The Effect of Increased Free Concentrations of Warfarin Due to Protein-binding Substitution in a Combination of Tolvaptan on the PT-INR.

We previously reported that tolvaptan may influence warfarin pharmacodynamics in vivo; however, the mechanism responsible for this influence was not clear. In this study, we investigated the drug-drug interactions between warfarin and tolvaptan by measuring warfarin blood concentrations in 18 patients who received warfarin therapy and in 24 who received warfarin + tolvaptan therapy. The free warfarin concentrations significantly increased in patients who were also receiving oral tolvaptan (p = 0.04). In vitro albumin-binding experiments showed that the free warfarin concentrations significantly increased with the addition of tolvaptan, in a dose-dependent manner, through albumin-binding substitution (approximately 2.5 times). Both clinical and in vitro data showed that tolvaptan increased the unbound warfarin serum concentration. The prothrombin time-international normalized ratio (PT-INR) tended to increase within 2 weeks when tolvaptan was added at clinically used doses (p = 0.14). Special attention is warranted in cases with a serum tolvaptan concentration of ≥ 125 ng/mL (≥7.5 mg/day) for at least 2 weeks following oral tolvaptan administration.