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BMC Med. 2018 Jan 18;16(1):11. doi: 10.1186/s12916-017-0990-6.

Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa.

Author information

1
Mahidol Oxford Tropical Medicine Research Unit (MORU), Mahidol University, 420/6 Rajvithi Road, Rajthevee, Bangkok, 10400, Thailand. bob@tropmedres.ac.
2
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. bob@tropmedres.ac.
3
Division of Tropical and Humanitarian Medicine, University Hospitals of Geneva, Geneva, Switzerland. bob@tropmedres.ac.
4
Mahidol Oxford Tropical Medicine Research Unit (MORU), Mahidol University, 420/6 Rajvithi Road, Rajthevee, Bangkok, 10400, Thailand.
5
KEMRI-Wellcome Trust Research Programme, Centre for Geographic Medicine Research-Coast, Kilifi, Kenya.
6
Wellcome Trust Centre for Clinical Tropical Medicine and Department of Paediatrics, Faculty of Medicine, Imperial College, London, UK.
7
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
8
MRC Unit, Fajara, Banjul, The Gambia.
9
Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.
10
Global Health Institute, University of Antwerp, Antwerp, Belgium.
11
Department of Tropical Medicine, University of Kinshasa, Kinshasa, Democratic Republic of Congo.
12
Unité Mixte de Recherche 198, URMITE, IRD, Dakar, Sénégal.
13
Institut Pasteur de Madagascar, BP 1274, Antananarivo, Madagascar.
14
Médecins Sans Frontières, Paris, France.
15
Kinshasa Mahidol Oxford Research Unit, Kinshasa, Democratic Republic of Congo.
16
Kinshasa School of Public Health, Kinshasa, Democratic Republic of Congo.
17
Epicentre, Paris, France.
18
National Malaria Control Programme, Monrovia, Sierra Leone.
19
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
20
Malaria Research and Training Centre, USTTB, Bamako, Mali.
21
Queen Elizabeth Hospital, Blantyre, Malawi.
22
Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi.
23
National Malaria Control Programme, Kigali, Rwanda.
24
Kenya Medical Research Institute, Kisumu, Kenya.
25
Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
26
Amref Health Africa in Kenya, Nairobi, Kenya.
27
Centre de Recherche Entomologique de Cotonou, Cotonou, Benin.
28
Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
29
Department of Pediatrics, Indiana University, Indianapolis, IN, USA.
30
Centre National de Recherche et de Formation sur le Paludisme, Ouagadougou, Burkina Faso.
31
Groupe de Recherche Action en Santé (GRAS), Ouagadougou, Burkina Faso.
32
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
33
Institute of Tropical Medicine, University of Tubingen, Tubingen, Germany.

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.

KEYWORDS:

Age-based dosing; Malaria; Plasmodium falciparum; Primaquine; Transmission blocking

PMID:
29347975
PMCID:
PMC5774032
DOI:
10.1186/s12916-017-0990-6
[Indexed for MEDLINE]
Free PMC Article

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