Unknown

Dataset Information

0

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

altmetric image

Publications

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]

Similar Datasets

| S-EPMC3894627 | biostudies-literature
| S-EPMC4137827 | biostudies-literature
| S-EPMC6182459 | biostudies-literature
| S-EPMC5315738 | biostudies-literature
| S-EPMC8613110 | biostudies-literature
| S-EPMC5814521 | biostudies-literature
| S-EPMC5702344 | biostudies-literature
| S-EPMC4282310 | biostudies-literature
| S-EPMC3489518 | biostudies-literature
| S-EPMC3248257 | biostudies-literature