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

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 efficie...

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Vydané v:PLOS ONE Ročník 11; číslo 3; s. e0150456
Hlavní autori: 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
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Public Library of Science (PLoS) 15.03.2016
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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.
AbstractList 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.
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 (R.sup.2) explained by the algorithm was 52.8% in the generation cohort and 64% in the validation cohort. The following R.sup.2 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.
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 (R 2 ) explained by the algorithm was 52.8% in the generation cohort and 64% in the validation cohort. The following R 2 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.
Audience Academic
Author Luis Javier Martinez-Gonzalez
Carmen Fernández-Capitán
Alberto M. Borobia
Cristina Lucía Dávila-Fajardo
Hoi Y. Tong
Antonio J. Carcas
Xando Díaz-Villamarín
R. Lubomirov
María Jesús Blanco Bañares
Laura María Perea León
José Cabeza Barrera
AuthorAffiliation 2 Department of Clinical Pharmacy, San Cecilio University Hospital, Institute for Biomedical Research, Ibs, Granada, Spain
4 Department of Pharmacology, School of Medicine, Autonomous University of Madrid, IdiPAZ, Madrid, Spain
3 Genomics Unit, Centre for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Andalusian Regional Government, Health Sciences Technology Park, PTS, Granada, Spain
6 Department of Internal Medicine, La Paz University Hospital, IdiPAZ, Madrid, Spain
National Cancer Center, JAPAN
1 Department of Clinical Pharmacology, La Paz University Hospital, IdiPAZ, Madrid, Spain
5 Department of Hematology, La Paz University Hospital, Madrid, Spain
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BackLink https://cir.nii.ac.jp/crid/1871146592944746752$$DView record in CiNii
https://www.ncbi.nlm.nih.gov/pubmed/26977927$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Contributor 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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[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
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Copyright COPYRIGHT 2016 Public Library of Science
2016 Tong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
2016 Tong et al 2016 Tong et al
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– notice: 2016 Tong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
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Competing Interests: The authors have declared that no competing interests exist.
Membership of the PGX-ACE Investigators Group is listed in S1 Appendix.
Conceived and designed the experiments: HYT CDF AMB LMG AJC. Performed the experiments: HYT CDF AMB LMG RL LPL MBB XDV CFC JCB AJC and the PGX-ACE Investigators Group. Analyzed the data: HYT CDF AMB RL AJC. Contributed reagents/materials/analysis tools: HYT CDF AMB LPL MBB XDV JCB AJC. Wrote the paper: HYT CDF AMB LMG RL LPL MBB XDV CFC JCB AJC.
ORCID 0000-0003-2202-0662
0000-0002-8584-3263
0000-0003-0849-9902
0000-0003-1823-4174
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Snippet There is a strong association between genetic polymorphisms and the acenocoumarol dosage requirements. Genotyping the polymorphisms involved in the...
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SubjectTerms 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
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Title A New Pharmacogenetic Algorithm to Predict the Most Appropriate Dosage of Acenocoumarol for Stable Anticoagulation in a Mixed Spanish Population
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