title: Age, Weight, andCYP2D6Genotype Are Major Determinants of Primaquine Pharmacokinetics in African Children.
abstract: Low-dose primaquine is recommended to preventPlasmodium falciparummalaria 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 40 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 primaquine administration according to partially overlapping sampling schedules. Physiological population pharmacokinetic modeling was used to assess the impact of weight, age, andCYP2D6genotype 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 a lower primaquine CYP2D6-mediated metabolism. Our data indicate that primaquine and carboxy-primaquine pharmacokinetics are influenced by age, weight, andCYP2D6genotype and suggest that dosing strategies may have to be reconsidered to maximize the transmission-blocking properties of primaquine. (This study has been registered at ClinicalTrials.gov under registration no. NCT01935882.).
authors.affiliation: Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Bronner P
authors.initials: BP
authors.lastname: Gonçalves
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Helmi
authors.initials: H
authors.lastname: Pett
authors.affiliation: Department of Biomedical Sciences, Centre National de Recherche et de Formation sur le Paludisme, Ouagadougou, Burkina Faso.
authors.forename: Alfred B
authors.initials: AB
authors.lastname: Tiono
authors.affiliation: Department of Pharmacy Practice, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Daryl
authors.initials: D
authors.lastname: Murry
authors.affiliation: Department of Biomedical Sciences, Centre National de Recherche et de Formation sur le Paludisme, Ouagadougou, Burkina Faso.
authors.forename: Sodiomon B
authors.initials: SB
authors.lastname: Sirima
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Teun
authors.initials: T
authors.lastname: Bousema
authors.affiliation: Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Drakeley
authors.affiliation: Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands r.terHeine@radboudumc.nl.
authors.forename: Rob
authors.initials: R
authors.lastname: Ter Heine
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000962:Antimalarials / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000627:therapeutic use; D001835:Body Weight; D002050:Burkina Faso; D002648:Child; D002675:Child, Preschool; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics; D004983:Ethanolamines / Q000627:therapeutic use; D005260:Female; D005449:Fluorenes / Q000627:therapeutic use; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000635:transmission; D008297:Male; D010963:Plasmodium falciparum / Q000187:drug effects*; D011319:Primaquine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; C035150:8-(3-carboxy-1-methylpropylamino)-6-methoxyquinoline; D019389:Cytochrome P-450 CYP2D6; D011319:Primaquine
keywords: CYP2D6; Plasmodium falciparum; pharmacokinetics; primaquine