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 (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. CONCLUSION:Warfarin doses do not need to be altered when co-administered with tolvaptan. 2012 American College of Clinical Pharmacology.
RCT Entities:
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 (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. CONCLUSION:Warfarin doses do not need to be altered when co-administered with tolvaptan. 2012 American College of Clinical Pharmacology.
Authors: Merrie Mosedale; J Scott Eaddy; O Joseph Trask; Natalie S Holman; Kristina K Wolf; Edward LeCluyse; Brenton R Ware; Salman R Khetani; Jingtao Lu; William J Brock; Sharin E Roth; Paul B Watkins Journal: Toxicol Sci Date: 2018-01-01 Impact factor: 4.849