title: A pharmacokinetic-pharmacodynamic model for predicting the impact of CYP2C9 and VKORC1 polymorphisms on fluindione and acenocoumarol during induction therapy.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Service de Gntique Molculaire, Pharmacogntique et Hormonologie, Hpital Bictre, Assistance Publique-Hpitaux de Paris, Le Kremlin Bictre, France. celine.verstuyft@bct.aphp.fr
authors.forename: Céline
authors.initials: C
authors.lastname: Verstuyft
authors.forename: Xavier
authors.initials: X
authors.lastname: Delavenne
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rousseau
authors.forename: Annie
authors.initials: A
authors.lastname: Robert
authors.forename: Michel
authors.initials: M
authors.lastname: Tod
authors.forename: Bertrand
authors.initials: B
authors.lastname: Diquet
authors.forename: Martine
authors.initials: M
authors.lastname: Lebot
authors.forename: Patrice
authors.initials: P
authors.lastname: Jaillon
authors.forename: Laurent
authors.initials: L
authors.lastname: Becquemont
mesh_terms: D000074:Acenocoumarol / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001835:Body Weight; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D010630:Phenindione / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D011110:Polymorphism, Genetic; D012907:Smoking / Q000378:metabolism; D064417:Vitamin K Epoxide Reductases
chemical_list: D000925:Anticoagulants; D010630:Phenindione; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; C017673:fluindione; D000074:Acenocoumarol