Researchers develop an age-based regimen for single low-dose primaquine to block transmission of malaria in sub-Saharan Africa

11 May 2018

The World Health Organization (WHO) recommended in 2012 to add single low-dose primaquine (SLDPQ) to standard artemisinin based combination treatments (ACTs) to block the transmission of Plasmodium falciparum malaria. The target dose of 0.25 mg base/kg body weight (15 mg in a 60 kg adult) was considered safe in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDd) and SLDPQ was recommended to be given without testing for G6PDd.  

While SLDPQ is not currently deployed anywhere in SSA, several low-transmission countries, including Botswana, Eritrea, Swaziland and Zimbabwe have added SLDPQ to their national treatment guidelines and plan to use SLDPQ treatment.

Implementation of the 2012 WHO recommendation has been slow due to concerns that SLDPQ might cause clinically significant acute haemolytic anaemia (AHA) in G6PDd individuals, together with the very real challenge of deploying a suitable G6PDd test to exclude this at-risk group from receiving SLDPQ,” suggests the study lead author Bob Taylor.

In response to the WHO recommendation, Bob Taylor, Mavuto Mukaka and Naw Htee Khu, together with colleagues from the Mahidol Oxford Research Unit (MORU) and multiple collaborators, assembled a large anthropometric database of Africans of all ages and modelled an age-based SLDPQ regimen, consisting of five dosing bands, for patients of all ages, including those with a G6PD deficiency.

Data-sharing by multiple partners was an essential element in constructing the growth curves, so we could design the optimal regimen”, added Htee Khu and Mavuto.    

The results were published earlier this year in BMC Medicine. The proposed tablet strengths of 2.5, 5, 7.5 and 15 mg overlap with those of an aged-based SLDPQ regimen designed for Cambodia, which was also developed by MORU and collaborators in Cambodia.   

The African age-based SDLPQ regimen requires a thorough examination of tolerability, efficacy, pharmacokinetics (PK), and PK–pharmacodynamic relationships. Htee Khu and Mavuto highlight, “The study also acknowledges additional hurdles relating to the future large-scale rollout of SLDPQ given the limited availability of primaquine tablet strengths, which are registered to international standards, and the lack of paediatric friendly formulations.”

Age-based dosing regimens exist for artesunate -amodiaquine (ASAQ) and artesunate –mefloquine (ASMQ). They have the advantage of being used widely where weighing scales are unavailable, including private chemists, and for mass drug administration in conflict or logistically-challenging settings, like complex emergencies.

Going forward, MORU will test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial of uncomplicated P. falciparum malaria in G6PDd African children aged 0.5 − 11 years (ISRCTN11594437). Two sites will conduct the study, the Mbale Clinical Research Institute, Uganda, and KIMORU, Kinshasa, in the Democratic Republic of Congo; the fully analysed results should be available next year.

With this new knowledge and the eventual definition of the dose–response relationship between primaquine metabolites and haemolysis and mosquito infectivity, the team’s proposed SLDPQ regimen may need to be fine-tuned in order to establish a robust regimen that could be adopted widely by national malaria control programmes to support malaria elimination efforts in sub-Saharan Africa.

“We also hope to have primaquine WHO prequalified so that SLDPQ can be more widely available. Preparatory work for this initiative has begun and we will be engaging with partners and funders to deliver our goal,” concludes Bob Taylor.

Read the full results here: W. Robert Taylor et al. Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria – a proposed model-derived age-based regimen for sub-Saharan Africa. BMC Medicine January 18, 2018 16:11

See details of WWARN’s Low dose primaquine efficacy and safety study group.

Watch an interview with Bob Taylor, MORU