Clinical, genetic, and nutritional determinants of INR: role of plasma warfarin and hydroxylated metabolite levels in anticoagulated Mexican patients.

Warfarin dosing guided by INR fails to account for pharmacokinetic/pharmacodynamic variability, leading to suboptimal outcomes; genetic and clinical factors, such as VKORC1 polymorphism and comorbidities, could refine dosing strategies and improve anticoagulation safety.  The aim of this was to identify the main determinants of INR variability in Mexican patients under long-term anticoagulation therapy. For this purpose, patients undergoing warfarin treatment were included and a clinical data was retrieved from medical record. A bioanalytical HPLC method to quantify warfarin (CPW) and its primary metabolite, 7-OH warfarin (CP7OH), in plasma samples was standardized and validated. INR variability was assessed in relation to Charlson comorbidity index (CCI), warfarin dose, drug interactions, vitamin K intake, CPW, CP7OH, metabolic ratio, and VKORC1 1693 polymorphism using univariate and multivariate analysis. The results showed that among 22 patients (64% women) with atrial fibrillation and aortic-mitral valve replacement, warfarin dosing ranged from 8.75 to 55 mg/week (median: 22.5 mg/week). Over half (68.2%) did not achieve the therapeutic INR goal (2.0-3.5). VKORC1 1693 genotype frequencies were GG (36%), GA (50%), and AA (14%), with AA carriers requiring lower maintenance doses (p<0.01). Multivariate analysis incorporating CCI, CPW and CP7OH explained up to 70% of INR variability (p<0.01). Furthermore, currently reported dosing algorithms showed limited accuracy in predicting the appropriate warfarin dose in this cohort. Overall, INR variability depends on plasma warfarin levels, metabolite concentration, and key comorbidities. Therefore, tailored population models are essential to optimize anticoagulation therapy in Mexico. This research highlights the need for more inclusive studies incorporating genetic and clinical factors to refine warfarin dosing and improve outcomes.