Efficacy of Tolvaptan Added to Furosemide in Heart Failure Patients with Advanced Kidney Dysfunction: A Pharmacokinetic and Pharmacodynamic Study

Background The pharmacokinetics and pharmacodynamics of tolvaptan (7.5 or 15 mg/day) in combination with furosemide have been investigated in heart failure (HF) patients with normal kidney function but not in HF patients with advanced kidney dysfunction. This study evaluated the efficacy of tolvaptan in HF patients with advanced kidney dysfunction (estimated glomerular filtration rate < 45 mL/min/1.73 m(2)) by conducting a pharmacokinetic and pharmacodynamic study in these patients. Methods Tolvaptan (15 mg once daily) was administered orally for 7 days in combination with furosemide (40-200 mg). Results The peak plasma tolvaptan concentration and area under the plasma concentration-time curve were 379.41 +/- A 149.69 ng/mL and 4,657.38 +/- A 2,741.79 ng center dot h/mL, respectively, in HF patients with advanced kidney dysfunction. These values were greater in HF patients with advanced kidney dysfunction than values reported in the literature for healthy subjects and HF patients with normal kidney function. Urine volume increased and body weight decreased significantly compared with those before tolvaptan administration in HF patients with advanced kidney dysfunction. Conclusion This study showed that adding tolvaptan to furosemide was effective in HF patients with advanced kidney dysfunction. This study also suggests that in these patients 15 mg/day of tolvaptan should be sufficient, and increasing the dose or the frequency of dosing to overcome diuretic resistance should not be necessary, and consideration should be given to using a lower dose and/or prolonging the dosing interval.