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Clinical and genetic determinants of warfarin pharmacokinetics and pharmacodynamics during treatment initiation
Authors
Natalie Crown
George K. Dresser
+10Β more
Inna Y. Gong
Richard B. Kim
Alejandro Lazo-Langner
Dan M. Roden
Marc Rodger
Ute I. Schwarz
C. Michael Stein
Rommel G. Tirona
Philip S. Wells
Guang Yong Zou
Publication date
1 January 2011
Publisher
Scholarship@Western
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Abstract
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. Β© 2011 Gong et al
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oai:doaj.org/article:5923b84df...
Last time updated on 13/10/2017
Scholarship@Western
See this paper in CORE
Go to the repository landing page
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oai:ir.lib.uwo.ca:paedpub-2707
Last time updated on 08/10/2022