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

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01302-21 ◽

2021 ◽

Author(s):

Cindy S Chu ◽

James A Watson ◽

Aung Pyae Phyo ◽

Htun Htun Win ◽

Widi Yotyingaphiram ◽

...

Keyword(s):

Young Children ◽

Plasmodium Vivax ◽

Plasma Concentrations ◽

Radical Cure ◽

Pharmacokinetic Properties ◽

Daily Dose ◽

Plasmodium Vivax Malaria ◽

Glucose 6 Phosphate Dehydrogenase ◽

To Receive ◽

Cyp 2D6

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.

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Protective effect of Mediterranean-type glucose-6-phosphate dehydrogenase deficiency against Plasmodium vivax malaria

eLife ◽

10.7554/elife.62448 ◽

2021 ◽

Vol 10 ◽

Author(s):

Ghulam R Awab ◽

Fahima Aaram ◽

Natsuda Jamornthanyawat ◽

Kanokon Suwannasin ◽

Watcharee Pagornrat ◽

...

Keyword(s):

Protective Effect ◽

Plasmodium Vivax ◽

G6pd Deficiency ◽

Vivax Malaria ◽

Malaria Incidence ◽

Large Population ◽

Credible Interval ◽

Radical Cure ◽

Plasmodium Vivax Malaria ◽

Glucose 6 Phosphate Dehydrogenase

X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy. The severe Mediterranean variant (G6PD Med) found across Europe and Asia is thought to confer protection against malaria, but its effect is unclear. We fitted a Bayesian statistical model to observed G6PD Med allele frequencies in 999 Pashtun patients presenting with acute Plasmodium vivax malaria and 1408 population controls. G6PD Med was associated with reductions in symptomatic P. vivax malaria incidence of 76% (95% credible interval [CI], 58–88) in hemizygous males and homozygous females combined and 55% (95% CI, 38–68) in heterozygous females. Unless there is very large population stratification within the Pashtun (confounding these results), the G6PD Med genotype confers a very large and gene-dose proportional protective effect against acute vivax malaria. The proportion of patients with vivax malaria at risk of haemolysis following 8-aminoquinoline radical cure is substantially overestimated by studies measuring G6PD deficiency prevalence in healthy subjects.

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Strong gene dose dependent protective effect of Mediterranean type glucose-6-phosphate dehydrogenase deficiency against Plasmodium vivax malaria

10.1101/2020.08.25.20181628 ◽

2020 ◽

Author(s):

Ghulam R Awab ◽

Fahima Aaram ◽

Natsuda Jamornthanyawat ◽

Kanokon Suwannasin ◽

Watcharee Pagornrat ◽

...

Keyword(s):

Protective Effect ◽

Plasmodium Vivax ◽

Vivax Malaria ◽

Large Population ◽

Epidemiological Studies ◽

Radical Cure ◽

Gene Dose ◽

Plasmodium Vivax Malaria ◽

Glucose 6 Phosphate Dehydrogenase ◽

Dose Dependent

X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy. The severe Mediterranean variant (G6PD Med) is common across Europe and Asia, and is thought to confer protection against malaria but its effect is unclear. We fit a Bayesian statistical model to observed G6PD Med allele frequencies in 999 Pashtun patients with acute Plasmodium vivax malaria and 1408 population controls. G6PD Med was associated with a reduction in the incidence of symptomatic P. vivax malaria of 76% (95% CI 58-88) in hemizygous males and homozygous females combined, and of 55% (95% CI 38-68) in heterozygous females. Thus, in absence of very large population stratification (i.e. confounding) the G6PD Med genotype confers a very large and gene dose proportional protective effect against acute vivax malaria. The proportion of patients with vivax malaria at risk of haemolysis following 8-aminoquinoline radical cure is substantially overestimated by epidemiological studies in healthy subjects.

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