Pharmacokinetic and Pharmacodynamic Interaction Between Tolvaptan and Warfarin in Healthy Subjects.
OBJECTIVE
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 (Cmax ) 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 Cmax 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.


CONCLUSIONS
Warfarin doses do not need to be altered when co-administered with tolvaptan.
Otsuka Pharmaceutical Development & Commercialization, Inc, Rockville, MD, USA.
Susan E
SE
Shoaf
Otsuka Pharmaceutical Development & Commercialization, Inc, Rockville, MD, USA.
Suresh
S
Mallikaarjun
pharmacodynamics; pharmacokinetics; tolvaptan; warfarin