Determinants of primaquine and carboxyprimaquine exposures in children and adults with Plasmodium vivax malaria

Abstract

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; plus either 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 days 1, 4, 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 0.55 (95% CI: 0.39- 0.78) fold lower, trough carboxyprimaquine concentrations 0.43 (95% CI: 0.34- 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 also associated with higher day 7 primaquine and carboxyprimaquine concentrations. Increased 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.

Methaemoglobinaemia and the radical curative efficacy of 8‐aminoquinoline antimalarials

“…After adjusting for age and partner drug, the day 7 concentrations of primaquine and carboxyprimaquine were not associated with the risk of recurrence, but methaemoglobinaemia was. Higher levels of methaemoglobinaemia were associated with reduced recurrences; a 1% absolute increase in day 7 methaemoglobin was associated with a hazard ratio for recurrence of 0.9 (95% CI: 0.85–0.99, P = .02) 28 …”

“…More recent studies in which methaemoglobinaemia has been assessed after different dose regimens of primaquine whether given alone, 23,39–41 or in combination with antimalarial drugs, 18,32,35,38 either to healthy volunteers, in antimalarial prophylaxis, or in the treatment of vivax malaria 15,19,21–23,25,26,28–33,38 . These do not suggest attenuation of primaquine‐induced methaemoglobinaemia by concomitant antimalarial drugs (as reported by Clayman et al 38 ), nor are there differences between healthy subjects and patients with malaria.…”

“…Dose–response relationships for primaquine and tafenoquine in generating methaemoglobinaemia 21–23,25,26,28–32 . Peak values are shown.…”

“…Higher levels of methaemoglobinaemia were associated with reduced recurrences; a 1% absolute increase in day 7 methaemoglobin was associated with a hazard ratio for recurrence of 0.9 (95% CI: 0.85-0.99, P = .02). 28 Tafenoquine is a slowly eliminated 8-aminoquinoline which has been introduced recently. At the currently recommended dose (adult dose 300 mg) tafenoquine provides radical cure rates which are significantly inferior to the lower dose of primaquine (total dose, 3.5 mg/kg) in Southeast Asia.…”

“…The size of the circles is proportional to the number of subjects recruited as shown in the inset box F I G U R E 4 Dose-response relationships for primaquine and tafenoquine in generating methaemoglobinaemia. [21][22][23]25,26,[28][29][30][31][32] Peak values are shown. The dose shown is the daily adult dose of primaquine, whereas for tafenoquine the dose shown is the total dose administered.…”