Single- and multiple-dose studies were conducted to assess the pharmacokinetics, pharmacodynamics and safety of tolvaptan in healthy Japanese subjects.

All studies were single-center, randomized, placebo-controlled, single-blind or double-blind. In an ascending single-dose study, subjects were given a single oral dose of 15–120 mg tolvaptan or placebo. In multiple-dose studies, subjects were given 30, 60, 90 or 120 mg tolvaptan or placebo once daily for 7 days.

After a single dose of 15–120 mg tolvaptan, the maximum plasma concentration (C_max) and the area under the plasma concentration-time curve from zero to time t (AUC_t) increased dose-dependently, and increases in AUC_t were dose-proportional. Increases in 24-hour cumulative urine volume were dose- and AUC_24hr-dependent. Urine excretion rates reached a maximum within 2–4 h after dosing. The maximal urine excretion rates increased dose-dependently, and appeared to reach a plateau at doses≥ 60 mg. A decrease in urine osmolality and an increase in free water clearance indicated an aquaretic effect of tolvaptan. Serum sodium concentrations were increased by tolvaptan and were higher than that with placebo, even 24 h after dosing, while serum potassium concentrations were unchanged. No tolvaptan accumulation was found after multiple dosing for 7 days. Although 24-hour cumulative urine volume following multiple dosing slightly decreased, a sustained diuretic effect was observed throughout the dosing period. The most common adverse event was mild thirst.

Single and multiple oral doses of tolvaptan exhibited dose-dependent aquaretic effects. Tolvaptan was well tolerated at all doses tested.