A multicenter, open-label, dose-ranging study to exploratively evaluate the efficacy, safety, and dose-response of tolvaptan in patients with decompensated liver cirrhosis

Objectives We examined the efficacy of tolvaptan, an orally effective nonpeptide vasopressin V-2 receptor antagonist, in a Japanese clinical study in patients with intractable ascites and/or lower limb edema associated with decompensated liver cirrhosis. Methods Tolvaptan was orally administrated at titrated doses of 15, 30, and 60 mg once daily after breakfast for 3 days at each dose to 18 liver cirrhosis patients with persistent ascites and/or lower limb edema despite receiving oral furosemide at 40 mg/day or higher. Results Decreased body weight and abdominal circumference and improvement of ascites and edema were observed following tolvaptan administration beginning from 15 mg. Composite ascites/edema improvement rate was 88.2% at individual maximum doses and 64.7, 80.0, and 90.9%, respectively, after 3-day administration at 15, 30, and 60 mg. Changes in body weight after 3-day administration at 15, 30, and 60 mg were -1.6 +/- 0.9, -2.6 +/- 1.2, and -3.4 +/- 2.1 kg (mean +/- SD), respectively, and decreases of 1 kg or more were seen from day 2 (24 h after first dosing). Changes in abdominal circumference ranged from -2.8 to -6.0 cm. Cumulative 24-h urine volumes after 3-day administration at 15, 30, and 60 mg were, respectively, 3240.3 +/- 1014.5, 3943.3 +/- 1060.6, and 4537.4 +/- 1621.3 mL/day (mean +/- SD). Urine osmolarity was markedly decreased and remained decreased until the end of treatment. Conclusion Tolvaptan dose-dependently decreased body weight and abdominal circumference and improved ascites and edema beginning from 15 mg, demonstrating a potent aquaretic effect.