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Pharmacokinetics, Pharmacodynamics, and Safety of Tolvaptan, a Nonpeptide AVP Antagonist, During Ascending Single-Dose Studies in Healthy Subjects

From Clinical Pharmacology, Otsuka Pharmaceutical Development & Commercialization, Inc, Rockville, Maryland.

Two single-center, double-blind, randomized, placebo-controlled, sequentially enrolled studies were conducted. In study 1, 8 subjects (6 active/2 placebo) received 60-, 90-, 120-, 180-, or 240-mg tolvaptan/matching placebo. In study 2, 9 subjects (6 active/3 placebo) received 180-, 240-, 300-, 360-, 420-, or 480-mg tolvaptan/matching placebo. Increases in tolvaptan C_max were less than dose-proportional and plateaued at doses greater than 240 mg; AUC increased proportionally with dose. Changes in serum K⁺, creatinine clearance, and Na⁺, K⁺, and osmolality urinary excretion were similar to the placebo group for the 0- to 24-hour interval following dosing. Changes were observed in plasma arginine vasopressin, serum aldosterone, and plasma renin activity but were not clinically significant. Increases were seen in mean serum Na⁺ concentrations (4-6 mEq/L), plasma osmolality (8 mOsm/kg), and free water clearance (6 mL/min) throughout 0 to 24 hours; none of these increases was dose dependent. Only total urine volume excretion (0-72 hours postdose) increased linearly with dose. As plasma tolvaptan concentrations increased, the duration that the urine excretion rate remained above baseline rates also increased. The most frequent adverse events—excess thirst, frequent urination, and dry mouth—appeared to be related to the pharmacological action of tolvaptan. No dose-limiting toxicities were observed.

Key Words: Tolvaptan • pharmacokinetics • pharmacodynamics • aquaretic • arginine vasopressin

Address for correspondence: Susan E. Shoaf, PhD, 2440 Research Blvd, Rockville, MD 20850; e-mail: susan.shoaf{at}otsuka.com.

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