Within-host modeling of primaquine-induced hemolysis in hemizygote glucose-6-phosphate dehydrogenase deficient healthy volunteers

Abstract

Primaquine is the only widely available drug to prevent relapses of Plasmodium vivax malaria. Primaquine is underused because of concerns over oxidant hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficiency. A pharmacometric trial showed that ascending-dose radical cure primaquine regimens causing ‘slow burn’ hemolysis were safe in G6PD-deficient Thai and Burmese male volunteers. We developed and calibrated a within-host model of primaquine hemolysis in G6PD deficiency, using detailed serial hemoglobin and reticulocyte count data from 23 hemizygote deficient volunteers given ascending-dose primaquine (1,523 individual measurements over 656 unique time points). We estimate that primaquine doses of ~0.75 mg base/kg reduce the circulating lifespan of deficient erythrocytes by ~30 days in individuals with common Southeast Asian G6PD variants. We predict that 5 mg/kg primaquine total dose can be administered safely to G6PD-deficient individuals over 14 days with expected hemoglobin drops of 18 to 43% (2.7 to 6.5 g/dL drop from a baseline of 15 g/dL).