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01.12.2018 | Research article | Ausgabe 1/2018 Open Access

BMC Medicine 1/2018

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

Zeitschrift:
BMC Medicine > Ausgabe 1/2018
Autoren:
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
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:https://​doi.​org/​10.​1186/​s12916-017-0990-6) contains supplementary material, which is available to authorized users.

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.
Zusatzmaterial
Additional file 1: Weight-for-age growth curves. (PDF 1202 kb)
12916_2017_990_MOESM1_ESM.pdf
Additional file 2: Table S1. Data type by country. (DOCX 14 kb)
12916_2017_990_MOESM2_ESM.docx
Literatur
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