RESUMEN
: Coumadin oral anticoagulants are widely used in multiple clinical scenarios. Their narrow therapeutic range and a dosing strategy based on 'a posteriori' algorithms, pose them as an interesting group for prediction modelling research. Extensive literature explaining the association between clinical and genetic variables with the dose of warfarin have been published. Limited information exists regarding these factors and acenocoumarol dosing. The aim of the study is to explain through clinical/genetic variables, the weekly dose of acenocoumarol necessary for achieving stable anticoagulation status. We performed a cross-sectional study enrolling adults under treatment with acenocoumarol with at least three consecutive INRs between 2 and 3. To explain the association between demographic, clinical and genotype data (VKORC1, CYP2C9 and CYP4F2) and the mean weekly dose of acenocoumarol, we performed a multiple linear regression model. In our cohort, a higher age, the presence of atrial fibrillation, chronic renal failure and VKORC1 haplotype A were associated with a lower mean weekly dose of acenocoumarol. On the other side, a higher weight was associated with a higher weekly dose. Amongst anticoagulated adult patients, VKORC1 genotype and baseline clinical factors can explain acenocoumarol dosing, and therefore, help clinicians while deciding the initial anticoagulant dose.
Asunto(s)
Acenocumarol/uso terapéutico , Anticoagulantes/uso terapéutico , Acenocumarol/administración & dosificación , Anciano , Anciano de 80 o más Años , Anticoagulantes/administración & dosificación , Estudios Transversales , Citocromo P-450 CYP2C9/genética , Familia 4 del Citocromo P450/genética , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Farmacogenómica , Vitamina K Epóxido Reductasas/genéticaRESUMEN
5-Fluorouracil (5-FU) has long been used for the treatment of gastrointestinal tumors harboring interindividual variability in both the pharmacokinetic and the pharmacogenetic profiles, which in turn may lead to life-threatening toxicities. We carried out a prospective cohort study of adult patients initiating treatment with 5-FU between 2013 and 2015. Primary exposures of interest were the methylenetetrahydrofolate reductase single nucleotide polymorphism in exons 4 and 7 and 5'-untranslated region-thymidylate synthase VNTR genotypes, in addition to baseline clinical and demographic variables. The primary outcome was the time to the occurrence of severe toxicity. We used a Cox regression model to evaluate patients' survival and toxicity experience and its association with baseline characteristics and a priori determined genetic polymorphisms. A total of 197 patients were included, 40.1% developed severe toxicity during follow-up. Variables that were significantly associated with developing severe toxicity were the European Organization for Research and Treatment of Cancer functional score [hazard ratio (HR): 0.98; 95% confidence interval (CI): 0.97-0.99]; type of tumor [anus (HR: 2.50; 95% CI: 1.07-5.82), head and neck/esophagus/stomach (HR: 2.95; 95% CI: 1.64-5.33)] and 5-FU continuous infusion regimens over 4-5 days (HR: 9.35; 95% CI: 2.68-32.59). We found a significant association between baseline functional status, type of tumor and continuous infusion regimens and the occurrence of severe toxicity during the follow-up of patients receiving 5-FU. No association was found with the genotypic variants evaluated. Future validation and modeling of an everyday easy-to-use score to predict toxicity among these subgroup of patients remains warranted.