estrella Lasry Caterina Fanello Marie Onyamboko Birgit Schramm Zolia Yah Joel Jones Rick M. Fairhurst Mahamadou Diakite Grace Malenga Malcolm Molyneux Claude Rwagacondo Charles Obonyo Endalamaw Gadisa Abraham Aseffa Mores Loolpapit Marie-Claire Henry Grant Dorsey Chandy John Sodiomon B. Sirima Karen I. Barnes Peter Kremsner Nicholas P. Day Nicholas J. White Mavuto Mukaka |
author_sort |
W. Robert Taylor |
title |
Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria – a proposed model-derived age-based regimen for sub-Saharan Africa |
title_short |
Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria – a proposed model-derived age-based regimen for sub-Saharan Africa |
title_full |
Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria – a proposed model-derived age-based regimen for sub-Saharan Africa |
title_fullStr |
Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria – a proposed model-derived age-based regimen for sub-Saharan Africa |
title_full_unstemmed |
Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria – a proposed model-derived age-based regimen for sub-Saharan Africa |
title_sort |
single low-dose primaquine for blocking transmission of plasmodium falciparum malaria – a proposed model-derived age-based regimen for sub-saharan africa |
publisher |
BMC |
series |
BMC Medicine |
issn |
1741-7015 |
publishDate |
2018-01-01 |
description |
Abstract Background In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. Methods Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15–0.4 mg PQ base/kg for children aged 1–5 years and 0.15–0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6–11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box–Cox transformation power exponential and tested PQ doses of 1–15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. Results From the Box–Cox transformation power exponential model, five age categories were selected: (i) 6–11 months (n = 39,886, 6.03%), (ii) 1–5 years (n = 261,036, 45.46%), (iii) 6–9 years (n = 20,770, 3.14%), (iv) 10–14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12–0.25), (ii) 0.21 (0.13–0.37), (iii) 0.25 (0.16–0.38), (iv) 0.26 (0.15–0.38) and (v) 0.27 (0.17–0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8% (327,620/328,132), respectively. Conclusions We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5 − 11 years. If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination. |
topic |
Primaquine Age-based dosing Plasmodium falciparum Malaria Transmission blocking |
url |
http://link.springer.com/article/10.1186/s12916-017-0990-6 |
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doaj-2a4bf5506f7541d1a72a265703af40862020-11-25T02:14:55ZengBMCBMC Medicine1741-70152018-01-0116111410.1186/s12916-017-0990-6Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria – a proposed model-derived age-based regimen for sub-Saharan AfricaW. Robert Taylor0Htee Khu Naw1Kathryn Maitland2Thomas N. Williams3Melissa Kapulu4Umberto D’Alessandro5James A. Berkley6Philip Bejon7Joseph Okebe8Jane Achan9Alfred Ngwa Amambua10Muna Affara11Davis Nwakanma12Jean-Pierre van Geertruyden13Muhindo Mavoko14Pascal Lutumba15Junior Matangila16Philipe Brasseur17Patrice Piola18Rindra Randremanana19Estrella Lasry20Caterina Fanello21Marie Onyamboko22Birgit Schramm23Zolia Yah24Joel Jones25Rick M. Fairhurst26Mahamadou Diakite27Grace Malenga28Malcolm Molyneux29Claude Rwagacondo30Charles Obonyo31Endalamaw Gadisa32Abraham Aseffa33Mores Loolpapit34Marie-Claire Henry35Grant Dorsey36Chandy John37Sodiomon B. Sirima38Karen I. Barnes39Peter Kremsner40Nicholas P. Day41Nicholas J. White42Mavuto Mukaka43Mahidol Oxford Tropical Medicine Research Unit (MORU), Mahidol UniversityMahidol Oxford Tropical Medicine Research Unit (MORU), Mahidol UniversityKEMRI–Wellcome Trust Research Programme, Centre for Geographic Medicine Research-CoastKEMRI–Wellcome Trust Research Programme, Centre for Geographic Medicine Research-CoastCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of OxfordMRC UnitCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of OxfordCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of OxfordMRC UnitMRC UnitMRC UnitMRC UnitMRC UnitGlobal Health Institute, University of AntwerpDepartment of Tropical Medicine, University of KinshasaDepartment of Tropical Medicine, University of KinshasaDepartment of Tropical Medicine, University of KinshasaUnité Mixte de Recherche 198, URMITE, IRDInstitut Pasteur de MadagascarMédecins Sans FrontièresKinshasa Mahidol Oxford Research UnitCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of OxfordKinshasa Mahidol Oxford Research UnitEpicentreNational Malaria Control ProgrammeNational Malaria Control ProgrammeLaboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of HealthMalaria Research and Training Centre, USTTBQueen Elizabeth HospitalMalawi-Liverpool-Wellcome Trust Clinical Research ProgrammeNational Malaria Control ProgrammeKenya Medical Research InstituteArmauer Hansen Research InstituteArmauer Hansen Research InstituteAmref Health Africa in KenyaCentre de Recherche Entomologique de CotonouDepartment of Medicine, University of California San FranciscoDepartment of Pediatrics, Indiana UniversityCentre National de Recherche et de Formation sur le PaludismeDivision of Clinical Pharmacology, Department of Medicine, University of Cape TownInstitute of Tropical Medicine, University of TubingenMahidol Oxford Tropical Medicine Research Unit (MORU), Mahidol UniversityMahidol Oxford Tropical Medicine Research Unit (MORU), Mahidol UniversityMahidol Oxford Tropical Medicine Research Unit (MORU), Mahidol UniversityAbstract Background In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. Methods Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15–0.4 mg PQ base/kg for children aged 1–5 years and 0.15–0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6–11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box–Cox transformation power exponential and tested PQ doses of 1–15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. Results From the Box–Cox transformation power exponential model, five age categories were selected: (i) 6–11 months (n = 39,886, 6.03%), (ii) 1–5 years (n = 261,036, 45.46%), (iii) 6–9 years (n = 20,770, 3.14%), (iv) 10–14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12–0.25), (ii) 0.21 (0.13–0.37), (iii) 0.25 (0.16–0.38), (iv) 0.26 (0.15–0.38) and (v) 0.27 (0.17–0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8% (327,620/328,132), respectively. Conclusions We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5 − 11 years. If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination.http://link.springer.com/article/10.1186/s12916-017-0990-6PrimaquineAge-based dosingPlasmodium falciparumMalariaTransmission blocking |