CYP2D6 Polymorphisms and the Safety and Gametocytocidal Activity of Single-Dose Primaquine for Plasmodium falciparum

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Pett , H , Bradley , J , Okebe , J , Dicko , A , Tiono , A B , Goncalves , B P , Stone , W , Chen , I , Lanke , K , Neuvonen , M , Mustaniemi , A-L , Eziefula , A C , Gosling , R , D'Alessandro , U , Drakeley , C , Niemi , M & Bousema , T 2019 , ' CYP2D6 Polymorphisms and the Safety and Gametocytocidal Activity of Single-Dose Primaquine for Plasmodium falciparum ' , Antimicrobial Agents and Chemotherapy , vol. 63 , no. 10 , ARTN e00538-19 . https://doi.org/10.1128/AAC.00538-19

Title: CYP2D6 Polymorphisms and the Safety and Gametocytocidal Activity of Single-Dose Primaquine for Plasmodium falciparum
Author: Pett, Helmi; Bradley, John; Okebe, Joseph; Dicko, Alassane; Tiono, Alfred B.; Goncalves, Bronner P.; Stone, Will; Chen, Ingrid; Lanke, Kjerstin; Neuvonen, Mikko; Mustaniemi, Anna-Liina; Eziefula, Alice C.; Gosling, Roly; D'Alessandro, Umberto; Drakeley, Chris; Niemi, Mikko; Bousema, Teun
Contributor: University of Helsinki, HUSLAB
University of Helsinki, Department of Clinical Pharmacology
University of Helsinki, Department of Forensic Medicine
University of Helsinki, HUSLAB
Date: 2019-10
Language: eng
Number of pages: 9
Belongs to series: Antimicrobial Agents and Chemotherapy
ISSN: 0066-4804
URI: http://hdl.handle.net/10138/306665
Abstract: Single-dose primaquine (PQ) clears mature gametocytes and reduces the transmission of Plasmodium fakiparurn 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 Plasmodium vivax malaria. Using blood and saliva samples of varying quantity and quality from 8 clinical trials across Africa (n = 1,076), 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 a genetically inferred CYP2D6 poor/intermediate metabolizer status had a higher gametocyte prevalence on day 7 or 10 after PQ than those with an extensive/ultrarapid CYP2D6 metabolizer status (odds ratio [OR] = 1.79 [95% confidence interval {CI}, 1.10, 2.90]; P = 0.018). The mean minimum hemoglobin concentrations during follow-up for G6PD-deficient individuals were 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 anemia 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.
Subject: cytochrome P450
drug metabolism
elimination
gametocyte
genetic polymorphisms
malaria
metabolite
primaquine
safety
transmission
ARTEMETHER-LUMEFANTRINE
CYTOCHROME-P450 2D6
DOUBLE-BLIND
MALARIA
TRANSMISSION
CHILDREN
UPDATE
VIVAX
3111 Biomedicine
1183 Plant biology, microbiology, virology
317 Pharmacy
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