High total primaquine dose provides superior protection against malaria recurrence in children

A high total dose of primaquine outperforms a low dose at preventing the recurrence of Plasmodium vivax malaria in children, although it comes with more serious adverse events, according to the results of a meta-analysis.

Pooled data from 27 studies involving 3,514 children younger than 15 years across 15 countries showed that the cumulative incidence of recurrence by day 180 was 10.2 percent following treatment with a high total dose (7 mg/kg) of primaquine, 16.0 percent following a low total dose (3.5 mg/kg), and 51.4 percent following treatment without primaquine. [Lancet Child Adolesc Health 2024;8:798-808]

Increasing the total dose of primaquine from 3.5 mg/kg to 7 mg/kg would reduce the risk of recurrent P vivax parasitaemia by more than 40 percent in all children (adjusted hazard ratio [aHR], 0.54, 95 percent confidence interval [CI], 0.35–0.85) and by about 60 percent in children younger than 5 years (n=525; aHR, 0.41, 95 percent CI, 0.21–0.78).

“These results suggest that younger children might require a higher total dose to achieve the same antirelapse benefit as older individuals,” the investigators noted.

Safety

Compared with no primaquine, treatment with any dose of primaquine was associated with a greater risk of gastrointestinal symptoms (vomiting, anorexia, or diarrhoea) on days 5–7. The covariate-adjusted estimated percentage of gastrointestinal intolerance was 3.9 percent with no primaquine, 9.2 percent with a low daily dose (0.25 mg/kg), 6.8 percent with an intermediate daily dose (0.5 mg/kg), and 9.6 percent with a high daily dose (1 mg/kg).

In the subgroup of children with glucose-6-phosphate dehydrogenase (G6PD) activity of at least 30 percent, the rate of severe haemolysis (haemoglobin decrease of at least 25 percent to <7g/dL) was 0.4 percent with no primaquine, 0 percent with a low daily dose, 0.5 percent with an intermediate daily dose, and 0.7 percent with a high daily dose.

Of 15 possibly drug-related serious adverse events documented within 28 days, two occurred following a low daily dose of primaquine, four following an intermediate daily dose, and nine following a high daily dose.

According to the researchers, a high total dose of primaquine could be achieved by administering 0.5 mg/kg per day for 14 days or 1 mg/kg per day for 7 days. A 14-day regimen at 0.5 mg/kg per day “seemed to be safe and highly effective in patients with G6PD activity of 30 percent or higher.”

Meanwhile, “a higher daily dose of 1 mg/kg administered for 7 days might provide greater adherence and thus effectiveness through a shorter course regimen, but this might come with a greater risk of severe haemolysis and, thus, should potentially be reserved for patients with G6PD activity of 70 percent or higher,” they said.

Optimal dosing

“An estimated 85 percent of recurrences are caused by relapses; hence, it is crucial that children and adults receive appropriate radical cure treatment. The current absence of child-friendly primaquine formulations hampers effective implementation of primaquine radical cure in children, who have a disproportionately high burden of P vivax-associated anaemia,” the investigators pointed out. [Am J Trop Med Hyg 2020;103:1094-1099; PLoS Med 2013;10:e1001575]

“Our study provides important evidence that will inform optimal weight-based primaquine dosing guidelines for children and the development of novel paediatric primaquine formulations,” they concluded.