Within-host modelling of primaquine-induced haemolysis 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 haemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficiency. A pharmacometric trial showed that ascending-dose radical cure primaquine regimens causing 'slow burn' haemolysis were safe in G6PD deficient male volunteers. We developed and calibrated a within-host model of primaquine haemolysis in G6PD deficiency, using detailed serial haemoglobin and reticulocyte count data from 23 hemizygote deficient volunteers given ascending-dose primaquine (1,523 individual measurements over 656 unique timepoints). We estimate that primaquine doses of ~0.75mg base/kg reduce the circulating lifespan of deficient erythrocytes by ~30 days in individuals with common Southeast Asian G6PD variants. We predict that 5mg/kg primaquine total dose can be administered safely to G6PD deficient individuals over 14 days with expected haemoglobin drops of 18 to 43% (2.7 to 6.5g/dL drop from a baseline of 15g/dL).