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Pharmacokinetic and Pharmacodynamic Interaction Between Tolvaptan and Warfarin in Healthy Subjects
Author(s) -
Shoaf Susan E.,
Mallikaarjun Suresh
Publication year - 2012
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1177/2160763x12439702
Subject(s) - tolvaptan , warfarin , medicine , partial thromboplastin time , pharmacokinetics , pharmacodynamics , prothrombin time , pharmacology , placebo , crossover study , heart failure , atrial fibrillation , coagulation , alternative medicine , pathology
Purpose : Tolvaptan, a nonpeptide V2 receptor antagonist approved in Japan and in the United States, is likely to be co‐administered with warfarin in patients with heart failure (HF). Therefore, the effect of tolvaptan on warfarin pharmacokinetics, pharmacodynamics, and protein binding was evaluated. Methods : An open‐label, randomized, 2‐period crossover trial was conducted involving healthy subjects (N = 24) administered 25 mg warfarin sodium on day 4 of a 13‐day regimen of either 60 mg once daily tolvaptan or matching placebo. Blood samples were taken over 240 hours postdose for analysis of tolvaptan, R‐ and S‐warfarin, and 7‐ and 10‐hydroxywarfarin concentrations and for the measurement of activated partial thromboplastin time, prothrombin time, and international normalized ratio. Results : For S‐warfarin, the geometric mean ratios (warfarin+tolvaptan/warfarin alone; 90% confidence interval) for maximum plasma concentration (C max ) and area under the concentration‐time curve from time 0 to infinity (AUC ∞ ) were 1.09 (1.05, 1.12) and 1.09 (1.04, 1.13), respectively. Corresponding ratios for R‐warfarin were 1.06 (1.02, 1.09) and 1.05 (1.01, 1.11), respectively. No changes were observed in 7‐ or 10‐hydroxywarfarin C max or AUC ∞ values, prothrombin time, activated partial thromboplastin time, and international normalized ratio. The protein binding of racemic warfarin and tolvaptan was not significantly altered by the presence of the other compound. Conclusion : Warfarin doses do not need to be altered when co‐administered with tolvaptan.