1. A new pharmacogenetic algorithm to predict the most appropriate dosage of acenocoumarol for stable anticoagulation in a mixed Spanish population
- Author
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Xando Díaz-Villamarín, Hoi Y. Tong, Luis Javier Martinez-Gonzalez, María Jesús Blanco Bañares, R. Lubomirov, Cristina Lucía Dávila-Fajardo, Laura María Perea León, José Cabeza Barrera, Alberto M. Borobia, Antonio J. Carcas, Carmen Fernández-Capitán, UAM. Departamento de Medicina, UAM. Departamento de Farmacología, Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ), PGX-ACE Investigators Group, [Tong,HY] Department of Clinical Pharmacology, La Paz University Hospital, IdiPAZ, Madrid, Spain. [Dávila-Fajardo,CL, Perea León,LM, Cabeza Barrera,J] Department of Clinical Pharmacy, San Cecilio University Hospital, Institute for Biomedical Research, Ibs, Granada, Spain. [Borobia,AM] Department of Clinical Pharmacology, La Paz University Hospital, IdiPAZ, Madrid, Spain, Department of Pharmacology, School of Medicine, Autonomous University of Madrid, IdiPAZ, Madrid, Spain. [Martínez-González,LJ] Genomics Unit, Centre for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Andalusian Regional Government, Health Sciences Technology Park, PTS, Granada, Spain. [Lubomirov,R] Department of Pharmacology, School of Medicine, Autonomous University of Madrid, IdiPAZ, Madrid, Spain. [Blanco Bañares,MJ] Department of Hematology, La Paz University Hospital, Madrid, Spain. [Fernández-Capitán,C] Department of Internal Medicine, La Paz University Hospital, IdiPAZ, Madrid, Spain. [Carcas,AJ] Department of Clinical Pharmacology, La Paz University Hospital, IdiPAZ, Madrid, Spain, Department of Pharmacology, School of Medicine, Autonomous University of Madrid, IdiPAZ, Madrid, Spain., and This study was funded by a grant from the Spanish Ministry of Health and Social Policy (Instituto de Salud Carlos III, PI07/0710) and the Andalusian Regional Ministry of Health (Progress and Health Foundation, PI-0717-2013).
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0301 basic medicine ,Male ,Heredity ,CYP4F2 ,España ,lcsh:Medicine ,Named Groups::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings] ,030204 cardiovascular system & hematology ,Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Benzopyrans::Coumarins::4-Hydroxycoumarins::Acenocoumarol [Medical Subject Headings] ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,0302 clinical medicine ,Quality of life ,Coumarins ,Atrial Fibrillation ,Medicine and Health Sciences ,Medicine ,lcsh:Science ,Geographicals::Geographic Locations::Europe::Spain [Medical Subject Headings] ,Acenocoumarol ,Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Hematologic Agents::Anticoagulants [Medical Subject Headings] ,Multidisciplinary ,Algoritmos ,Pharmaceutics ,Applied Mathematics ,Simulation and Modeling ,Pharmacogenetic ,Farmacogenética ,Middle Aged ,Farmacia ,Humanos ,Chemistry ,Genetic Mapping ,Cohort ,Physical Sciences ,Female ,VKORC1 ,Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Pharmacology::Pharmacogenetics [Medical Subject Headings] ,Algorithm ,Arrhythmia ,Algorithms ,medicine.drug ,Research Article ,Phenomena and Processes::Mathematical Concepts::Algorithms [Medical Subject Headings] ,Medicina ,Cardiology ,Check Tags::Male [Medical Subject Headings] ,Variant Genotypes ,Research and Analysis Methods ,03 medical and health sciences ,Dose Prediction Methods ,Linear regression ,Genetics ,A new algorithm ,Humans ,Named Groups::Persons::Age Groups::Adult::Aged [Medical Subject Headings] ,Acenocoumarol dosage ,CYP2C9 ,Aged ,Pharmacology ,Clinical Genetics ,business.industry ,lcsh:R ,Chemical Compounds ,Biology and Life Sciences ,Anticoagulants ,Human Genetics ,Appropriate acenocoumarol dosag ,Stable anticoagulation ,Acenocumarol ,Anticoagulantes ,030104 developmental biology ,Check Tags::Female [Medical Subject Headings] ,Pharmacogenetics ,Spain ,lcsh:Q ,business ,Mathematics - Abstract
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.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 (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., This study was funded by a grant from the Spanish Ministry of Health and Social Policy (Instituto de Salud Carlos III, PI07/0710) and the Andalusian Regional Ministry of Health (Progress and Health Foundation, PI-0717-2013)
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- 2016