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Céline Verstuyft - One of the best experts on this subject based on the ideXlab platform.

  • A pharmacokinetic-pharmacodynamic model for predicting the impact of CYP2C9 and VKORC1 polymorphisms on Fluindione and acenocoumarol during induction therapy.
    Clinical Pharmacokinectics, 2012
    Co-Authors: Céline Verstuyft, Bertrand Diquet, Xavier Delavenne, Alexandra Rousseau, Annie Robert, Michel Tod, Martine Lebot, Patrice Jaillon, Laurent Becquemont
    Abstract:

    Background and Objective Vitamin K epoxide reductase complex, subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) polymorphisms are taken into account when predicting a safe oral dose of coumarin anticoagulant therapy, but little is known about the effects of genetic predictors on the response to Fluindione and acenocoumarol. The aims of this study were to characterize the relationship between Fluindione and acenocoumarol concentrations and the international normalized ratio (INR) response, and to identify genetic predictors that are important for dose individualization.

  • Impact of genetic factors (VKORC1, CYP2C9, CYP4F2 and EPHX1) on the anticoagulation response to Fluindione.
    British Journal of Clinical Pharmacology, 2012
    Co-Authors: Karine Lacut, Estelle Ayme-dietrich, Lenaick Gourhant, Elise Poulhazan, Marion Andro, Laurent Becquemont, Dominique Mottier, Grégoire Le Gal, Céline Verstuyft
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * CYP2C9 and VKORC1 genetic variants contribute to differences in patients' responses to anticoagulant coumarin derivatives. Patients carrying the VKORC1 1173TT genotype have a decreased time to the first INR within the therapeutic range and to the first INR >4, and also require lower warfarin maintenance doses. Patients carrying the *2 or *3 CYP2C9 allele have lower maintenance warfarin requirements than those carrying the wild-type allele. The role of CYP2C9 and VKORC1 genetic variants in Fluindione response is unknown. WHAT THIS STUDY ADDS * Our results showed that VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P < 0.0001), on the time required to reach a first INR within the therapeutic range (P < 0.0001), on the time to obtain a first INR value >4 (P= 0.0002) and on the average daily dose of Fluindione during the first period of stability (19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT, P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to Fluindione. This report provides new information on the respective role of common genetic polymorphisms on anticoagulation induced by another class of anticoagulant drugs rather than coumarin derivatives. AIM Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9) and of a key pharmacologic target of vitamin K antagonists, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to coumarin derivatives. The role of these variants in Fluindione response is unknown. Our aim was to assess whether genetic factors contribute to the variability in the response to Fluindione. METHODS Four hundred sixty-five patients with a venous thromboembolic event treated by Fluindione for at least 3 months with a target international normalized ratio (INR) of 2.0 to 3.0 were studied. VKORC1, CYP2C9, CYP4F2 and EPHX1 genotypes were assessed. INR checks, Fluindione doses and bleeding events were collected. RESULTS VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P < 0.0001), on the time required to reach a first INR within the therapeutic range (P < 0.0001) and on the time to obtain a first INR value > 4 (P= 0.0002). The average daily dose of Fluindione during the first period of stability was significantly associated with the VKORC1 genotype: 19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT (P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to Fluindione. CONCLUSIONS VKORC1 genotype strongly affected anticoagulation induced by Fluindione whereas CYP2C9, CYP4F2 and EPHX1 genotypes seemed less determining.

  • Impact of genetic factors (VKORC1, CYP2C9, CYP4F2 and EPHX1) on the anticoagulation response to Fluindione
    British Journal of Clinical Pharmacology, 2012
    Co-Authors: Karine Lacut, Estelle Ayme-dietrich, Lenaick Gourhant, Elise Poulhazan, Marion Andro, Laurent Becquemont, Dominique Mottier, Grégoire Le Gal, Céline Verstuyft
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • CYP2C9 and VKORC1 genetic variants contribute to differences in patients' responses to anticoagulant coumarin derivatives. Patients carrying the VKORC1 1173TT genotype have a decreased time to the first INR within the therapeutic range and to the first INR >4, and also require lower warfarin maintenance doses. Patients carrying the *2 or *3 CYP2C9 allele have lower maintenance warfarin requirements than those carrying the wild-type allele. The role of CYP2C9 and VKORC1 genetic variants in Fluindione response is unknown. WHAT THIS STUDY ADDS • Our results showed that VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P 4 (P= 0.0002) and on the average daily dose of Fluindione during the first period of stability (19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT, P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to Fluindione. This report provides new information on the respective role of common genetic polymorphisms on anticoagulation induced by another class of anticoagulant drugs rather than coumarin derivatives. AIM Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9) and of a key pharmacologic target of vitamin K antagonists, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to coumarin derivatives. The role of these variants in Fluindione response is unknown. Our aim was to assess whether genetic factors contribute to the variability in the response to Fluindione. METHODS Four hundred sixty-five patients with a venous thromboembolic event treated by Fluindione for at least 3 months with a target international normalized ratio (INR) of 2.0 to 3.0 were studied. VKORC1, CYP2C9, CYP4F2 and EPHX1 genotypes were assessed. INR checks, Fluindione doses and bleeding events were collected. RESULTSVKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P 4 (P= 0.0002). The average daily dose of Fluindione during the first period of stability was significantly associated with the VKORC1 genotype: 19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT (P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to Fluindione. CONCLUSIONSVKORC1 genotype strongly affected anticoagulation induced by Fluindione whereas CYP2C9, CYP4F2 and EPHX1 genotypes seemed less determining.

  • A Pharmacokinetic-Pharmacodynamic Model for Predicting the Impact of CYP2C9 and VKORC1 Polymorphisms on Fluindione and Acenocoumarol During Induction Therapy
    Clinical Pharmacokinetics, 2012
    Co-Authors: Céline Verstuyft, Bertrand Diquet, Xavier Delavenne, Alexandra Rousseau, Annie Robert, Michel Tod, Martine Lebot, Patrice Jaillon, Laurent Becquemont
    Abstract:

    Background and Objective Vitamin K epoxide reductase complex, subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) polymorphisms are taken into account when predicting a safe oral dose of coumarin anticoagulant therapy, but little is known about the effects of genetic predictors on the response to Fluindione and acenocoumarol. The aims of this study were to characterize the relationship between Fluindione and acenocoumarol concentrations and the international normalized ratio (INR) response, and to identify genetic predictors that are important for dose individualization. Methods Fluindione concentrations, S - and R -acenocoumarol concentrations, the INR and genotype data from healthy subjects were used to develop a population pharmacokinetic-pharmacodynamic model in Monolix software. Twenty-four White healthy subjects were enrolled in the pharmacogenetic study. The study was an open-label, randomized, two-period cross-over study. The subjects received two doses of an oral anticoagulant: 20 mg of Fluindione (period A) or 4 mg of acenocoumarol (period B). The pharmacokinetics and pharmacodynamics were studied from day 2 to day 3. Results A two-compartment model with a first-order input model was selected as the base model for the two drugs. The pharmacodynamic response was best described by an indirect action model with S -acenocoumarol concentrations and Fluindione concentrations as the only exposure predictors of the INR response. Three covariates ( CYP2C9 genotype, VKORC1 genotype and body weight) were identified as important predictors for the pharmacokinetic-pharmacodynamic model of S -acenocoumarol, and four covariates ( CYP2C9 genotype, VKORC1 genotype, CYP1A2 phenotype and body weight) were identified as predictors for the pharmacokinetic-pharmacodynamic model of Fluindione. Because some previous studies have shown a dose-response relationship between smoking exposure and the CYP1A2 phenotype, it was also noted that smokers have greater CYP1A2 activity. Conclusion During initiation of therapy, CYP2C9 and VKORC1 genetic polymorphisms are important predictors of Fluindione and acenocoumarol pharmacokinetic-pharmacodynamic responses. Our result suggests that it is important to take the CYP1A2 phenotype into account to improve individualization of Fluindione therapy, in addition to genetic factors.

Laurent Becquemont - One of the best experts on this subject based on the ideXlab platform.

  • A pharmacokinetic-pharmacodynamic model for predicting the impact of CYP2C9 and VKORC1 polymorphisms on Fluindione and acenocoumarol during induction therapy.
    Clinical Pharmacokinectics, 2012
    Co-Authors: Céline Verstuyft, Bertrand Diquet, Xavier Delavenne, Alexandra Rousseau, Annie Robert, Michel Tod, Martine Lebot, Patrice Jaillon, Laurent Becquemont
    Abstract:

    Background and Objective Vitamin K epoxide reductase complex, subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) polymorphisms are taken into account when predicting a safe oral dose of coumarin anticoagulant therapy, but little is known about the effects of genetic predictors on the response to Fluindione and acenocoumarol. The aims of this study were to characterize the relationship between Fluindione and acenocoumarol concentrations and the international normalized ratio (INR) response, and to identify genetic predictors that are important for dose individualization.

  • Impact of genetic factors (VKORC1, CYP2C9, CYP4F2 and EPHX1) on the anticoagulation response to Fluindione.
    British Journal of Clinical Pharmacology, 2012
    Co-Authors: Karine Lacut, Estelle Ayme-dietrich, Lenaick Gourhant, Elise Poulhazan, Marion Andro, Laurent Becquemont, Dominique Mottier, Grégoire Le Gal, Céline Verstuyft
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * CYP2C9 and VKORC1 genetic variants contribute to differences in patients' responses to anticoagulant coumarin derivatives. Patients carrying the VKORC1 1173TT genotype have a decreased time to the first INR within the therapeutic range and to the first INR >4, and also require lower warfarin maintenance doses. Patients carrying the *2 or *3 CYP2C9 allele have lower maintenance warfarin requirements than those carrying the wild-type allele. The role of CYP2C9 and VKORC1 genetic variants in Fluindione response is unknown. WHAT THIS STUDY ADDS * Our results showed that VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P < 0.0001), on the time required to reach a first INR within the therapeutic range (P < 0.0001), on the time to obtain a first INR value >4 (P= 0.0002) and on the average daily dose of Fluindione during the first period of stability (19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT, P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to Fluindione. This report provides new information on the respective role of common genetic polymorphisms on anticoagulation induced by another class of anticoagulant drugs rather than coumarin derivatives. AIM Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9) and of a key pharmacologic target of vitamin K antagonists, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to coumarin derivatives. The role of these variants in Fluindione response is unknown. Our aim was to assess whether genetic factors contribute to the variability in the response to Fluindione. METHODS Four hundred sixty-five patients with a venous thromboembolic event treated by Fluindione for at least 3 months with a target international normalized ratio (INR) of 2.0 to 3.0 were studied. VKORC1, CYP2C9, CYP4F2 and EPHX1 genotypes were assessed. INR checks, Fluindione doses and bleeding events were collected. RESULTS VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P < 0.0001), on the time required to reach a first INR within the therapeutic range (P < 0.0001) and on the time to obtain a first INR value > 4 (P= 0.0002). The average daily dose of Fluindione during the first period of stability was significantly associated with the VKORC1 genotype: 19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT (P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to Fluindione. CONCLUSIONS VKORC1 genotype strongly affected anticoagulation induced by Fluindione whereas CYP2C9, CYP4F2 and EPHX1 genotypes seemed less determining.

  • Impact of genetic factors (VKORC1, CYP2C9, CYP4F2 and EPHX1) on the anticoagulation response to Fluindione
    British Journal of Clinical Pharmacology, 2012
    Co-Authors: Karine Lacut, Estelle Ayme-dietrich, Lenaick Gourhant, Elise Poulhazan, Marion Andro, Laurent Becquemont, Dominique Mottier, Grégoire Le Gal, Céline Verstuyft
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • CYP2C9 and VKORC1 genetic variants contribute to differences in patients' responses to anticoagulant coumarin derivatives. Patients carrying the VKORC1 1173TT genotype have a decreased time to the first INR within the therapeutic range and to the first INR >4, and also require lower warfarin maintenance doses. Patients carrying the *2 or *3 CYP2C9 allele have lower maintenance warfarin requirements than those carrying the wild-type allele. The role of CYP2C9 and VKORC1 genetic variants in Fluindione response is unknown. WHAT THIS STUDY ADDS • Our results showed that VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P 4 (P= 0.0002) and on the average daily dose of Fluindione during the first period of stability (19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT, P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to Fluindione. This report provides new information on the respective role of common genetic polymorphisms on anticoagulation induced by another class of anticoagulant drugs rather than coumarin derivatives. AIM Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9) and of a key pharmacologic target of vitamin K antagonists, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to coumarin derivatives. The role of these variants in Fluindione response is unknown. Our aim was to assess whether genetic factors contribute to the variability in the response to Fluindione. METHODS Four hundred sixty-five patients with a venous thromboembolic event treated by Fluindione for at least 3 months with a target international normalized ratio (INR) of 2.0 to 3.0 were studied. VKORC1, CYP2C9, CYP4F2 and EPHX1 genotypes were assessed. INR checks, Fluindione doses and bleeding events were collected. RESULTSVKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P 4 (P= 0.0002). The average daily dose of Fluindione during the first period of stability was significantly associated with the VKORC1 genotype: 19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT (P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to Fluindione. CONCLUSIONSVKORC1 genotype strongly affected anticoagulation induced by Fluindione whereas CYP2C9, CYP4F2 and EPHX1 genotypes seemed less determining.

  • A Pharmacokinetic-Pharmacodynamic Model for Predicting the Impact of CYP2C9 and VKORC1 Polymorphisms on Fluindione and Acenocoumarol During Induction Therapy
    Clinical Pharmacokinetics, 2012
    Co-Authors: Céline Verstuyft, Bertrand Diquet, Xavier Delavenne, Alexandra Rousseau, Annie Robert, Michel Tod, Martine Lebot, Patrice Jaillon, Laurent Becquemont
    Abstract:

    Background and Objective Vitamin K epoxide reductase complex, subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) polymorphisms are taken into account when predicting a safe oral dose of coumarin anticoagulant therapy, but little is known about the effects of genetic predictors on the response to Fluindione and acenocoumarol. The aims of this study were to characterize the relationship between Fluindione and acenocoumarol concentrations and the international normalized ratio (INR) response, and to identify genetic predictors that are important for dose individualization. Methods Fluindione concentrations, S - and R -acenocoumarol concentrations, the INR and genotype data from healthy subjects were used to develop a population pharmacokinetic-pharmacodynamic model in Monolix software. Twenty-four White healthy subjects were enrolled in the pharmacogenetic study. The study was an open-label, randomized, two-period cross-over study. The subjects received two doses of an oral anticoagulant: 20 mg of Fluindione (period A) or 4 mg of acenocoumarol (period B). The pharmacokinetics and pharmacodynamics were studied from day 2 to day 3. Results A two-compartment model with a first-order input model was selected as the base model for the two drugs. The pharmacodynamic response was best described by an indirect action model with S -acenocoumarol concentrations and Fluindione concentrations as the only exposure predictors of the INR response. Three covariates ( CYP2C9 genotype, VKORC1 genotype and body weight) were identified as important predictors for the pharmacokinetic-pharmacodynamic model of S -acenocoumarol, and four covariates ( CYP2C9 genotype, VKORC1 genotype, CYP1A2 phenotype and body weight) were identified as predictors for the pharmacokinetic-pharmacodynamic model of Fluindione. Because some previous studies have shown a dose-response relationship between smoking exposure and the CYP1A2 phenotype, it was also noted that smokers have greater CYP1A2 activity. Conclusion During initiation of therapy, CYP2C9 and VKORC1 genetic polymorphisms are important predictors of Fluindione and acenocoumarol pharmacokinetic-pharmacodynamic responses. Our result suggests that it is important to take the CYP1A2 phenotype into account to improve individualization of Fluindione therapy, in addition to genetic factors.

  • This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. A Pharmacokinetic-Pharmacodynamic Model for Predicting the Impact of CYP2C9 and VKORC1 Polymorphisms on Fluindione and Acenocoumarol During
    2012
    Co-Authors: Xavier Delavenne, Bertrand Diquet, Alexandra Rousseau, Annie Robert, Michel Tod, Martine Lebot, Patrice Jaillon, Laurent Becquemont
    Abstract:

    Background and Objective: Vitamin K epoxide reductase complex, subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) polymorphisms are taken into account when predicting a safe oral dose of coumarin anticoagulant therapy, but little is known about the effects of genetic predictors on the response to Fluindione and acenocoumarol. The aims of this study were to characterize the relationship between Fluindione and acenocoumarol concentrations and the international normalized ratio (INR) response, and to identify genetic predictors that are important for dose individualization. Methods: Fluindione concentrations, S- and R-acenocoumarol concentrations, the INR and genotype data from healthy subjects were used to develop a population pharmacokinetic–pharmacodynamic model in Monolix software. Twenty-four White healthy subjects were enrolled in the pharmacogenetic study. The study was an open-label, randomized, two-period cross-over study. The subjects received two doses of an oral anticoagulant: 20 mg of Fluindione (period A) or 4 mg of acenocoumarol (period B). The pharmacokinetics and pharmacodynamics were studied from day 2 to day 3. Results: A two-compartment model with a first-order input model was selected as the base model for the two drugs. The pharmacodynamic response was best described by an indirect action model with S-acenocoumarol concentrations and Fluindione concentrations as the only exposure predictors of the INR response. Three covariates (CYP2C9 genotype, VKORC1 genotype and body weight) were identified as important predictors for the pharmacokinetic–pharmacodynamic model of S-acenocoumarol, and four covariates (CYP2C9 genotype, VKORC1 genotype, CYP1A2 phenotype and body weight) were identified as predictors for the pharmacokinetic–pharmacodynamic model of Fluindione. Because some previous studies have shown a dose–response relationship between smoking exposure and the CYP1A2 phenotype, it was also noted that smokers have greater CYP1A2 activity. Conclusion: During initiation of therapy, CYP2C9 and VKORC1 genetic polymorphisms are important predictors of Fluindione and acenocoumarol pharmacokinetic–pharmacodynamic responses. Our result suggests that it is important to take the CYP1A2 phenotype into account to improve individualization of Fluindione therapy, in addition to genetic factors.

Michel Tod - One of the best experts on this subject based on the ideXlab platform.

  • interaction entre amoxicilline acide clavulanique et Fluindione a propos de deux cas
    Therapie, 2016
    Co-Authors: Elodie Farnier, Nicolas Charhon, Laurence Papillon, Michel Tod
    Abstract:

    Several drug classes, such as antibiotics, may interact with antivitamin K and increase anticoagulant effect. To date, interaction between Fluindione and amoxicillin/clavulanic acid is neither described in the literature, nor specified in the summary of product characteristics. We report the cases of two patients who overdose Fluindione after administration of amoxicillin/clavulanic acid.

  • Interaction entre amoxicilline/acide clavulanique et Fluindione : à propos de deux cas☆
    Therapie, 2016
    Co-Authors: Elodie Farnier, Nicolas Charhon, Laurence Papillon, Michel Tod
    Abstract:

    Several drug classes, such as antibiotics, may interact with antivitamin K and increase anticoagulant effect. To date, interaction between Fluindione and amoxicillin/clavulanic acid is neither described in the literature, nor specified in the summary of product characteristics. We report the cases of two patients who overdose Fluindione after administration of amoxicillin/clavulanic acid.

  • Interaction entre amoxicilline/acide clavulanique et Fluindione : à propos de deux cas
    EDP Sciences, 2015
    Co-Authors: Elodie Farnier, Nicolas Charhon, Laurence Papillon, Michel Tod
    Abstract:

    De nombreuses classes médicamenteuses, comme les antibiotiques, sont susceptibles d’interagir avec les antivitamines K et augmenter leur effet anticoagulant. L’interaction entre Fluindione et amoxicilline/acide clavulanique n’est à ce jour ni décrite dans la littérature, ni précisée dans les résumés caractéristiques des produits. Nous rapportons ici le cas de deux patients ayant présenté un surdosage en Fluindione suite à l’administration d’amoxicilline/acide clavulanique

  • A pharmacokinetic-pharmacodynamic model for predicting the impact of CYP2C9 and VKORC1 polymorphisms on Fluindione and acenocoumarol during induction therapy.
    Clinical Pharmacokinectics, 2012
    Co-Authors: Céline Verstuyft, Bertrand Diquet, Xavier Delavenne, Alexandra Rousseau, Annie Robert, Michel Tod, Martine Lebot, Patrice Jaillon, Laurent Becquemont
    Abstract:

    Background and Objective Vitamin K epoxide reductase complex, subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) polymorphisms are taken into account when predicting a safe oral dose of coumarin anticoagulant therapy, but little is known about the effects of genetic predictors on the response to Fluindione and acenocoumarol. The aims of this study were to characterize the relationship between Fluindione and acenocoumarol concentrations and the international normalized ratio (INR) response, and to identify genetic predictors that are important for dose individualization.

  • A Pharmacokinetic-Pharmacodynamic Model for Predicting the Impact of CYP2C9 and VKORC1 Polymorphisms on Fluindione and Acenocoumarol During Induction Therapy
    Clinical Pharmacokinetics, 2012
    Co-Authors: Céline Verstuyft, Bertrand Diquet, Xavier Delavenne, Alexandra Rousseau, Annie Robert, Michel Tod, Martine Lebot, Patrice Jaillon, Laurent Becquemont
    Abstract:

    Background and Objective Vitamin K epoxide reductase complex, subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) polymorphisms are taken into account when predicting a safe oral dose of coumarin anticoagulant therapy, but little is known about the effects of genetic predictors on the response to Fluindione and acenocoumarol. The aims of this study were to characterize the relationship between Fluindione and acenocoumarol concentrations and the international normalized ratio (INR) response, and to identify genetic predictors that are important for dose individualization. Methods Fluindione concentrations, S - and R -acenocoumarol concentrations, the INR and genotype data from healthy subjects were used to develop a population pharmacokinetic-pharmacodynamic model in Monolix software. Twenty-four White healthy subjects were enrolled in the pharmacogenetic study. The study was an open-label, randomized, two-period cross-over study. The subjects received two doses of an oral anticoagulant: 20 mg of Fluindione (period A) or 4 mg of acenocoumarol (period B). The pharmacokinetics and pharmacodynamics were studied from day 2 to day 3. Results A two-compartment model with a first-order input model was selected as the base model for the two drugs. The pharmacodynamic response was best described by an indirect action model with S -acenocoumarol concentrations and Fluindione concentrations as the only exposure predictors of the INR response. Three covariates ( CYP2C9 genotype, VKORC1 genotype and body weight) were identified as important predictors for the pharmacokinetic-pharmacodynamic model of S -acenocoumarol, and four covariates ( CYP2C9 genotype, VKORC1 genotype, CYP1A2 phenotype and body weight) were identified as predictors for the pharmacokinetic-pharmacodynamic model of Fluindione. Because some previous studies have shown a dose-response relationship between smoking exposure and the CYP1A2 phenotype, it was also noted that smokers have greater CYP1A2 activity. Conclusion During initiation of therapy, CYP2C9 and VKORC1 genetic polymorphisms are important predictors of Fluindione and acenocoumarol pharmacokinetic-pharmacodynamic responses. Our result suggests that it is important to take the CYP1A2 phenotype into account to improve individualization of Fluindione therapy, in addition to genetic factors.

Karine Lacut - One of the best experts on this subject based on the ideXlab platform.

  • A model predicting Fluindione dose requirement in elderly inpatients including genotypes, body weight, and amiodarone
    Thrombosis and Haemostasis, 2013
    Co-Authors: Caroline Moreau, Eric Pautas, Karine Lacut, Marion Andro, Grégoire Le Gal, Charlotte Duverlie, Celia Berndt, Isabelle Mahé, Joseph Emmerich, Isabelle Peyron
    Abstract:

    Indandione VKAs have been widely used for decades, especially in Eastern Europe and France. Contrary to coumarin VKAs, the relative contribution of individual factors to the indandione-VKA response is poorly known. In the present multicentre study, we sought to develop and validate a model including genetic and non-genetic factors to predict the daily Fluindione dose requirement in elderly patients in whom VKA dosing is challenging. We prospectively recorded clinical and therapeutic data in 230 Caucasian inpatients mean aged 85 ± 6 years, who had reached international normalized ratio stabilisation (range 2.0–3.0) on Fluindione. In the derivation cohort (n=156), we analysed 13 polymorphisms in seven genes potentially involved in the pharmacological effect or vitamin-K cycle (VKORC1, CYP4F2, EPHX1) and Fluindione metabolism/transport (CYP2C9, CYP2C19, CYP3A5, ABCB1). We built a regression model incorporating non-genetic and genetic data and evaluated the model performances in a separate cohort (n=74).Body-weight, amiodarone intake, VKORC1, CYP4F2, ABCB1 genotypes were retained in the final model, accounting for 31.5% of dose variability. None influence of CYP2C9 was observed. Our final model showed good performances: in 83.3% of the validation cohort patients, the dose was accurately predicted within 5 mg, i.e.the usual step used for adjusting Fluindione dosage. In conclusion, in addition to body-weight and amiodarone-intake, pharmacogenetic factors (VKORC1, CYP4F2, ABCB1) related to the pharmacodynamic effect and transport of Fluindione significantly influenced the dose requirement in elderly patients while CYP2C9 did not. Studies are required to know whether Fluindione could be an alternative VKA in carriers of polymorphic CYP2C9 alleles, hypersensitive to coumarins.

  • Impact of genetic factors (VKORC1, CYP2C9, CYP4F2 and EPHX1) on the anticoagulation response to Fluindione.
    British Journal of Clinical Pharmacology, 2012
    Co-Authors: Karine Lacut, Estelle Ayme-dietrich, Lenaick Gourhant, Elise Poulhazan, Marion Andro, Laurent Becquemont, Dominique Mottier, Grégoire Le Gal, Céline Verstuyft
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * CYP2C9 and VKORC1 genetic variants contribute to differences in patients' responses to anticoagulant coumarin derivatives. Patients carrying the VKORC1 1173TT genotype have a decreased time to the first INR within the therapeutic range and to the first INR >4, and also require lower warfarin maintenance doses. Patients carrying the *2 or *3 CYP2C9 allele have lower maintenance warfarin requirements than those carrying the wild-type allele. The role of CYP2C9 and VKORC1 genetic variants in Fluindione response is unknown. WHAT THIS STUDY ADDS * Our results showed that VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P < 0.0001), on the time required to reach a first INR within the therapeutic range (P < 0.0001), on the time to obtain a first INR value >4 (P= 0.0002) and on the average daily dose of Fluindione during the first period of stability (19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT, P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to Fluindione. This report provides new information on the respective role of common genetic polymorphisms on anticoagulation induced by another class of anticoagulant drugs rather than coumarin derivatives. AIM Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9) and of a key pharmacologic target of vitamin K antagonists, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to coumarin derivatives. The role of these variants in Fluindione response is unknown. Our aim was to assess whether genetic factors contribute to the variability in the response to Fluindione. METHODS Four hundred sixty-five patients with a venous thromboembolic event treated by Fluindione for at least 3 months with a target international normalized ratio (INR) of 2.0 to 3.0 were studied. VKORC1, CYP2C9, CYP4F2 and EPHX1 genotypes were assessed. INR checks, Fluindione doses and bleeding events were collected. RESULTS VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P < 0.0001), on the time required to reach a first INR within the therapeutic range (P < 0.0001) and on the time to obtain a first INR value > 4 (P= 0.0002). The average daily dose of Fluindione during the first period of stability was significantly associated with the VKORC1 genotype: 19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT (P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to Fluindione. CONCLUSIONS VKORC1 genotype strongly affected anticoagulation induced by Fluindione whereas CYP2C9, CYP4F2 and EPHX1 genotypes seemed less determining.

  • Impact of genetic factors (VKORC1, CYP2C9, CYP4F2 and EPHX1) on the anticoagulation response to Fluindione
    British Journal of Clinical Pharmacology, 2012
    Co-Authors: Karine Lacut, Estelle Ayme-dietrich, Lenaick Gourhant, Elise Poulhazan, Marion Andro, Laurent Becquemont, Dominique Mottier, Grégoire Le Gal, Céline Verstuyft
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • CYP2C9 and VKORC1 genetic variants contribute to differences in patients' responses to anticoagulant coumarin derivatives. Patients carrying the VKORC1 1173TT genotype have a decreased time to the first INR within the therapeutic range and to the first INR >4, and also require lower warfarin maintenance doses. Patients carrying the *2 or *3 CYP2C9 allele have lower maintenance warfarin requirements than those carrying the wild-type allele. The role of CYP2C9 and VKORC1 genetic variants in Fluindione response is unknown. WHAT THIS STUDY ADDS • Our results showed that VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P 4 (P= 0.0002) and on the average daily dose of Fluindione during the first period of stability (19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT, P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to Fluindione. This report provides new information on the respective role of common genetic polymorphisms on anticoagulation induced by another class of anticoagulant drugs rather than coumarin derivatives. AIM Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9) and of a key pharmacologic target of vitamin K antagonists, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to coumarin derivatives. The role of these variants in Fluindione response is unknown. Our aim was to assess whether genetic factors contribute to the variability in the response to Fluindione. METHODS Four hundred sixty-five patients with a venous thromboembolic event treated by Fluindione for at least 3 months with a target international normalized ratio (INR) of 2.0 to 3.0 were studied. VKORC1, CYP2C9, CYP4F2 and EPHX1 genotypes were assessed. INR checks, Fluindione doses and bleeding events were collected. RESULTSVKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P 4 (P= 0.0002). The average daily dose of Fluindione during the first period of stability was significantly associated with the VKORC1 genotype: 19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT (P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to Fluindione. CONCLUSIONSVKORC1 genotype strongly affected anticoagulation induced by Fluindione whereas CYP2C9, CYP4F2 and EPHX1 genotypes seemed less determining.

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  • nomogramme d equivalence entre les posologies de Fluindione previscan et de warfarine coumadine pour des patients de 70 ans et plus
    Revue de Médecine Interne, 2015
    Co-Authors: Eric Pautas, Isabelle Peyron, Jean-louis Golmard, Adeline Gouronnec, A. Monti, S. Bouhadiba, C. Badie, Isabelle Gouinthibault, Virginie Siguret
    Abstract:

    Resume Introduction En cas de changement de molecule d’antivitamine K, la warfarine remplacant la Fluindione ou inversement, se pose le probleme de la posologie du nouveau traitement, en l’absence de donnees sur les concordances de doses entre ces antivitamine K. Methodes Nous avons mene une etude prospective sur 288 patients ≥ 70 ans, pour lesquels la Fluindione etait remplacee par la warfarine. Etaient retenus pour l’analyse les patients avec dose d’equilibre connue pour les deux molecules. Resultats Ont ete analyses 82 patients, d’âge moyen 83 ± 6 ans, dont les doses moyennes d’equilibre de Fluindione et de warfarine etaient respectivement de 13,8 ± 6,7 et 3,7 ± 1,7 mg par jour. Un modele de regression lineaire entre ces doses d’equilibre a permis l’elaboration d’un nomogramme de concordance de doses. Conclusion Il s’agit de la premiere etude proposant un nomogramme de concordance de doses entre Fluindione et warfarine, aidant les prescripteurs en cas de substitution d’une molecule pour l’autre.

  • Nomogramme d’équivalence entre les posologies de Fluindione (Préviscan®) et de warfarine (Coumadine®) pour des patients de 70 ans et plus
    Revue de Médecine Interne, 2013
    Co-Authors: Eric Pautas, Isabelle Peyron, Jean-louis Golmard, Adeline Gouronnec, Isabelle Gouin-thibault, A. Monti, S. Bouhadiba, C. Badie, Virginie Siguret
    Abstract:

    Resume Introduction En cas de changement de molecule d’antivitamine K, la warfarine remplacant la Fluindione ou inversement, se pose le probleme de la posologie du nouveau traitement, en l’absence de donnees sur les concordances de doses entre ces antivitamine K. Methodes Nous avons mene une etude prospective sur 288 patients ≥ 70 ans, pour lesquels la Fluindione etait remplacee par la warfarine. Etaient retenus pour l’analyse les patients avec dose d’equilibre connue pour les deux molecules. Resultats Ont ete analyses 82 patients, d’âge moyen 83 ± 6 ans, dont les doses moyennes d’equilibre de Fluindione et de warfarine etaient respectivement de 13,8 ± 6,7 et 3,7 ± 1,7 mg par jour. Un modele de regression lineaire entre ces doses d’equilibre a permis l’elaboration d’un nomogramme de concordance de doses. Conclusion Il s’agit de la premiere etude proposant un nomogramme de concordance de doses entre Fluindione et warfarine, aidant les prescripteurs en cas de substitution d’une molecule pour l’autre.

  • A model predicting Fluindione dose requirement in elderly inpatients including genotypes, body weight, and amiodarone
    Thrombosis and Haemostasis, 2013
    Co-Authors: Caroline Moreau, Eric Pautas, Karine Lacut, Marion Andro, Grégoire Le Gal, Charlotte Duverlie, Celia Berndt, Isabelle Mahé, Joseph Emmerich, Isabelle Peyron
    Abstract:

    Indandione VKAs have been widely used for decades, especially in Eastern Europe and France. Contrary to coumarin VKAs, the relative contribution of individual factors to the indandione-VKA response is poorly known. In the present multicentre study, we sought to develop and validate a model including genetic and non-genetic factors to predict the daily Fluindione dose requirement in elderly patients in whom VKA dosing is challenging. We prospectively recorded clinical and therapeutic data in 230 Caucasian inpatients mean aged 85 ± 6 years, who had reached international normalized ratio stabilisation (range 2.0–3.0) on Fluindione. In the derivation cohort (n=156), we analysed 13 polymorphisms in seven genes potentially involved in the pharmacological effect or vitamin-K cycle (VKORC1, CYP4F2, EPHX1) and Fluindione metabolism/transport (CYP2C9, CYP2C19, CYP3A5, ABCB1). We built a regression model incorporating non-genetic and genetic data and evaluated the model performances in a separate cohort (n=74).Body-weight, amiodarone intake, VKORC1, CYP4F2, ABCB1 genotypes were retained in the final model, accounting for 31.5% of dose variability. None influence of CYP2C9 was observed. Our final model showed good performances: in 83.3% of the validation cohort patients, the dose was accurately predicted within 5 mg, i.e.the usual step used for adjusting Fluindione dosage. In conclusion, in addition to body-weight and amiodarone-intake, pharmacogenetic factors (VKORC1, CYP4F2, ABCB1) related to the pharmacodynamic effect and transport of Fluindione significantly influenced the dose requirement in elderly patients while CYP2C9 did not. Studies are required to know whether Fluindione could be an alternative VKA in carriers of polymorphic CYP2C9 alleles, hypersensitive to coumarins.

  • Sécabilité comparée des comprimés de warfarine et de Fluindione pour les patients âgés et leur entourage
    Geriatrie et psychologie neuropsychiatrie du vieillissement, 2011
    Co-Authors: Eric Pautas, Jérémie Despres, Isabelle Peyron, Jean-louis Golmard, Jennifer Grange, Nelly Koenig, Adeline Gouronnec, Nathalie Mitha, Virginie Siguret, Isabelle Gouin-thibault
    Abstract:

    Un patient âge sous AVK est souvent amene a fractionner des comprimes. Cette etude compare la secabilite des comprimes de warfarine bisecables et de Fluindione quadrisecables. Deux phases, en 2009 puis en 2010, correspondant aux periodes de disponibilite de la Fluindione dans deux formes galeniques. Dans chaque phase, 10 patients d’âge moyen 82 ans, 10 aidants familiaux, 10 infirmieres et 10 medecins coupent des comprimes de warfarine en deux, et de fluidione en deux et en quatre. Le critere primaire de qualite des coupes est l’ecart entre poids des fractions obtenues et poids theorique. Les ecarts sont statistiquement compares selon le groupe et la specialite. Les patients âges sont significativement moins performants que les autres sujets. La warfarine presente une secabilite significativement meilleure que la Fluindione ancienne forme mais cette difference n’apparait plus avec la nouvelle forme de Fluindione. La methodologie ne permet pas de relier la secabilite avec un retentissement clinique (thrombotique ou hemorragique) ou avec un retentissement biologique sur la stabilite des INR. En elargissant la problematique de secabilite a d’autres medicaments, nos resultats incitent cependant a la prudence quant a l’utilisation de fractions de comprimes pour des patients âges.