Prevalence of CYP2D6 Genotypes and Predicted Phenotypes in a Cohort of Cambodians at High Risk for Infections with Plasmodium vivax

Spring, Michele; Lon, Chanthap; Sok, Somethy; Sea, Darapiseth; Wojnarski, Mariusz; Chann, Soklyda; Kuntawunginn, Worachet; Heng, Thay Kheang; Nou, Samon; Arsanok, Montri; Sriwichai, Sabaithip; Vanachayangkul, Pattaraporn; Lin, Jessica T.; Manning, Jessica E.; Jongsakul, Krisada; Pichyangkul, Sathit; Prom, Satharath; Smith, Philip L.; Lek, Dysoley; Saunders, David; Waters, Norman C.

doi:10.4269/ajtmh.20-0061

Cited by 12 publications

(11 citation statements)

References 20 publications

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“…For a subset of samples, the variants *2, *4, *5, *10, *35, and *36 were identified with rapid identification of four polymorphic loci by allele-specific oligonucleotide probes using real-time SNPs genotyping. From the CYP 2D6 genotyping result the CYP 2D6 activity score was obtained (15,(19)(20)(21).…”

Section: Cyp 2d6 Genotypingmentioning

confidence: 99%

Determinants of primaquine and carboxyprimaquine exposures in children and adults with Plasmodium vivax malaria

Chu

Watson

Phyo

et al. 2021

Preprint

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Background: Primaquine is the only widely available drug for radical cure of Plasmodium vivax malaria. There is uncertainty whether the pharmacokinetic properties of primaquine are altered significantly in childhood or not. Methods: Glucose-6-phosphate dehydrogenase normal patients with uncomplicated P. vivax malaria were randomized to receive either chloroquine (25mg base/kg) or dihydroartemisinin-piperaquine (dihydroartemisinin 7mg/kg and piperaquine 55mg/kg) plus primaquine; plus either 0.5 mg base/kg/day for 14 days or 1 mg/kg/day for 7 days. Pre-dose day 7 venous plasma concentrations of chloroquine, desethylchloroquine, piperaquine, primaquine and carboxyprimaquine were measured. Methemoglobin levels were measured on days 1, 4, 7. Results: Day 7 primaquine and carboxyprimaquine concentrations were available for 641 patients. After adjustment for the primaquine mg/kg daily dose, day of sampling, partner drug, and fever clearance, there was a significant non-linear relationship between age and trough primaquine and carboxyprimaquine concentrations, and day methemoglobin levels. Compared to adults 30 years of age, children 5 years of age had trough primaquine concentrations 0.55 (95% CI: 0.39- 0.78) fold lower, trough carboxyprimaquine concentrations 0.43 (95% CI: 0.34- 0.55) fold lower, and day 7 methemoglobin levels 0.87 (95% CI: 0.58-1.27) fold lower. Increasing concentrations of piperaquine and chloroquine and poor metabolizer CYP 2D6 alleles were also associated with higher day 7 primaquine and carboxyprimaquine concentrations. Increased methemoglobin concentrations were associated with a lower risk of recurrence. Conclusion: Young children have lower primaquine and carboxyprimaquine exposures, and lower levels of methemoglobinemia, than adults. Young children may need higher weight adjusted primaquine doses than adults.

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Section: Cyp 2d6 Genotypingmentioning

confidence: 99%

Determinants of primaquine and carboxyprimaquine exposures in children and adults with Plasmodium vivax malaria

Chu

Watson

Phyo

et al. 2021

Preprint

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“…Patients having impaired metabolic activity of CYP2D6 are at much higher risk of therapeutic failure of primaquine against relapse . The extraordinarily high frequency of the impaired *10 allele in Asia may compromise primaquine efficacy (Spring et al, 2020). Tafenoquine does not appear to be CYP2D6-dependent (St Jean et al, 2016), but it may nonetheless require activation by other means; its very poor efficacy when administered with dihydroartemisinin (Centers for Disease Control and Prevention (CDC), 2020) suggests interference with that activation.…”

Section: Human Metabolism Of 8-aminoquinolinesmentioning

confidence: 99%

Basic Research of Plasmodium vivax Biology Enabling Its Management as a Clinical and Public Health Problem

Baird

2021

Front. Cell. Infect. Microbiol.

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The emerging understanding of Plasmodium vivax as an infection seated in extravascular spaces of its human host carries fundamentally important implications for its management as a complex clinical and public health problem. This progress begins to reverse decades of neglected research borne of the false dogma of P. vivax as an intrinsically benign and inconsequential parasite. This Review provides real world context for the on-going laboratory explorations of the molecular and cellular events in the life of this parasite. Chemotherapies against the latent reservoir impose extraordinarily complex and difficult problems of science and medicine, but great strides in studies of the biology of hepatic P. vivax promise solutions. Fundamental assumptions regarding the interpretation of parasitaemia in epidemiology, clinical medicine, and public health are being revisited and reassessed in light of new studies of P. vivax cellular/molecular biology and pathogenesis. By examining these long overlooked complexities of P. vivax malaria, we open multiple new avenues to vaccination, chemoprevention, countermeasures against transmission, epidemiology, diagnosis, chemotherapy, and clinical management. This Review expresses how clarity of vision of biology and pathogenesis may rationally and radically transform the multiple means by which we may combat this insidiously harmful infection.

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“…In the Brazilian Amazon, ~25% of the population was found to have reduced CYP2D6 activity [146,147]. In Cambodia, 52 and 1% of subjects were found to have intermediate and poor metabolism, respectively [157]. Most surveys are based on genotyping results, whereas direct measurement of the CYP2D6 activity using CYP2D6 substrate metabolism (dextromethorphan to dextrorphan conversion) could more accurately determine the phenotype [145].…”

Section: Host Cytochrome P450 (Cyp) 2d6 Activitymentioning

confidence: 99%

Elimination ofPlasmodium vivaxMalaria: Problems and Solutions

Brashear¹,

Menezes²,

Adams³

2021

Current Topics and Emerging Issues in Malaria Elimination

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Malaria is caused by multiple parasitic species of the genus Plasmodium. Although P. falciparum accounts for the highest mortality, P. vivax is the most geographically dispersed and the most common species outside of Africa. Several unique biological features make P. vivax less responsive to conventional control measures and allow it to persist even after elimination of P. falciparum. The ability of P. vivax to develop in diverse vectors at lower ambient temperatures bestows it a greater distribution range and resilience to ecological changes. Its tropism for reticulocytes often causes low-density infections below the levels detectable by routine diagnostic tests, demanding the development of more sensitive diagnostics. P. vivax produces gametocytes early enabling transmission before the manifestation of clinical symptoms, thus emphasizing the need for an integrated vector control strategy. More importantly, its dormant liver stage which engenders relapse is difficult to diagnose and treat. The deployment of available treatments for the liver hypnozoites, including primaquine and the recent U.S. Food and Drug Administration-approved tafenoquine, requires point-of-care diagnostics to detect glucose-6-phosphate dehydrogenase deficiency among endemic human populations. Here we review the continued challenges to effectively control P. vivax and explore integrated technologies and targeted strategies for the elimination of vivax malaria.

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Prevalence of CYP2D6 Genotypes and Predicted Phenotypes in a Cohort of Cambodians at High Risk for Infections with Plasmodium vivax

Cited by 12 publications

References 20 publications

Determinants of primaquine and carboxyprimaquine exposures in children and adults with Plasmodium vivax malaria

Determinants of primaquine and carboxyprimaquine exposures in children and adults with Plasmodium vivax malaria

Basic Research of Plasmodium vivax Biology Enabling Its Management as a Clinical and Public Health Problem

Elimination ofPlasmodium vivaxMalaria: Problems and Solutions

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