A New Pharmacogenetic Algorithm to Predict the Most Appropriate Dosage of Acenocoumarol for Stable Anticoagulation in a Mixed Spanish Population

• Published in: PLOS ONE Vol. 11; no. 3; p. e0150456
• Main Authors: Cabeza Barrera, José, Dávila-Fajardo, Cristina Lucía, Tong, Hoi Y, Perea León, Laura María, Martínez-González, Luis Javier, Blanco Bañares, María J, Fernández-Capitán, Carmen, Borobia, Alberto M, Lubomirov, Rubin, Díaz-Villamarín, Xando, Carcas, Antonio J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science (PLoS) 15.03.2016; Public Library of Science
• Subjects: A new algorithm; Acenocoumarol; Acenocoumarol - administration & dosage; Acenocoumarol - pharmacology; Acenocoumarol dosage; Aged; Algorithms; Amiodarone; Analysis; Anticoagulants; Anticoagulants - administration & dosage; Anticoagulants - pharmacology; Appropriate acenocoumarol dosag; Biology and Life Sciences; Biomedical research; Cardiac arrhythmia; Dependent variables; Dosage; Drug dosages; Embolisms; Farmacia; Female; Fibrillation; Genetic algorithms; Genetic polymorphisms; Genomics; Genotypes; Genotyping; Health care; Humans; Independent variables; Male; Medical Subject Headings::Check Tags::Female; Medical Subject Headings::Check Tags::Male; Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Hematologic Agents::Anticoagulants; Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Benzopyrans::Coumarins::4-Hydroxycoumarins::Acenocoumarol; Medical Subject Headings::Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Pharmacology::Pharmacogenetics; Medical Subject Headings::Geographicals::Geographic Locations::Europe::Spain; Medical Subject Headings::Named Groups::Persons::Age Groups::Adult::Aged; Medical Subject Headings::Named Groups::Persons::Age Groups::Adult::Middle Aged; Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans; Medical Subject Headings::Phenomena and Processes::Mathematical Concepts::Algorithms; Medicina; Medicine; Medicine and Health Sciences; Middle Aged; Patients; Pharmacodynamics; Pharmacogenetic; Pharmacogenetics; Pharmacokinetics; Pharmacology; Pharmacy; Physical Sciences; Q; Quality of life; R; Research and Analysis Methods; Research Article; Science; Spain; Stable anticoagulation; Thromboembolism; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0150456

There is a strong association between genetic polymorphisms and the acenocoumarol dosage requirements. Genotyping the polymorphisms involved in the pharmacokinetics and pharmacodynamics of acenocoumarol before starting anticoagulant therapy would result in a better quality of life and a more efficient use of healthcare resources. The objective of this study is to develop a new algorithm that includes clinical and genetic variables to predict the most appropriate acenocoumarol dosage for stable anticoagulation in a wide range of patients. We recruited 685 patients from 2 Spanish hospitals and 1 primary healthcare center. We randomly chose 80% of the patients (n = 556), considering an equitable distribution of genotypes to form the generation cohort. The remaining 20% (n = 129) formed the validation cohort. Multiple linear regression was used to generate the algorithm using the acenocoumarol stable dosage as the dependent variable and the clinical and genotypic variables as the independent variables. The variables included in the algorithm were age, weight, amiodarone use, enzyme inducer status, international normalized ratio target range and the presence of CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), VKORC1 (rs9923231) and CYP4F2 (rs2108622). The coefficient of determination (R2) explained by the algorithm was 52.8% in the generation cohort and 64% in the validation cohort. The following R2 values were evaluated by pathology: atrial fibrillation, 57.4%; valve replacement, 56.3%; and venous thromboembolic disease, 51.5%. When the patients were classified into 3 dosage groups according to the stable dosage (<11 mg/week, 11-21 mg/week, >21 mg/week), the percentage of correctly classified patients was higher in the intermediate group, whereas differences between pharmacogenetic and clinical algorithms increased in the extreme dosage groups. Our algorithm could improve acenocoumarol dosage selection for patients who will begin treatment with this drug, especially in extreme-dosage patients. The predictability of the pharmacogenetic algorithm did not vary significantly between diseases.