Allelic Variants in the
            <i>CYP2C9</i>
            and
            <i>VKORC1</i>
            Loci and Interindividual Variability in the Anticoagulant Dose Effect Of Warfarin in Italians

Borgiani, Paola; Ciccacci, Cinzia; Forte, Vittorio; Romano, Silvia; Federici, Giorgio; Novelli, Giuseppe

doi:10.2217/14622416.8.11.1545

Cited by 55 publications

(48 citation statements)

References 22 publications

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“…Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 correlated with INR and plasma R-and S-warfarin concentrations. The mean warfarin daily dose requirement was highest in patients with the allelic variant CYP2C9 *1/*1 compared with those with the variant *2 and *3 alleles and highest 64 Gage et al, 65 Bodin et al, 66 Voora et al, 67 Hillman et al, 68 Kimura et al, 69 Loebstein et al, 39 and Borgiani et al 50 reported similar findings when genotypes were distributed by race. Studies articulating combined CYP2C9 and VKORC1 allelic frequencies and associated warfarin doses are summarized in Table 5.…”

Section: Effect Of Allelic Variants On Warfarin Activitymentioning

confidence: 82%

Warfarin Sensitivity Genotyping: A Review of the Literature and Summary of Patient Experience

Moyer

O’Kane

Baudhuin

et al. 2009

Mayo Clinic Proceedings

112

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ADE = adverse drug event; AEI = American Enterprise Institute; ASPE = allele-specific primer extension; CYP2C9 = cytochrome P450 2C9; INR = international normalized ratio; PCR = polymerase chain reaction; SNP = single-nucleotide polymorphism; VitKH 2 = vitamin K hydroquinone; VKOR = vitamin K epoxide reductase; VKORC1 = VKOR complex, subunit 1 W arfarin is a well-accepted therapy used for the prevention of stroke in patients with atrial fibrillation, for prophylaxis of venous thromboembolism and pulmonary embolism in patients with prosthetic heart valves and myocardial infarction, and for prevention of pulmonary embolism or deep venous thrombosis in patients undergoing orthopedic surgery or with a history of venous or arterial thromboembolism. Many reviews and clinical practice guidelines (summarized by Ansell et al, 1 Baglin et al, 2 Flockhart et al, 3 Husted et al, 4 and Singer et al 5 ) outline the substantial benefits of warfarin therapy for the prevention of strokes in these patients. The American Enterprise Institute (AEI)-Brookings Joint Center for Regulatory Studies Report, which reviewed the use of warfarin in the United States, estimates that approximately 2 million US citizens are prescribed warfarin annually. 6 In 2003, a total of 21.2 million prescriptions were written for oral warfarin in the United States. 7 Warfarin interferes with coagulation by inhibiting regeneration of the reduced form of vitamin K, a cofactor in the γ-glutamyl-carboxylase -mediated activation of coagulation factors II, VII, IX, and X ( Figure 1). The oxidized, inactive form of vitamin K is converted to the reduced form of vitamin K by vitamin K epoxide reductase (VKOR); warfarin inhibits VKOR, resulting in less of the reduced form of vitamin K available to support the factor carboxylation required to sustain the coagulation cascade. 8 Warfarin has a narrow therapeutic index that contributes either to therapeutic failure (potentially leading to stroke or other complications) or therapeutic excess (potentially leading to bleeding and hemorrhage). Many surveys have described the incidence of warfarin-related adverse drugThe antithrombotic benefits of warfarin are countered by a narrow therapeutic index that contributes to excessive bleeding or cerebrovascular clotting and stroke in some patients. This article reviews the current literature describing warfarin sensitivity genotyping and compares the results of that review to the findings of our study in 189 patients at Mayo Clinic conducted between June 2001 and April 2003. For the review of the literature, we identified relevant peer-reviewed articles by searching the Web of Knowledge using key word warfarin-related adverse event. For the 189 Mayo Clinic patients initiating warfarin therapy to achieve a target international normalized ratio (INR) in the range of 2.0 to 3.5, we analyzed the CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genetic loci to study the relationship among the initial warfarin dose, steady-state dose, time to ach...

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Section: Effect Of Allelic Variants On Warfarin Activitymentioning

confidence: 82%

Warfarin Sensitivity Genotyping: A Review of the Literature and Summary of Patient Experience

Moyer

O’Kane

Baudhuin

et al. 2009

Mayo Clinic Proceedings

112

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“…The anticoagulant effects of warfarin are modifi ed also by diet and foods containing vitamin K, although the dietary infl uences tend to be of more short-term character (25). VKORC1*3 haplotype (3730G>A, rs7294) was also defi ned and is present in 38 % of Europeans (13). It causes an increase in the dosage of warfarin (AA) up to 30 % compared with WT (7).…”

Section: Discussionmentioning

confidence: 99%

“…In the early stages of therapy, PM phenotypes are at risk of increased bleeding after warfarin treatment. These individuals require lower doses of warfarin to achieve the desired anticoagulant effect compared to patients with at least one CYP2C9*1 (WT) haplotype (13). The enzyme activity is reduced to 12 % (CYP2C9*2) and 5 % (CYP2C9*3), respectively to WT (14).…”

mentioning

confidence: 99%

Frequencies of polymorphisms in CYP2C9 and VKORC1 genes influencing warfarin metabolism in Slovak population: implication for clinical practice

Krajčíová¹,

Déžiová²,

Petrovič³

et al. 2014

BLL

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Objectives: The study was aimed at establishing an effective molecular-genetic method for detecting polymorphisms in genes CYP2C9 and VKORC1, which affect the pharmacogenetics of warfarin, and at determining their prevalence in Slovak population. Background: Warfarin, derivative of coumarin, belongs to the most commonly prescribed oral anticoagulants with narrow therapeutic index. An insuffi cient dose of warfarin can result in failure to produce the antithrombotic effect, whereas an overdose increases the risk of bleeding. It was proven that genetic variability in two genes, CYP2C9 a VKORC1, has a signifi cant infl uence on the individual's response to the dosage of warfarin. Methods: In a control group of 112 randomly selected individuals, we tested the frequency of selected single nucleotide polymorphisms including CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), VKORC1*2 (1173C>T) by allele-specifi c Real-Time PCR and VKORC1*2 (-1639G>A) by using PCR-RFLP. Results: Due to the combination of frequent alleles CYP2C9*2, CYP2C9*3 and VKORC1*2 in Slovak population we determine that 25% of population need a standard 5-mg daily dose of warfarin, while 44%, 23%, and 8% need 4 mg, 3 mg and 2 mg of warfarin per day. Conclusion: Slovak population is in Hardy-Weinberg equilibrium and frequencies of SNPs were in accordance with other published results in European populations (Tab. 5. Fig. 3, Ref. 51). Text in PDF www.elis.sk.

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“…However, these values include uncertainties due to bias or imprecision in calculating them from incomplete data and also because of the inherent variability. Reported clinical PK parameters are subject to both inter-and intrastudy variability, which stems from different sources such as ethnicity; genetic variation in cytochrome P450 metabolizing enzymes (Tucker, 1994) such as CYP2D6 (Dorne et al, 2002;Abduljalil et al, 2010;Thompson et al, 2011), CYP2C9 (Loebstein et al, 2001;Borgiani et al, 2007), and CYP2C19 (Dorne et al, 2003;Crettol et al, 2005); comedication; health status; different assay and analysis; environmental factors; and clinical settings of the study such as sample size.…”

Section: Introductionmentioning

confidence: 99%

Deciding on Success Criteria for Predictability of Pharmacokinetic Parameters from In Vitro Studies: An Analysis Based on In Vivo Observations

et al. 2014

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Prediction accuracy of pharmacokinetic parameters is often assessed using prediction fold error, i.e., being within 2-, 3-, or n-fold of observed values. However, published studies disagree on which fold error represents an accurate prediction. In addition, "observed data" from only one clinical study are often used as the gold standard for in vitro to in vivo extrapolation (IVIVE) studies, despite data being subject to significant interstudy variability and subjective selection from various available reports. The current study involved analysis of published systemic clearance (CL) and volume of distribution at steady state (V ss ) values taken from over 200 clinical studies. These parameters were obtained for 17 different drugs after intravenous administration. Data were analyzed with emphasis on the appropriateness to use a parameter value from one particular clinical study to judge the performance of IVIVE and the ability of CL and V ss values obtained from one clinical study to "predict" the same values obtained in a different clinical study using the n-fold criteria for prediction accuracy. The twofold criteria method was of interest because it is widely used in IVIVE predictions. The analysis shows that in some cases the twofold criteria method is an unreasonable expectation when the observed data are obtained from studies with small sample size. A more reasonable approach would allow prediction criteria to include clinical study information such as sample size and the variance of the parameter of interest. A method is proposed that allows the "success" criteria to be linked to the measure of variation in the observed value.

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Allelic Variants in the CYP2C9 and VKORC1 Loci and Interindividual Variability in the Anticoagulant Dose Effect Of Warfarin in Italians

Cited by 55 publications

References 22 publications

Warfarin Sensitivity Genotyping: A Review of the Literature and Summary of Patient Experience

Warfarin Sensitivity Genotyping: A Review of the Literature and Summary of Patient Experience

Frequencies of polymorphisms in CYP2C9 and VKORC1 genes influencing warfarin metabolism in Slovak population: implication for clinical practice

Deciding on Success Criteria for Predictability of Pharmacokinetic Parameters from In Vitro Studies: An Analysis Based on In Vivo Observations

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