An acenocoumarol dosing algorithm using clinical and pharmacogenetic data in Spanish patients with thromboembolic disease
Entity
UAM. Departamento de FarmacologíaPublisher
Public Library of ScienceDate
2012-07-20Citation
10.1371/journal.pone.0041360
Plos One 7.7 (2012): e41360
ISSN
1932-6203 (online)DOI
10.1371/journal.pone.0041360Funded by
This study was supported by a research grant from Instituto de Salud Carlos III (FIS PI070710)Subjects
Acenocoumarol; Algorithms; Cohort Studies; Drug; Pharmacogenetics; Thromboembolism; MedicinaRights
© 2012 Borobia et al.Abstract
Appropriate dosing of coumarins is difficult to establish, due to significant inter-individual variability in the dose required to obtain stable anticoagulation. Several genetic and other clinical factors have been associated with the coumarins dose, and some pharmacogenetic-guided dosing algorithms for warfarin and acenocoumarol have been developed for mixed populations. We recruited 147 patients with thromboembolic disease who were on stable doses and with an international normalized ratio (INR) between 2 and 3. We ascertained the influence of clinical and genetic variables on the stable acenocoumarol dose by multiple linear regression analysis in a derivation cohort (DC; n = 117) and developed an algorithm for dosing that included clinical factors (age, body mass index and concomitant drugs) and genetic variations of VKORC1, CYP2C9, CYP4F2 and APOE. For purposes of comparison, a model including only clinical data was created. The clinical factors explained 22% of the dose variability, which increased to 60.6% when pharmacogenetic information was included (p<0.001); CYP4F2 and APOE variants explained 4.9% of this variability. The mean absolute error of the predicted acenocoumarol dose (mg/week) obtained with the pharmacogenetic algorithm was 3.63 vs. 5.08 mg/week with the clinical algorithm (95% CI: 0.88 to 2.04). In the testing cohort (n = 30), clinical factors explained a mere 7% of the dose variability, compared to 39% explained by the pharmacogenetic algorithm. Considering a more clinically relevant parameter, the pharmacogenetic algorithm correctly predicted the real stable dose in 59.8% of the cases (DC) vs. only 37.6% predicted by the clinical algorithm (95% CI: 10 to 35). Therefore the number of patients needed to genotype to avoid one over- or under-dosing was estimated to be 5
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Google Scholar:Borobia Pérez, Alberto M.
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Lubomirov, Rubin
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Ramírez García, Elena
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Lorenzo, Alicia García De
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Campos, Armando J.
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Muñoz-Romo, Raul
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Fernández Capitán, María del Carmen
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Frías Iniesta, Jesús A.
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Carcas Sansuán, Antonio Javier
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