Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing

Caudle, Kelly E.; Rettie, Allan E.; Whirl‐Carrillo, Michelle; Smith, Lissa; Mintzer, Scott; Lee, M T M; Klein, Teri E.; Callaghan, JT

doi:10.1038/clpt.2014.159

Cited by 210 publications

(162 citation statements)

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“…3,[7][8][9][10][11] Recently the discussion in the scientific community about the clinical effectiveness of pharmacogenetics has given rise to the publication of drug dosing guidelines with indications and recommendations about drug-related genetic tests and their integration in the clinical routine. In particular, the Clinical Pharmacogenetics Implementation Consortium (CPIC) 12,13 and the Dutch Pharmacogenetics Working Group of the Royal Dutch Association for the Advancement of Pharmacy (DPWG) 14 have published drug-specific guidelines based on the patient genotype.…”

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confidence: 99%

Clinical validity of a DPYD‐based pharmacogenetic test to predict severe toxicity to fluoropyrimidines

Toffoli

Giodini

Buonadonna

et al. 2015

Intl Journal of Cancer

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Pre-therapeutic DPYD pharmacogenetic test to prevent fluoropyrimidines (FL)-related toxicities is not yet common practice in medical oncology. We aimed at investigating the clinical validity of DPYD genetic analysis in a large series of oncological patients. Six hundred three cancer patients, treated with FL, have been retrospectively tested for eight DPYD polymorphisms (DPYD-rs3918290, DPYD-rs55886062, DPYD-rs67376798, DPYD-rs2297595, DPYD-rs1801160, DPYD-rs1801158, DPYDrs1801159, DPYD-rs17376848) for association with Grade 3 toxicity, developed within the first three cycles of therapy. DPYD-rs3918290 and DPYD-rs67376798 were associated to Grade 3 toxicity after bootstrap validation and Bonferroni correction (p 5 0.003, p 5 0.048). DPYD-rs55886062 was not significant likely due to its low allelic frequency, nonetheless one out of two heterozygous patients (compound heterozygous with DPYD-rs3918290) died from toxicity after one cycle. Test specificity for the analysis of DPYD-rs3918290, DPYD-rs55886062 and DPYD-rs67376798 was assessed to 99%. Among the seven patients carrying one variant DPYD-rs3918290, DPYD-rs55886062 or DPYD-rs67376798 allele, not developing Grade 3 toxicity, 57% needed a FL dose or schedule modification for moderate chronic toxicity. No other DPYD polymorphism was associated with Grade 3 toxicity. Our data demonstrate the clinical validity and specificity of the DPYD-rs3918290, DPYDrs55886062, DPYD-rs67376798 genotyping test to prevent FL-related Grade 3 toxicity and to preserve treatment compliance, and support its introduction in the clinical practice.The identification of the genetic bases of inter-individual variability in terms of response or toxicity to pharmacological treatments is a key point in the field of personalized therapy. Specifically, in the oncological setting the high variability observed in the tumor response to treatment and in the severity of toxicity emphasizes the importance of improving the knowledge on the clinical validity of the pharmacogenetic tests.Fluoropyrimidines (FL) are listed among the drugs with pharmacogenetic warnings. 1 Despite the acknowledged efficacy of these drugs in the treatment of different solid tumors, 2 the FL treatment remains challenging as a result of a considerable inter-patient variability in terms of efficacy and toxicity. 3,4 The pharmacogenetic research, aimed at defining predictive markers of FL response, mainly focused on the dihydropyrimidine dehydrogenase (DPD), which is the first and rate-limiting enzyme of FL catabolic pathway. Up to date, 160 single nucleotide polymorphisms (SNPs) that alter the DPD aminoacids sequence have been identified within the gene (DPYD) codifying for this enzyme 5,6 and many clinical studies have been trying to investigate their association with FL-related severe toxicities. 3,[7][8][9][10][11] Recently the discussion in the scientific community about the clinical effectiveness of pharmacogenetics has given rise to the publication of drug dosing guidelines with indications and recommendations about drug...

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confidence: 99%

Clinical validity of a DPYD‐based pharmacogenetic test to predict severe toxicity to fluoropyrimidines

Toffoli

Giodini

Buonadonna

et al. 2015

Intl Journal of Cancer

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“…For the CYP2C9 and CYP2C19 gene, we determined the metabolizer status in all of the patients as deduced from the genotype according to the CPIC guidelines for the CYP2C9 [18] and the CYP2C19 genes [19] and described in Materials and Methods section.…”

Section: Resultsmentioning

confidence: 99%

“…However, it should be underlined that the patients were carefully selected, and the genotyping techniques, that we used, have 100% of sensitivity and specificity. The haplotypes are well defined, it includes the promoter region, and phenotypes are deducted from the genotypes according to the more recent definition [18, 19, 20]. All these settings could represent a new direction of investigation.…”

Section: Discussionmentioning

confidence: 99%

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Assessment of CYP2C9, CYP2C19, and CYP2D6 Polymorphisms in Allergic Patients with Chemical Sensitivity

D'Attis

Massari

Mazzei

et al. 2019

Int Arch Allergy Immunol

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Background: Self-reported chemical sensitivity (SCS) is characterized by adverse effects due to exposure to low levels of chemical substances. The clinical manifestations of SCS are similar to the allergy, and a high percentage of individuals with both diseases have been found. Various genes, especially genes of importance to the metabolism of xenobiotic compounds, have been associated with SCS. Objectives: The purpose of this study was to investigate whether allergic individuals with chemical sensitivity differed from allergic patients without chemical sensitivity with regard to the distribution of genotype and phenotype of CYP2C9, CYP2C19, and CYP2D6 polymorphisms. Methods: A total of 180 patients were enrolled for this study. A questionnaire was employed to collect information on individual chemical sensitivity, while the Skin prick test and the PATCH test were used to verify the presence of an allergic condition against inhalants or contact allergens, respectively. For the evaluation of the CYP2C9, CYP2C19, and CYP2D6 polymorphisms, we used a strategy based on the amplification of the entire gene coupled to direct genomic DNA sequencing analysis. Results: Overall, a total of 15 different CYP2C9, CYP2C19, and CYP2D6 haplotypes were identified in our population. If the 5 CYP2C9 and the 2 CYP2C19 identified alleles correspond to the previously described ones, 4 of the 8 CYP2D6 haplotypes, detected in the study group, present new SNPs combinations. These new suballeles were categorized as CYP2D6*2M Salento Variant 1, CYP2D6*35B Salento Variant 2, CYP2D6*41 Salento Variant 3, and CYP2D6*4P Salento Variant 4 due to the presence of the key SNPs 2,850 C>T, 31G>A, 2,988 G>A, and 1,846 G>A, respectively. When the allergic individuals are divided into 2 groups according to their SCS score, we observed that the distribution of the CYP2D6 phenotypes was significantly different between the 2 groups. Conclusions: Our idea is that the application of the questionnaire that we have adopted has enabled us to diagnose a degree of chemical sensitivity, which results as comorbid of the allergic disease and in which a condition of poor or intermediate metabolizes for the detrimental CYP2D6 alleles, could represent a discriminant between the chemical sensitivity and the health state.

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“…The adverse effects can be eliminated by giving the drug only when the patient's enzyme activity is normal or by reducing the drug dose if the activity is low. [27][28][29] Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin Kepoxide reductase complex (VKORC1) enzymes, in addition to known non-genetic factors, account for ~50% of warfarin dose variability.…”

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confidence: 99%

Pharmacogenetics: an Emerging Therapeutic option for Bangladesh

Ahmed

2015

Dhaka Univ. J. Pharm. Sci

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From socioeconomic point of view adverse drug reactions (ADRs) present a challenging and expensive public health problem worldwide. Most important factors involved in this life threatening events are false diagnosis, failure of treatment, lack of proper patient counseling, lack of knowledge regarding medication use and polypharmacy. Pharmacogenetic research explores genetic variability between patients to explain observed differences in effectiveness of a drug therapy as well as adverse event profile. Thus, pharmacogenetic testings could help to prevent treatment failure and adverse drug reaction in patients. It also allows the detection and prediction of ADRs and is a tool that can reduce the risks associated with ADRs. In this particular review we will discuss how genetic variation can influence drug response and how personalized medicine can be achieved as well as some recent pharmacogenetic works carried out in Bangladesh. The aim of this review is to increase awareness of the physicians and other health care practitioners and professionals about the variation of drug response due to genetic variation. This review can help the physicians to identify genetic factors associated with ADRs with all drugs and effectively incorporate pharmacogenetics into the practice of pharmacovigilance.

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Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing

Cited by 210 publications

References 36 publications

Clinical validity of a DPYD‐based pharmacogenetic test to predict severe toxicity to fluoropyrimidines

Clinical validity of a DPYD‐based pharmacogenetic test to predict severe toxicity to fluoropyrimidines

Assessment of CYP2C9, CYP2C19, and CYP2D6 Polymorphisms in Allergic Patients with Chemical Sensitivity

Pharmacogenetics: an Emerging Therapeutic option for Bangladesh

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