Pharmacometric assessment of primaquine induced haemolysis in glucose-6-phosphate dehydrogenase deficiency

Primaquine is the only widely available treatment to prevent relapses of Plasmodium vivax malaria, but is underused because of concerns over haemolysis in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals. G6PDd is common in malaria endemic areas but testing is often not available.We conducted a pharmacometric study to characterise the relationship between primaquine dose and haemolysis in G6PDd. The aim was to explore shorter and safer pri-maquine radical cure regimens compared to those currently recommended, potentially obviating the need for G6PD testing. Hemizygous G6PDd healthy adult Thai male volunteers were admitted to the Hospital for Tropical Diseases in Bangkok. In Part 1, volunteers were given ascending dose primaquine regimens whereby daily doses were increased from 7.5 mg up to 45 mg over 15 to 20 days. In Part 2, a single primaquine 45 mg dose was given.24 volunteers were enrolled in Part 1, and 16 in Part 2 (13 participated in both studies). In three volunteers the ascending dose regimen was stopped because of primaquine related safety concerns (two had increased levels of transaminases, one haemolysis). Other-wise the ascending regimens were well tolerated with no drug-related serious adverse events. In Part 1, haemoglobin concentrations fell 3.7 g/dL (median; range: 2.1 to 5.9; relative fall of -26% [range: -15 to 40%]). Primaquine doses up to 0.87 mg/kg/day were tolerated subsequently without clinically significant further falls in haemoglobin. In Part 2, the haemoglobin concentrations fell by 1.7 g/dL (median; range -0.9 to 4.1; relative fall of 12% [range: 7 to 30%]). The ascending dose primaquine regimens gave 7 times more drug but resulted in only double the haemoglobin fall.In patients with Southeast Asian G6PDd variants full radical cure treatment can be given in under three weeks compared with the current 8 week regimen.MRC (MR/R015252/1); Wellcome (223099/Z/21/Z)