title: Single-Dose Primaquine in a Preclinical Model of Glucose-6-Phosphate Dehydrogenase Deficiency: Implications for Use in Malaria Transmission-Blocking Programs.
abstract: Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) are at risk for developing hemolytic anemia when given the antimalarial drug primaquine (PQ). The WHO Evidence Review Group released a report suggesting that mass administration of a single dose of PQ at 0.25 mg of base/kg of body weight (mpk) (mouse equivalent of 3.125 mpk) could potentially reduce malaria transmission based on its gametocytocidal activity and could be safely administered to G6PD-deficient individuals, but there are limited safety data available confirming the optimum single dose of PQ. A single-dose administration of PQ was therefore assessed in our huRBC-SCID mouse model used to predict hemolytic toxicity with respect to G6PD deficiency. In this model, nonobese diabetic (NOD)/SCID mice are engrafted with human red blood cells (huRBC) from donors with the African or Mediterranean variant of G6PDd (A-G6PDd or Med-G6PDd, respectively) and demonstrate dose-dependent sensitivity to PQ. In mice engrafted with A-G6PD-deficient huRBC, single-dose PQ at 3.125, 6.25, or 12.5 mpk had no significant loss of huRBC compared to the vehicle control group. In contrast, in mice engrafted with Med-G6PDd huRBC, a single dose of PQ at 3.125, 6.25, or 12.5 mpk resulted in a significant, dose-dependent loss of huRBC compared to the value for the vehicle control group. Our data suggest that administration of a single low dose of 0.25 mpk of PQ could induce hemolytic anemia in Med-G6PDd individuals but that use of single-dose PQ at 0.25 mpk as a gametocytocidal drug to block transmission would be safe in areas where A-G6PDd predominates.
authors.affiliation: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Kristina S
authors.initials: KS
authors.lastname: Wickham
authors.affiliation: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Baresel
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Sean R
authors.identifier: 0000-0002-1988-6185
authors.initials: SR
authors.lastname: Marcsisin
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Sousa
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Chau T
authors.initials: CT
authors.lastname: Vuong
authors.affiliation: Military Malaria Research Program, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Reichard
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Brice
authors.initials: B
authors.lastname: Campo
authors.affiliation: National Center for Natural Products Research and Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
authors.forename: Babu L
authors.initials: BL
authors.lastname: Tekwani
authors.affiliation: National Center for Natural Products Research and Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Walker
authors.affiliation: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York, USA rosemary.rochford@ucdenver.edu.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Rochford
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D017707:Erythrocyte Transfusion; D004912:Erythrocytes / Q000187:drug effects; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000469:parasitology*; D006801:Humans; D008288:Malaria / Q000635:transmission*; D016513:Mice, SCID; D011319:Primaquine / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000493:pharmacokinetics
chemical_list: D000962:Antimalarials; C035150:8-(3-carboxy-1-methylpropylamino)-6-methoxyquinoline; D011319:Primaquine