Primaquine Therapy in Plasmodium vivax Malaria

Plasmodium vivax poses a distinctive challenge to malaria control due to its ability to form dormant liver stages (hypnozoites) that can reactivate weeks to months after the initial blood‐stage infection, leading to relapses. Primaquine, an 8-aminoquinoline, remains the only widely available drug capable of achieving radical cure by targeting both hypnozoites and gametocytes. Standard regimens historically span 14 days at 0.25–0.5 mg base/kg per day, though total doses vary regionally. Efficacy correlates closely with cumulative dosing, while safety is constrained by the risk of haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Adherence to prolonged courses is suboptimal in many endemic settings, prompting exploration of shorter high-dose regimens and supervised administration. Interindividual variability in drug metabolism, particularly CYP2D6 polymorphisms, further influences therapeutic outcomes. Recent mechanistic insights into active metabolites and population pharmacokinetics in special groups such as lactating women have begun to inform more precise dosing strategies, aiming to maximise radical cure, minimise adverse events and reduce transmission potential globally.

Research from Nature Portfolio

Population pharmacokinetic modelling in lactating women has characterised primaquine and carboxyprimaquine concentrations in maternal plasma and breast milk, demonstrating that infant exposure is less than 1 percent of maternal levels. This finding supports the safe use of standard primaquine regimens in breastfeeding mothers after the neonatal period, even in cases of severe G6PD deficiency. Complementary mechanistic work has elucidated a two-step biochemical relay in which hydroxylated primaquine metabolites exert antimalarial activity independently of CYP2D6, with potency markedly enhanced by cytochrome P450 reductase. This mechanistic clarity paves the way for rational redesign of 8-aminoquinolines with improved efficacy and safety profiles against both liver and sexual transmission stages.

Primaquine Therapy in Plasmodium vivax Malaria publication trend

The graph below shows the total number of articles in primaquine therapy in plasmodium vivax malaria across all publications each year (not limited to Nature Index journals).

Technical terms

Hypnozoite: Dormant liver-stage form of P. vivax responsible for relapse.

Radical cure: Therapeutic strategy aiming to eliminate both blood and liver parasite stages.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency: Genetic enzymopathy that increases red cell susceptibility to drug-induced haemolysis.

Pharmacokinetics: Study of drug absorption, distribution, metabolism and excretion in the body.

Gametocyte: Sexual stage of the parasite transmissible to mosquitoes.

Cytochrome P450 2D6 (CYP2D6): Hepatic enzyme critical for primaquine metabolism to active forms.

References

1. Effect of primaquine dose on the risk of recurrence in patients with uncomplicated Plasmodium vivax: a systematic review and individual patient data meta-analysis. The Lancet Infectious Diseases (2023).
2. Population pharmacokinetic modelling of primaquine exposures in lactating women and breastfed infants. Nature Communications (2024).
3. Primaquine for uncomplicated Plasmodium vivax malaria in children younger than 15 years: a systematic review and individual patient data meta-analysis. The Lancet Child & Adolescent Health (2024).
4. Supervised administration of primaquine may enhance adherence to radical cure for P. vivax malaria in India. The Lancet Regional Health - Southeast Asia (2023).
5. Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trial. The Lancet (2019).
6. Association of Impaired Cytochrome P450 2D6 Activity Genotype and Phenotype With Therapeutic Efficacy of Primaquine Treatment for Latent Plasmodium vivax Malaria. JAMA Network Open (2018).
7. Antimalarial activity of primaquine operates via a two-step biochemical relay. Nature Communications (2019).