Dataset Information

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

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.

SUBMITTER: Gong IY

PROVIDER: S-EPMC3218053 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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

Gong Inna Y IY Schwarz Ute I UI Crown Natalie N Dresser George K GK Lazo-Langner Alejandro A Zou GuangYong G Roden Dan M DM Stein C Michael CM Rodger Marc M Wells Philip S PS Kim Richard B RB Tirona Rommel G RG

PloS one 20111116 11

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)) par ...[more]

PMID: 22114699

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Dataset Information

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

Publications

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

Similar Datasets

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