Details

Autor(en) / Beteiligte

• Gong, Inna Y
• Schwarz, Ute I
• Crown, Natalie
• Dresser, George K
• Lazo-Langner, Alejandro
• Zou, GuangYong
• Roden, Dan M
• Stein, C Michael
• Rodger, Marc
• Wells, Philip S
• Kim, Richard B
• Tirona, Rommel G
• Zanger, Ulrich M.

Titel

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

Ist Teil von

• PloS one, 2011-11, Vol.6 (11), p.e27808

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2011

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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.