Doses of primaquine administered to children with <i>Plasmodium vivax</i> according to an age-based dose regimen

Vieira, Michelle Valeria Dias Ferreira; Lopes, Tamyris Regina Matos; Mello, Amanda Gabryelle Nunes Cardoso; Sena, Luann Wendel Pereira de; Commons, Robert J.; Vieira, José Luiz Fernandes

doi:10.1080/20477724.2020.1799166

Cited by 9 publications

(14 citation statements)

References 26 publications

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“…For many antimalarial drugs, exposures in children are lower than in adults and an increase in the weight adjusted dosing is needed (1). The limited pharmacokinetic evidence to date for primaquine does not provide a clear picture, with a study from Papua New Guinea suggesting little difference between adults and older children (2), whereas a study of single dose primaquine (used as a P. falciparum gametocytocide) in Tanzania (3) and a study of primaquine for P. vivax radical cure in Brazil (4) both suggested that younger children had lower exposures. Primaquine is metabolized rapidly (elimination half-life ~5 hours) via monoamine oxidase to a biologically inert metabolite carboxyprimaquine and, through a separate pathway, to several active hydroxylated metabolites mainly via CYP 2D6 (6,24).…”

Section: Discussionmentioning

confidence: 99%

“…Although the slowly eliminated 8-aminoquinoline tafenoquine has been registered in a few countries for use in adults, primaquine is by far the most widely used drug in this class. There is uncertainty whether or not children have lower exposures to primaquine and its bioactive metabolites than adults for the same weight adjusted doses, and thus whether they should receive higher doses than currently recommended (2)(3)(4)(5). Primaquine is combined with either an artemisinin combination treatment (ACT) or chloroquine to prevent relapse of vivax or ovale malaria (radical cure) (1).…”

Section: Introductionmentioning

confidence: 99%

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

Chu

Watson

Phyo

et al. 2021

Preprint

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Chu

Watson

Phyo

et al. 2021

Preprint

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“…Primaquine has several challenges, including adherence to 7-or 14-day regimens [28] [29], and the limited availability of tablet strengths that are made according to international good manufacturing practice, 7.5 and 15 mg, leading to inaccurate, impractical regimens necessitating tablet fractions. Owing to the paucity of pharmacokinetic data in malaria patients, especially in children [9] [19] [5], there are no internationally accepted, evidenced-based, allometrically-scaled, weight-based dosing regimens.…”

Section: Discussionmentioning

confidence: 99%

“…In the absence of established dosing regimens, researchers and malaria control programmes (MCPs) have used many different weight-and age-based regimens, adapting the recommended weight-based target doses to their populations [5] (Additional file 1: Table S1). Complex regimens with multiple dosing bands (20 and 21 in two trials 12 [6] [7]) result in more accurate dosing but are too cumbersome to administer outside of the research setting.…”

Section: Introductionmentioning

confidence: 99%

Development of Weight and Age-based Dosing of Daily Primaquine for Radical Cure of Vivax Malaria

Taylor

Hoglund

Peerawaranun

et al. 2021

Preprint

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Background In many endemic areas, Plasmodium vivax malaria is predominantly a disease of young adults and children. International recommendations for radical cure recommend fixed target doses of 0.25 or 0.5 mg/kg/day of primaquine for 14 days in glucose-6-phosphate dehydrogenase normal patients. As for many antimalarial drugs there is evidence that children have lower exposures than adults for the same weight adjusted dose. We, therefore, aimed to develop 14-day weight-based and age-based primaquine regimens against high-frequency relapsing tropical P. vivax. Methods The recommended adult target dose of 0.5 mg/kg/day (30 mg in a 60 kg patient) is highly efficacious against tropical P. vivax and was assumed to produce optimal drug exposure. Primaquine doses were calculated using allometric scaling to derive a weight-based primaquine regimen over a weight range from 5 to 100 kg. Growth curves were constructed from an anthropometric database of 53,467 individuals from the Greater Mekong Subregion to define weight-for-age relationships. The median age associated with each weight was used to derive an age-based dosing regimen from the weight-based regimen.Results The proposed weight-based regimen had 5 dosing bands: (i) 5 – 7 kg, 5 mg, resulting in 0.71 – 1.0 mg/kg/day; (ii) 8 – 16 kg, 7.5 mg, 0.47 – 0.94 mg/kg/day; (iii) 17 – 40 kg, 15 mg, 0.38 – 0.88 mg/kg/day; (iv) 41 – 80 kg, 30 mg, 0.37 – 0.73 mg/kg/day; and (v) 81 – 100 kg, 45 mg, 0.45 – 0.56 mg/kg/day. The age-based regimen had 4 dosing bands: 6 – 11 months, 5 mg, 0.43 – 1.0 mg/kg/day; (ii) 1 – 5 years, 7.5 mg, 0.35 – 1.25 mg/kg/day; (iii) 6 – 14 years, 15 mg, 0.30 – 1.36 mg/kg/day; and (iv) ≥ 15 years, 30 mg, 0.35 – 1.07 mg/kg/day.Conclusion The proposed weight-based regimens showed less variability around the optimal dose within each dosing band compared to the age-based regimen and is preferred. Increased dose accuracy could be achieved by additional dosing bands. Pharmacokinetic data in small children are needed urgently to inform the proposed regimen.

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“…Because the hydroxylated active metabolite cannot be measured accurately and its data were not available, the PK model for PQ in our study was built on the basis of exposure data for the inactive metabolite CPQ, as reported in previous studies [ 12 , 26 , 27 ]. In those studies, although the PK-PD relationship of the active metabolite was undocumented, the authors made inferences about the PK characteristics of active metabolites based on the PK characteristics of PQ and CPQ [ 12 ], insisting that enhanced anti-malarial effectiveness was likely to be related to higher plasma concentrations of PQ [ 27 ], and PQ underdosing and subsequent low levels of PQ may contribute to a high risk of recurrent malaria infection [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Primaquine in the Korean Population

et al. 2021

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While primaquine has long been used for malaria treatment, treatment failure is common. This study aims to develop a population pharmacokinetic model of primaquine and its metabolite, carboxyprimaquine, and examine factors influencing pharmacokinetic variability. The data was obtained from a clinical study in 24 Korean subjects randomly assigned to normal and obese groups. The participants received primaquine 15 mg daily for 4 days and blood samples were collected at day 4. Pharmacokinetic modeling was performed with NONMEM and using simulations; the influences of doses and covariates on drug exposure were examined. A minimal physiology-based pharmacokinetic model connected with a liver compartment comprehensively described the data, with CYP450 mediated clearance being positively correlated with the body weight and CYP2D6 activity score (p < 0.05). In the simulation, while the weight-normalized area under drug concentration for primaquine in the obese group decreased by 29% at the current recommended dose of 15 mg, it became similar to the normal weight group at a weight-normalized dose of 3.5 mg/kg. This study has demonstrated that the body weight and CYP2D6 activity score significantly influence the pharmacokinetics of primaquine. The developed model is expected to be used as a basis for optimal malaria treatment in Korean patients.

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Doses of primaquine administered to children with Plasmodium vivax according to an age-based dose regimen

Cited by 9 publications

References 26 publications

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

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

Development of Weight and Age-based Dosing of Daily Primaquine for Radical Cure of Vivax Malaria

Population Pharmacokinetics of Primaquine in the Korean Population

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