Genetic Variation of G6PD and CYP2D6: Clinical Implications on the Use of Primaquine for Elimination of Plasmodium vivax

Abstract

Primaquine, an 8-aminoquinoline, is the only medication approved by the World Health Organization to treat the hypnozoite stage of Plasmodium vivax and P. ovale malaria. Relapse, triggered by activation of dormant hypnozoites in the liver, can occur weeks to years after primary infection, and provides the predominant source of transmission in endemic settings. Hence, primaquine is essential for individual treatment and P. vivax elimination efforts. However, primaquine use is limited by the risk of life-threatening acute hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. More recently, studies have demonstrated decreased efficacy of primaquine due to cytochrome P450 2D6 (CYP2D6) polymorphisms conferring an impaired metabolizer phenotype. Failure of standard primaquine therapy has occurred in individuals with decreased or absent CYP2D6 activity. Both G6PD and CYP2D6 are highly polymorphic genes, with considerable geographic and interethnic variability, adding complexity to primaquine use. Innovative strategies are required to overcome the dual challenge of G6PD deficiency and impaired primaquine metabolism. Further understanding of the pharmacogenetics of primaquine is key to utilizing its full potential. Accurate CYP2D6 genotype-phenotype translation may optimize primaquine dosing strategies for impaired metabolizers and expand its use in a safe, efficacious manner. At an individual level the current challenges with G6PD diagnostics and CYP2D6 testing limit clinical implementation of pharmacogenetics. However, further characterisation of the overlap and spectrum of G6PD and CYP2D6 activity may optimize primaquine use at a population level and facilitate region-specific dosing strategies for mass drug administration. This precision public health approach merits further investigation for P. vivax elimination.

Influence of CYP2C19, CYP2D6 and CYP3A4 genetic variants on the biological effect of malaria treatment with primaquine in G6PD- deficient and G6PD-normal patients

“…Both G6PD and CYP2D6 are highly polymorphic genes, which makes the use of primaquine more complex (34). In studies that evaluated the pharmacokinetics of PQ with CYP2D6 metabolizers, it was observed that the drug concentration was higher in gPM, and that the low production of active metabolites was responsible for its effectiveness, which would result in relapse and failure (14).…”

Global perspectives on CYP2D6 associations with primaquine metabolism and Plasmodium vivax radical cure

“…Resulting predictions of activity indicate that the use of PQ following current protocols may be more effective in some malaria-endemic regions than in others as a result of high frequencies of poor metabolizer alleles in East Asia. Stewart et al have called further attention to similar populationspecific concerns in Central America as summarized previously (Stewart et al, 2021).…”

“…This is consistent with recent clinical trials to test optimal dosing strategies against relapse infections ( Brito-Sousa et al, 2022 ; Chamma-Siqueira et al, 2022 ). An adjoining article by Stewart et al focuses on implications of CYP2D6 and G6PD genetic variation on potential treatment approaches and limitations for P. vivax as well as P. ovale (that also produces hypnozoites) liver stage parasites ( Stewart et al, 2021 ).…”

The challenges of Plasmodium vivax human malaria infection models for vaccine development

“…As a final test, they monitored participants’ sera for satisfactory clearance of PQ over 24 hours after administration of a test dose. These parameters are also of major relevance to the field as it is estimated that the combination of G6PDH deficiency and reduced functioning CYP2D6 account for nearly 40% of the population at risk of P. vivax infection ineligible for PQ therapy ( 50 ). For blood-stage CHMI in which hypnozoite formation does not occur, screening for G6PD and CYP2D6 can be omitted, as PQ treatment is not indicated.…”