title: Anticoagulation endpoints with clinical implementation of warfarin pharmacogenetic dosing in a real-world setting: A proposal for a new pharmacogenetic dosing approach.
abstract: 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.
authors.affiliation: Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, Florida, USA.|Center for Pharmacogenomics, University of Florida, Gainesville, Florida, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Arwood
authors.affiliation: Center for Pharmacometrics and Systems Pharmacology, University of Florida at Lake Nona, Orlando, Florida, USA.
authors.forename: J
authors.initials: J
authors.lastname: Deng
authors.affiliation: Genomics and Targeted Therapy, Office of Clinical Pharmacology, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: K
authors.initials: K
authors.lastname: Drozda
authors.affiliation: Institute for Health Research and Policy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: O
authors.initials: O
authors.lastname: Pugach
authors.affiliation: Personalized Medicine Program, University of Illinois at Chicago, Chicago, Illinois, USA.|Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago, Chicago, Illinois, USA.|Center for Pharmacoepidemiology and Pharmacoeconomic Research, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Nutescu
authors.affiliation: Center for Pharmacometrics and Systems Pharmacology, University of Florida at Lake Nona, Orlando, Florida, USA.
authors.forename: S
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, Florida, USA.|Center for Pharmacogenomics, University of Florida, Gainesville, Florida, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Duarte
authors.affiliation: Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, Florida, USA.|Center for Pharmacogenomics, University of Florida, Gainesville, Florida, USA.
authors.forename: L H
authors.initials: LH
authors.lastname: Cavallari
mesh_terms: D000465:Algorithms; D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases