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

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 provid...

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Autores principales:	Alexandra G. A. Stewart, Peter A. Zimmerman, James S. McCarthy
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Plasmodium vivax primaquine CYP2D6 G6PD (glucose-6-phosphate dehydrogenase) pharmacogenetics elimination Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/bcdae92ec9de4d6b8ac6fb0e2b29e11b
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spelling	oai:doaj.org-article:bcdae92ec9de4d6b8ac6fb0e2b29e11b2021-12-01T06:59:00ZGenetic Variation of G6PD and CYP2D6: Clinical Implications on the Use of Primaquine for Elimination of Plasmodium vivax1663-981210.3389/fphar.2021.784909https://doaj.org/article/bcdae92ec9de4d6b8ac6fb0e2b29e11b2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.784909/fullhttps://doaj.org/toc/1663-9812Primaquine, 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.Alexandra G. A. StewartPeter A. ZimmermanJames S. McCarthyJames S. McCarthyFrontiers Media S.A.articlePlasmodium vivaxprimaquineCYP2D6G6PD (glucose-6-phosphate dehydrogenase)pharmacogeneticseliminationTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Plasmodium vivax primaquine CYP2D6 G6PD (glucose-6-phosphate dehydrogenase) pharmacogenetics elimination Therapeutics. Pharmacology RM1-950
spellingShingle	Plasmodium vivax primaquine CYP2D6 G6PD (glucose-6-phosphate dehydrogenase) pharmacogenetics elimination Therapeutics. Pharmacology RM1-950 Alexandra G. A. Stewart Peter A. Zimmerman James S. McCarthy James S. McCarthy Genetic Variation of G6PD and CYP2D6: Clinical Implications on the Use of Primaquine for Elimination of Plasmodium vivax
description	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.
format	article
author	Alexandra G. A. Stewart Peter A. Zimmerman James S. McCarthy James S. McCarthy
author_facet	Alexandra G. A. Stewart Peter A. Zimmerman James S. McCarthy James S. McCarthy
author_sort	Alexandra G. A. Stewart
title	Genetic Variation of G6PD and CYP2D6: Clinical Implications on the Use of Primaquine for Elimination of Plasmodium vivax
title_short	Genetic Variation of G6PD and CYP2D6: Clinical Implications on the Use of Primaquine for Elimination of Plasmodium vivax
title_full	Genetic Variation of G6PD and CYP2D6: Clinical Implications on the Use of Primaquine for Elimination of Plasmodium vivax
title_fullStr	Genetic Variation of G6PD and CYP2D6: Clinical Implications on the Use of Primaquine for Elimination of Plasmodium vivax
title_full_unstemmed	Genetic Variation of G6PD and CYP2D6: Clinical Implications on the Use of Primaquine for Elimination of Plasmodium vivax
title_sort	genetic variation of g6pd and cyp2d6: clinical implications on the use of primaquine for elimination of plasmodium vivax
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/bcdae92ec9de4d6b8ac6fb0e2b29e11b
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Genetic Variation of G6PD and CYP2D6: Clinical Implications on the Use of Primaquine for Elimination of Plasmodium vivax

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