Anticoagulation Endpoints With Clinical Implementation of Warfarin Pharmacogenetic Dosing in a Real‐World Setting: A Proposal for a New Pharmacogenetic Dosing Approach

Anticoagulation Endpoints With Clinical Implementation of Warfarin Pharmacogenetic Dosing in a Real‐World Setting: A Proposal for a New Pharmacogenetic Dosing Approach

Clinical Pharmacology & Therapeutics, December 2016

28032893

MJ Arwood, J Deng, K Drozda, O Pugach, EA Nutescu, S Schmidt, JD Duarte, LH Cavallari

Achieving therapeutic anticoagulation efficiently with warfarin is important to reduce thrombotic and bleeding risks and is influenced by genotype. Utilizing data from a diverse population of 257 patients who received VKORC1 and CYP2C9 genotype-guided warfarin dosing, we aimed to examine genotype-associated differences in anticoagulation endpoints and derive a novel pharmacogenetic nomogram to more optimally dose warfarin. We observed significant differences across patients with 0, 1, or ≥2 reduced-function VKORC1 or CYP2C9 alleles, respectively, in time to achieve therapeutic international normalized ratio (INR) (7.8 ± 5.8, 7.2 ± 4.7, and 5.4 ± 4.6 days, P = 0.0004) and mean percentage of time in therapeutic range in the first 28 days (22.2, 27.8, and 32.2%, P = 0.0127) with use of existing pharmacogenetic algorithms. These data suggest that more aggressive dosing is necessary for patients with 0 to 1 VKORC1/CYP2C9 variants to more efficiently achieve therapeutic anticoagulation. Herein, we provide a novel kinetic/pharmacodynamic-derived dosing nomogram optimized for a heterogeneous patient population.