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Title: Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa
Authors: 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
Unité de Recherche sur les Maladies Infectieuses et Tropicales émergentes
Universite de Kinshasa
Queen Elizabeth Central Hospital Malawi
Malawi-Liverpool-Wellcome Trust Clinical Research Programme
Institut Pasteur de Madagascar
Centre de Recherche Entomologique de Cotonou
Medical Research Council Laboratories Gambia
Armauer Hansen Research Institute
Kenya Medical Research Institute
Wellcome Trust Research Laboratories Nairobi
African Medical Research Foundation Nairobi
London School of Hygiene & Tropical Medicine
Indiana University-Purdue University Indianapolis
University of California, San Francisco
Wellcome Trust
National Institute of Allergy and Infectious Diseases
Universität Tübingen
Universiteit Antwerpen
Mahidol University
Hôpitaux universitaires de Genève
Nuffield Department of Clinical Medicine
Medecins Sans Frontieres
University of Cape Town
Kinshasa Mahidol Oxford Research Unit
National Malaria Control Programme
Groupe de Recherche Action en Santé (GRAS)
National Malaria Control Program
Kinshasa School of Public Health
Centre National de Recherche et de Formation sur le Paludisme
Keywords: Medicine
Issue Date: 18-Jan-2018
Citation: BMC Medicine. Vol.16, No.1 (2018)
Abstract: © 2018 The Author(s). 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.
ISSN: 17417015
Appears in Collections:Scopus 2018

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