Dan Roden
Faculty Member
Last active: 2/8/2016

Clinical and genetic determinants of warfarin pharmacokinetics and pharmacodynamics during treatment initiation.

Gong IY, Schwarz UI, Crown N, Dresser GK, Lazo-Langner A, Zou G, Roden DM, Stein CM, Rodger M, Wells PS, Kim RB, Tirona RG
PLoS One. 2011 6 (11): e27808

PMID: 22114699 · PMCID: PMC3218053 · DOI:10.1371/journal.pone.0027808

Variable warfarin response during treatment initiation poses a significant challenge to providing optimal anticoagulation therapy. We investigated the determinants of initial warfarin response in a cohort of 167 patients. During the first nine days of treatment with pharmacogenetics-guided dosing, S-warfarin plasma levels and international normalized ratio were obtained to serve as inputs to a pharmacokinetic-pharmacodynamic (PK-PD) model. Individual PK (S-warfarin clearance) and PD (I(max)) parameter values were estimated. Regression analysis demonstrated that CYP2C9 genotype, kidney function, and gender were independent determinants of S-warfarin clearance. The values for I(max) were dependent on VKORC1 and CYP4F2 genotypes, vitamin K status (as measured by plasma concentrations of proteins induced by vitamin K absence, PIVKA-II) and weight. Importantly, indication for warfarin was a major independent determinant of I(max) during initiation, where PD sensitivity was greater in atrial fibrillation than venous thromboembolism. To demonstrate the utility of the global PK-PD model, we compared the predicted initial anticoagulation responses with previously established warfarin dosing algorithms. These insights and modeling approaches have application to personalized warfarin therapy.

MeSH Terms (25)

Adult Aged Aged, 80 and over Algorithms Anticoagulants Aryl Hydrocarbon Hydroxylases Blood Coagulation Cytochrome P-450 CYP2C9 Cytochrome P-450 Enzyme System Cytochrome P450 Family 4 Dose-Response Relationship, Drug Female Gene Frequency Genotype Humans Kidney Function Tests Male Middle Aged Mixed Function Oxygenases Prospective Studies Tissue Distribution Vitamin K Vitamin K Epoxide Reductases Warfarin Young Adult

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