Age, weight, and CYP2D6 genotype are major determinants of primaquine pharmacokinetics in African children.


Gonçalves, BP; Pett, H; Tiono, AB; Murry, D; Sirima, S; Niemi, M; Bousema, T; Drakeley, C; Ter Heine, R; (2017) Age, weight, and CYP2D6 genotype are major determinants of primaquine pharmacokinetics in African children. Antimicrobial agents and chemotherapy. ISSN 0066-4804 DOI: https://doi.org/10.1128/AAC.02590-16

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Abstract

Low dose primaquine is recommended to prevent Plasmodium falciparum malaria transmission in areas threatened by artemisinin resistance and areas aiming for malaria elimination. Community treatment campaigns with artemisinin-based combination therapy in combination with the gametocytocidal primaquine dose target all age groups but no studies thus far have assessed the pharmacokinetics of this gametocytocidal drug in African children. We recruited forty children participating in a primaquine efficacy trial in Burkina Faso to study primaquine pharmacokinetics. These children received artemether-lumefantrine and either a 0.25 or a 0.40 mg/kg primaquine dose. Seven blood samples were collected from each participant for primaquine and carboxy-primaquine plasma levels determinations: one sample was collected before primaquine administration and six, after, according to partially overlapping sampling schedules Physiological population pharmacokinetic modelling was used to assess the impact of weight, age and CYP2D6 genotype on primaquine and carboxy-primaquine pharmacokinetics. Despite linear weight normalized dosing, the areas under the plasma concentration - time curves and the peak concentrations for both primaquine and carboxy-primaquine increased with age and body weight. Children who were CYP2D6 poor metabolizers had higher levels of the parent compound, indicating lower PQ CYP2D6-mediated metabolism. Our data indicate that primaquine and carboxy-primaquine pharmacokinetics are influenced by age, weight and CYP2D6 genotype and suggest that dosing strategies may have to be re-considered to maximize the transmission-blocking properties of primaquine.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
PubMed ID: 28289025
URI: http://researchonline.lshtm.ac.uk/id/eprint/3682736

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