The Effect of SNPs in CYP450 in Chloroquine/Primaquine
 Plasmodium Vivax
 Malaria Treatment

Sortica, Vinicius Albuquerque; Lindenau, Juliana Dal-Ri; Cunha, Mariana; Ohnishi, Maria Do; Ventura, Ana M. R. S.; Ribeiro-dos-Santos, Ândrea; Santos, Sidney; Guimaraes, Luciano S.P.; Hutz, Mara Helena

doi:10.2217/pgs-2016-0131

Cited by 27 publications

(27 citation statements)

References 33 publications

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“…A recent study reported for the first time the influence of the CYP2C8 gene on clearance in patients with chloroquine/primaquine therapy. 121 Wild-type CYP2C8 homozygous individuals achieved greater reduction in gametocytes as compared to individuals without this genotype. 121 Another study demonstrated CYP2D6 polymorphisms in systemic lupus erythematosus patients treated with hydroxychloroquine.…”

Section: Discussionmentioning

confidence: 91%

“… 121 Wild-type CYP2C8 homozygous individuals achieved greater reduction in gametocytes as compared to individuals without this genotype. 121 Another study demonstrated CYP2D6 polymorphisms in systemic lupus erythematosus patients treated with hydroxychloroquine. CYP2D6*10 allelic variants were found to be significantly associated with altered metabolism of HCQ.…”

Section: Discussionmentioning

confidence: 91%

“… 120 In a study reported in 2016, assessment of genetic polymorphisms in chloroquine metabolizing enzymes was identified as a need. 121 To that end, the investigators focused on a cohort consisting of 164 P. vivax malaria patients followed during malaria treatment from 2007 to 2009. The study reported for the first time the influence of the CYP2C8 gene on gametocyte clearance rate with patients undergoing chloroquine/primaquine malaria treatment.…”

Section: Resultsmentioning

confidence: 99%

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Repurposing Drugs for COVID-19: Pharmacokinetics and Pharmacogenomics of Chloroquine and Hydroxychloroquine

Babayeva¹,

Loewy²

2020

PGPM

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Background A new coronavirus SARS-CoV-2 has been identified as the etiological agent of the severe acute respiratory syndrome, COVID-19, the source and cause of the 2019–20 coronavirus pandemic. Hydroxychloroquine and chloroquine have gathered extraordinary attention as therapeutic candidates against SARS-CoV-2 infections. While there is growing scientific data on the therapeutic effect, there is also concern for toxicity of the medications. The therapy of COVID-19 by hydroxychloroquine and chloroquine is off-label. Studies to analyze the personalized effect and safety are lacking. Methods A review of the literature was performed using Medline/PubMed/Embase database. A variety of keywords were employed in keyword/title/abstract searches. The electronic search was followed by extensive hand searching using reference lists from the identified articles. Results A total of 126 results were obtained after screening all sources. Mechanisms underlying variability in drug concentrations and therapeutic response with chloroquine and hydroxychloroquine in mediating beneficial and adverse effects of chloroquine and hydroxychloroquine were reviewed and analyzed. Pharmacogenomic studies from various disease states were evaluated to elucidate the role of genetic variation in drug response and toxicity. Conclusion Knowledge of the pharmacokinetics and pharmacogenomics of chloroquine and hydroxychloroquine is necessary for effective and safe dosing and to avoid treatment failure and severe complications.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

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Repurposing Drugs for COVID-19: Pharmacokinetics and Pharmacogenomics of Chloroquine and Hydroxychloroquine

Babayeva¹,

Loewy²

2020

PGPM

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“…G6PD deficiency prevalence was estimated in 4.5% in the Western Brazilian Amazon and was related to decreased malaria susceptibility [ 8 ], which led us to develop studies for the implementation of a rapid test to detect the G6PD deficiency in patients diagnosed with malaria. Comparatively, the impact of other pharmacogenomic polymorphisms in the response and/or disposition of primaquine and chloroquine in P. vivax malaria patients has drawn less attention [ 9 ]. However, an original observation by Bennet et al [ 10 ] followed by a case report by Ingram et al [ 11 ] triggered considerable interest in a novel aspect of the pharmacogenomics of P. vivax malaria.…”

Section: Introductionmentioning

confidence: 99%

CYP2D6 activity and the risk of recurrence of Plasmodium vivax malaria in the Brazilian Amazon: a prospective cohort study

Brasil

Rodrigues‐Soares

Santoro

et al. 2018

Malar J

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BackgroundCYP2D6 pathway mediates the activation of primaquine into active metabolite(s) in hepatocytes. CYP2D6 is highly polymorphic, encoding CYP2D6 isoforms with normal, reduced, null or increased activity. It is hypothesized that Plasmodium vivax malaria patients with defective CYP2D6 function would be at increased risk for primaquine failure to prevent recurrence. The aim of this study was to investigate the association of CYP2D6 polymorphisms and inferred CYP2D6 phenotypes with malaria recurrence in patients from the Western Brazilian Amazon, following chloroquine/primaquine combined therapy.MethodsThe prospective cohort consisted of P. vivax malaria patients who were followed for 6 months after completion of the chloroquine/primaquine therapy. Recurrence was defined as one or more malaria episodes, 28–180 days after the initial episode. Genotyping for nine CYP2D6 SNPs and copy number variation was performed using TaqMan assays in a Fast 7500 Real-Time System. CYP2D6 star alleles (haplotypes), diplotypes and CYP2D6 phenotypes were inferred, and the activity score system was used to define the functionality of the CYP2D6 diplotypes. CYP2D6 activity scores (AS) were dichotomized at ≤ 1 (gPM, gIM and gNM-S phenotypes) and ≥ 1.5 (gNM-F and gUM phenotypes).ResultsGenotyping was successfully performed in 190 patients (44 with recurrence and 146 without recurrences). Recurrence incidence was higher in individuals presenting reduced activity CYP2D6 phenotypes (adjusted relative risk = 1.89, 95% CI 1.01–3.70; p = 0.049). Attributable risk and population attributable fraction were 11.5 and 9.9%, respectively. The time elapsed from the first P. vivax malaria episode until the recurrence did not differ between patients with AS of ≤ 1 versus ≥ 1.5 (p = 0.917).ConclusionsThe results suggest that CYP2D6 polymorphisms are associated with increased risk of recurrence of vivax malaria, following chloroquine–primaquine combined therapy. This association is interpreted as the result of reduced conversion of primaquine into its active metabolites in patients with reduced CYP2D6 enzymatic activity.

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“…PGx studies of CYP2C9 , not related to anticoagulants, explored associations with the antimalarial effect of chloroquine/primaquine therapy and the efficacy of piroxicam for post‐operative pain, with negative results in both cases.…”

Section: Resultsmentioning

confidence: 99%

Pharmacogenomics research and clinical implementation in Brazil

Rodrigues‐Soares

Suarez‐Kurtz

2019

Basic Clin Pharma Tox

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We searched PubMed entries and the Lattes database of Brazilian Pharmacogenetics Network investigators, for pharmacogenetic/genomic (PGx) studies in the Brazilian population, focusing on the drugs and genes included in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Warfarin was the most extensively studied drug in a PGx context: a genomewide association study targeting warfarin stable dose identified significant signals in VKORC1 and CYP2C9, several PGx dosing algorithms were developed based on these and other genes, and the implications of population admixture on extrapolation of dosing recommendations in the CPIC guidelines were examined. A study in renal transplanted patients disclosed association of CYP3A5*6 and CYP3A5*7 with tacrolimus dosing, which led to addition of these variants to CYP3A5*3 in the CPIC tacrolimus guideline. Studies verified predisposition of HIV-positive carriers of UGT1A1*28 to severe atazanavir-induced hyperbilirubinaemia, intolerance to 5-fluorouracyl in gastrointestinal cancer patients with deleterious DPYD variants, failure of HCV-infected carriers of IFNL3 rs12979860 to obtain a sustained viral response to PEG-IFN-α, and hypersensitivity reactions to abacavir in HIV-positive carriers of HLA-B*57:01. No prospective analyses of drug therapy outcomes or cost-effectiveness assessments of PGx-guided therapy were found. In conclusion, the limited adoption of PGx-informed drug prescription in Brazil reflects combination of recognized barriers to PGx implementation worldwide plus factors specific to the Brazilian population. The latter include rarity/absence of genetic variants on which international PGx guidelines are based (eg HLA-B*15.02 for phenytoin and carbamazepine) and the caveat of extrapolating to the admixed Brazilian population, guidelines based on categorical variables, such as continental ancestry (eg warfarin guidelines), "race" or ethnicity.

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The Effect of SNPs in CYP450 in Chloroquine/Primaquine Plasmodium Vivax Malaria Treatment

Abstract: Future studies should be performed to access the extent of CYP2C8, CYP2C9 and CYP3A5 gene polymorphisms influence on cloroquine/primaquine treatment.

Cited by 27 publications

References 33 publications

<p>Repurposing Drugs for COVID-19: Pharmacokinetics and Pharmacogenomics of Chloroquine and Hydroxychloroquine</p>

<p>Repurposing Drugs for COVID-19: Pharmacokinetics and Pharmacogenomics of Chloroquine and Hydroxychloroquine</p>

CYP2D6 activity and the risk of recurrence of Plasmodium vivax malaria in the Brazilian Amazon: a prospective cohort study

Pharmacogenomics research and clinical implementation in Brazil

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