title: A New Pharmacogenetic Algorithm to Predict the Most Appropriate Dosage of Acenocoumarol for Stable Anticoagulation in a Mixed Spanish Population.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology, La Paz University Hospital, IdiPAZ, Madrid, Spain.
authors.forename: Hoi Y
authors.initials: HY
authors.lastname: Tong
authors.affiliation: Department of Clinical Pharmacy, San Cecilio University Hospital, Institute for Biomedical Research, Ibs, Granada, Spain.
authors.forename: Cristina Lucía
authors.initials: CL
authors.lastname: Dávila-Fajardo
authors.affiliation: Department of Clinical Pharmacology, La Paz University Hospital, IdiPAZ, Madrid, Spain.|Department of Pharmacology, School of Medicine, Autonomous University of Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Borobia
authors.affiliation: Genomics Unit, Centre for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Andalusian Regional Government, Health Sciences Technology Park, PTS, Granada, Spain.
authors.forename: Luis Javier
authors.initials: LJ
authors.lastname: Martínez-González
authors.affiliation: Department of Pharmacology, School of Medicine, Autonomous University of Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Rubin
authors.initials: R
authors.lastname: Lubomirov
authors.affiliation: Department of Clinical Pharmacy, San Cecilio University Hospital, Institute for Biomedical Research, Ibs, Granada, Spain.
authors.forename: Laura María
authors.initials: LM
authors.lastname: Perea León
authors.affiliation: Department of Hematology, La Paz University Hospital, Madrid, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Blanco Bañares
authors.affiliation: Department of Clinical Pharmacy, San Cecilio University Hospital, Institute for Biomedical Research, Ibs, Granada, Spain.
authors.forename: Xando
authors.initials: X
authors.lastname: Díaz-Villamarín
authors.affiliation: Department of Internal Medicine, La Paz University Hospital, IdiPAZ, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Fernández-Capitán
authors.affiliation: Department of Clinical Pharmacy, San Cecilio University Hospital, Institute for Biomedical Research, Ibs, Granada, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Cabeza Barrera
authors.affiliation: Department of Clinical Pharmacology, La Paz University Hospital, IdiPAZ, Madrid, Spain.|Department of Pharmacology, School of Medicine, Autonomous University of Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Carcas
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage* / Q000494:pharmacology; D000368:Aged; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D013030:Spain
chemical_list: D000925:Anticoagulants; D000074:Acenocoumarol