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 MedG6PDd 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.

Furin-mediated intracellular self-assembly of olsalazine nanoparticles for enhanced magnetic resonance imaging and tumour therapy

“…As for possible clinical translation, an Olsa-RVRR dosage extrapolation from our mouse studies to humans can be calculated based on the FDA body surface area normalization method using the following formula 51 : Human-equivalent dose (HED, mg/kg) = 139 mg/kg × (3/37) = 11.3 mg/kg. Besides colon cancer, Olsa-RVRR may be used in theranostic studies of other forms of cancer known to overexpress furin, including breast 52 , lung 53 , ovary 10 , head and neck 55 , and brain tumors 55 .…”

Genotype–Phenotype Correlations of Glucose-6-Phosphate–Deficient Variants Throughout an Activity Distribution

“…pharmgkb.org) has 3 risk categories of hemolytic anemia (low risk, at risk, and unknown risk) regarding rasburicase administration to G6PD-deficient patients. Understanding what dose of primaquine might be safe for use for various deficiency types in malaria transmission-blocking programs is still being investigated (16,17).…”

Modelling the therapeutic dose range of single low dose primaquine to reduce malaria transmission through age-based dosing

“…Currently, there are no guidelines of how to adapt the dosing in the variants of G6PD deficiency, especially taking into account that PQ causes a dose-dependent haemolysis [17]. Wickham et al, reports that LDP that was shown to be safe in African G6PD deficient individuals was shown to induce haemolysis in Mediterranean variant of G6PD in a mouse model [18]. Therefore, the difficulty will be in determining the lower safety margin and risk of underdosing in the African variant of G6PD.…”