Background Primaquine is the only widely available drug for radical cure of Plasmodium vivax malaria. There is uncertainty whether the pharmacokinetic properties of primaquine are altered significantly in childhood or not. Methods Glucose-6-phosphate dehydrogenase normal patients with uncomplicated P. vivax malaria were randomized to receive either chloroquine (25mg base/kg) or dihydroartemisinin-piperaquine (dihydroartemisinin 7mg/kg and piperaquine 55mg/kg) plus primaquine; given either as 0.5 mg base/kg/day for 14 days or 1 mg/kg/day for 7 days. Pre-dose day 7 venous plasma concentrations of chloroquine, desethylchloroquine, piperaquine, primaquine and carboxyprimaquine were measured. Methemoglobin levels were measured on day 7. Results Day 7 primaquine and carboxyprimaquine concentrations were available for 641 patients. After adjustment for the primaquine mg/kg daily dose, day of sampling, partner drug, and fever clearance, there was a significant non-linear relationship between age and trough primaquine and carboxyprimaquine concentrations, and day methemoglobin levels. Compared to adults 30 years of age, children 5 years of age had trough primaquine concentrations 0.53 (95% CI: 0.39- 0.73) fold lower, trough carboxyprimaquine concentrations 0.45 (95% CI: 0.35- 0.55) fold lower, and day 7 methemoglobin levels 0.87 (95% CI: 0.58-1.27) fold lower. Increasing concentrations of piperaquine and chloroquine and poor metabolizer CYP 2D6 alleles were associated with higher day 7 primaquine and carboxyprimaquine concentrations. Higher blood methemoglobin concentrations were associated with a lower risk of recurrence. Conclusion Young children have lower primaquine and carboxyprimaquine exposures, and lower levels of methemoglobinemia, than adults. Young children may need higher weight adjusted primaquine doses than adults.
Radical cure of Plasmodium vivax malaria in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals employs weekly primaquine dosing. This is the only recommended regimen for this patient sub-group. If national malaria programs mandate daily primaquine dosing (the recommended regimen for G6PD normal individuals), then G6PD testing before prescription is necessary to avoid iatrogenic haemolysis in G6PD deficient individuals. In this case series, two P. vivax infected patients with unknown G6PD status from two different countries were prescribed primaquine as per national malaria program guidelines. During treatment both patients presented to the clinic with symptoms of anaemia after taking primaquine incorrectly. The clinical management of the iatrogenic severe haemolysis that occurred in these patients demonstrates the various adverse effects primaquine can cause, that other common medical treatments also have haemolytic potential, and how the diagnosis of G6PD deficiency can be elusive during acute haemolysis. Health care providers should provide careful instructions about primaquine dosing, be watchful for haemolysis, and have a high index of suspicion for G6PD deficiency in the presence of haemolysis if the G6PD status is previously unknown.
Radical cure of malaria in glucose-6-phosphate Plasmodium vivax dehydrogenase (G6PD) deficient individuals employs weekly primaquine dosing. This is the only recommended regimen for this patient sub-group. If national malaria programs mandate daily primaquine dosing (the recommended regimen for G6PD normal individuals), then G6PD testing before prescription is necessary to avoid iatrogenic haemolysis in G6PD deficient individuals. In this case series, two infected patients with P. vivax unknown G6PD status from two different countries were prescribed primaquine as per national malaria program guidelines. During treatment both patients presented to the clinic with symptoms of anaemia after taking primaquine incorrectly. The clinical management of the iatrogenic severe haemolysis that occurred in these patients demonstrates the various adverse effects primaquine can cause, that other common medical treatments also have haemolytic potential, and how the diagnosis of G6PD deficiency can be elusive during acute haemolysis. Health care providers should provide careful instructions about primaquine dosing, be watchful for haemolysis, and have a high index of suspicion for G6PD deficiency in the presence of haemolysis if the G6PD status is previously unknown.
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