Determinants of Primaquine and Carboxyprimaquine Exposures in Children and Adults with Plasmodium vivax Malaria

Abstract

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. Patients with uncomplicated P. vivax malaria and with normal glucose-6-phosphate dehydrogenase were randomized to receive either chloroquine (25 mg base/kg of body weight) or dihydroartemisinin-piperaquine (dihydroartemisinin at 7 mg/kg and piperaquine at 55 mg/kg) plus primaquine, given either as 0.5 mg base/kg/day for 14 days or 1 mg/kg/day for 7 days. Predose day 7 venous plasma concentrations of chloroquine, desethylchloroquine, piperaquine, primaquine, and carboxyprimaquine were measured. Methemoglobin levels were measured at frequent intervals. Day 7 primaquine and carboxyprimaquine concentrations were available for 641 patients. After adjustment for the milligram-per-kilogram primaquine daily dose, day of sampling, partner drug, and fever clearance, there was a significant nonlinear relationship between age and trough primaquine and carboxyprimaquine concentrations and daily methemoglobin levels. Compared to adults 30 years of age, children 5 years of age had trough primaquine concentrations that were 0.53 (95% confidence interval [CI], 0.39 to 0.73)-fold lower, trough carboxyprimaquine concentrations that were 0.45 (95% CI, 0.35 to 0.55)-fold lower, and day 7 methemoglobin levels that were 0.87 (95% CI, 0.58 to 1.27)-fold lower. Increasing plasma concentrations of piperaquine and chloroquine and poor metabolizer CYP 2D6 alleles were associated with higher day 7 primaquine and carboxyprimaquine plasma concentrations. Higher blood methemoglobin concentrations were associated with a lower risk of recurrence. 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. (This study has been registered at ClinicalTrials.gov under identifier NCT01640574.).

Keywords: Plasmodium vivax; chloroquine; dihydroartemisinin-piperaquine; pharmacokinetics; primaquine; radical cure; relapse.

FIG 1

Effect of age on primaquine and carboxyprimaquine exposures in patients with acute vivax malaria. (A) Age versus mg/kg primaquine daily dose; (B) age versus the primaquine plasma concentration on day 7; (C) age versus the plasma carboxyprimaquine concentration on day 7; (D) age versus the ratio of the day 7 carboxyprimaquine to primaquine concentrations. The black lines show model fits using a generalized additive model with a smooth spline term for age, with adjustment for the daily mg/kg dose, the number of days of primaquine received, the time since the last dose, the partner drug, and the fever clearance time (dashed line, mean predicted concentration for 1 mg/kg daily; solid line, mean predicted concentration for 0.5 mg/kg daily).

FIG 2

Relationship between CYP 2D6 genotypes and primaquine and carboxyprimaquine exposures, and day 7 methemoglobin levels. (A and B) The y axis shows the model residuals (observed minus predicted) for the main model of exposure (adjusting for age, daily mg/kg primaquine dose, partner drug, and fever clearance time). (C) The y axis shows the observed day 7 methemoglobin percentage. In all three panels, the x axis is the activity score predicted from the CYP 2D6 diplotype (26). Each box-and-whisker plot shows the median value, the interquartile range, and the range. The box widths are proportional to the square root of the number of observations per activity score.

FIG 3

Age and drug exposure relationships with hemolysis and methemoglobinemia. (A) Age and day 7 methemoglobin; (B) age and the day 7 change in hematocrit from baseline; (C) day 7 methemoglobin and predose primaquine concentrations; (D) day 7 methemoglobin and predose carboxyprimaquine concentrations. (A and B) The black lines show model fits under a generalized additive model with a smooth spline term for age and with adjustment for daily mg/kg dose, the number of days of primaquine received, the time since the last dose, and G6PD status (dashed line, mean predicted concentration for 1 mg/kg daily; solid line, mean predicted concentration for 0.5 mg/kg daily).