Trial reportClinical pharmacokinetics2012
A pharmacokinetic-pharmacodynamic model for predicting the impact of CYP2C9 and VKORC1 polymorphisms on fluindione and acenocoumarol during induction therapy.
Trial report in Clinical pharmacokinetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 28 citations in OpenAlex.
- Pharmacogenetic studies with oral anticoagulants. Genome-wide association studies in vitamin K antagonist and direct oral anticoagulants.Oncotarget · 2018Review
- Theory-based pharmacokinetics and pharmacodynamics of S- and R-warfarin and effects on international normalized ratio: influence of body size, composition and genotype in cardiac surgery patients.British journal of clinical pharmacology · 2017Article
- Polymorphisms of VKORC1 and CYP2C9 are associated with warfarin sensitivity in Chinese population.Therapeutics and clinical risk management · 2017Article
- Dosing Recommendations for Concomitant Medications During 3D Anti-HCV Therapy.Clinical pharmacokinetics · 2016Review
- Use of vitamin K antagonist therapy in geriatrics: a French national survey from the French Society of Geriatrics and Gerontology (SFGG).Drugs & aging · 2013Article
- Quantitative prediction of the impact of drug interactions and genetic polymorphisms on cytochrome P450 2C9 substrate exposure.Clinical pharmacokinetics · 2013Article
- Pharmacokinetic and pharmacodynamic variability of fluindione in octogenarians.Clinical pharmacology and therapeutics · 2012Article
- Article
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Authors and funding
9 authors at 7 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND AND
objectiveVitamin 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.
methodsFluindione 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.
resultsA 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.
conclusionDuring 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.
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