CYP2D6 polymorphisms and the safety and gametocytocidal activity of single dose primaquine for P. falciparum

Single dose primaquine (PQ) clears mature gametocytes and reduces transmission of Plasmodium falciparum after artemisinin combination therapy. Genetic variation in CYP2D6, the gene producing the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6), influences plasma concentrations of PQ and its metabolites and is associated with PQ treatment failure in P. vivax. Using blood and saliva samples of varying quantity and quality from 8 clinical trials across Africa, (n=1076), we were able to genotype CYP2D6 for 774 samples (72%). We determined whether genetic variation in CYP2D6 has implications for PQ efficacy in individuals with gametocytes at the time of PQ administration (n=554) and for safety in Glucose-6-phosphate dehydrogenase (G6PD) deficient individuals treated with PQ (n=110). Individuals with genetically inferred CYP2D6 poor/intermediate metabolizer status had higher gametocyte prevalence on day 7 or 10 post PQ compared to those with extensive/ultrarapid CYP2D6 metabolizer status (OR = 1.79 [1.10, 2.90], p = 0.018). Mean minimum haemoglobin concentration during follow-up for G6PD deficient individuals was 11.8 g/dL for CYP2D6 extensive/ultrarapid metabolizers and 12.1 g/dL for CYP2D6 poor/intermediate metabolizers (p = 0. 803). CYP2D6 genetically inferred metabolizer status was also not associated with anaemia following PQ treatment. (p = 0.331). We conclude that CYP2D6 poor/intermediate metabolizer status may be associated with prolonged gametocyte carriage after treatment with single low dose PQ but not with treatment safety.