Abstract Proceedings of the 2014 Thrombosis and Hemostasis Summit of North America
Authors: Luis Bermudez Bosch, Giselle Rivera, Iadelisse Cruz, Marcos Felici, Alga Ramos, Jorge Duconge, Luis Bermudez, Giselle Rivera-Miranda, Aaron Dush, Abby Williams, Michael Fearon, Paul Wegener, Scott Grosse, Rodney Presley, Hussain Yusuf, Lisa Richardson, Alpesh Amin, Fatima Khan, Yvonne Datta
Journal: American Journal of Hematology (2014)

Background: Although warfarin is the standard-of-care in oral anticoagulation, its clinical use is challenging due to significant inter-individual dosing variability.Several investigations have been conducted to predict effective warfarin doses in multiple populations using pharmacogenetic-guided algorithms, but not in Caribbean Hispanics.A gap exists in the literature with respect to the pharmacogenetics of warfarin in persons of Hispanic ancestry.Moreover, most of these studies are mainly focused on maintenance doses but the information is scarce concerning dosing during warfarin initiation.Objectives: This study was aimed at predicting individual warfarin doses in Puerto Rican patients commencing anticoagulation therapy, using a pharmacogenetic algorithm and pharmacokinetic-pharmacodynamic (PK-PD) simulations.The derivation of a pharmacogenetic dose-refinement algorithm to predict warfarin dosing after 3rd day of therapy was also aimed.Methods: A retrospective, observational, pharmacogenetic study was conducted in 138 male patients on warfarin from the VA Caribbean Healthcare System (VACHS) in San Juan, Puerto Rico, who constituted the derivation cohort.Genotyping of participants for common CYP2C9 and VKORC1 genetic variants was performed using the Tag-It™ Mutation Detection assay.A stepwise multiple linear regression analyses were performed using log-transformed warfarin doses and combining genotyping with other relevant clinical and demographic variables, all available at the initiation of therapy.Final algorithm for dose initiation was also based on estimated warfarin half-lives according to individual CYP2C9 genotypes.Predicted initial doses were fractioned over the first 3 days to reduce risk of overshooting the target INR range.Predictability was assessed by using WinNonlin® one compartment/indirect response PK-PD simulations.Results: A pharmacogenetic algorithm for 3-day initial dosing that includes preemptive genotypes, target INR, age, BSA, co-medications, admixture, co-morbidities and vitamin K intake was derived and explained ~half of the dose variability in the study cohort (R2=0.48).Individual genotype-adjusted PK-PD simulations of INR responses fall within the target range in 92% of cases, confirming good predictability.A pharmacogenetic-guided revision dose algorithm after 3rd dose was also developed and accounted for 76% of observed variability, after incorporating lnINR at day 4 and initial doses for days 1-3.This algorithm in Puerto Ricans provided consistently better dose prediction than the IWPC algorithm, particularly for patients who required low or intermediate-doses (≤7mg/day).Absolute difference between actual and predicted doses was <1mg/day (i.e., within 20% of ideal dose) in 80% of participants.Study limitations include gender, single-center and issues related to its observational and retrospective nature.Conclusions: Pharmacogenetic algorithms that incorporate clinical, INR measurement, admixture and genetic factors to predict initial dosing over the first week of therapy were developed and tested in a cohort of Puerto Rican patients on warfarin.The adoption of a pharmacogenetic-driven approach to predict initial doses in Puerto Rican patients commencing warfarin therapy, along with a doserefinement algorithm for warfarin dose adjustments after 3rd day of therapy, is expected to improve the safety of warfarin initiation and subsequent clinical management of high-risk patients at the VACHS anticoagulation clinic in Puerto Rico.Further studies are warranted to validate these findings and determine superiority of the pharmacogenetic approach over current practice.