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

• Published in: Clinical pharmacology and therapeutics 2017-05, Vol.101 (5), p.675-683
• Main Authors: Arwood, MJ, Deng, J, Drozda, K, Pugach, O, Nutescu, EA, Schmidt, S, Duarte, JD, Cavallari, LH
• Format: Article
• Language: English
• Subjects: Algorithms; Alleles; Anticoagulants - administration & dosage; Anticoagulants - pharmacokinetics; Anticoagulants - therapeutic use; Cytochrome P-450 CYP2C9 - genetics; Dose-Response Relationship, Drug; Endpoint Determination; Female; Genotype; Humans; Male; Middle Aged; Pharmacogenetics; Vitamin K Epoxide Reductases - genetics; Warfarin - administration & dosage; Warfarin - pharmacokinetics; Warfarin - therapeutic use
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1002/cpt.558

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.