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(infinity) 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 ( approximately 8 mOsm/kg), and free water clearance ( approximately 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.

Two 14-day, placebo-controlled, double-blind studies evaluated the fasting pharmacokinetics, safety, and tolerability of aripiprazole, a new antipsychotic, in healthy male subjects. In Study 1, 37 subjects were randomized to aripiprazole 5 mg, 10 mg, 15 mg, 20 mg, or placebo once daily. In Study 2, 11 subjects were randomized to aripiprazole, titrated from 10 to 30 mg/day, or placebo. Aripiprazole had linear pharmacokinetics over 5 to 30 mg/day, which were described by a two-compartment open model, with first-order absorption. In Study 1, mean elimination half-life ranged from 47 to 68 hours with aripiprazole, with apparent systemic clearance (CL/F) of approximately 3.45 L/h. In Study 2, mean elimination half-life was 59 hours (CL/F approximately 4.0 L/h). Adverse events were generally mild to moderate, were transient in nature, and commonly occurred within the first 3 days of dosing. Clinical laboratory assessments, electrocardiogram, electroencephalogram, and prolactin levels showed no clinically significant changes during the studies.

This 24-week, open-label, Phase Ib, parallel-arm, multiple-dose trial assessed the pharmacokinetics, safety and tolerability of a once-monthly injection of aripiprazole (aripiprazole once-monthly) in 41 subjects with schizophrenia. The objective was to determine if aripiprazole plasma concentrations (at doses of 200, 300 and 400mg) were within the therapeutic range observed for the oral tablet (10-30 mg). Completion rates were 36.4% (n=4/11), 50.0% (n=8/16) and 71.4% (n=10/14) for the 200mg, 300 mg and 400mg groups, respectively. Patients were stabilized on oral aripiprazole (10mg/day) before the first injection and received oral aripiprazole (10mg/day) concomitantly with the first dose of aripiprazole once-monthly for 14 days. Administration of aripiprazole once-monthly at doses of 300 and 400mg provided sustained mean aripiprazole plasma concentrations comparable with the concentration range observed following multiple consecutive daily doses of oral aripiprazole. In contrast, plasma concentrations following administration of aripiprazole once-monthly at a dose of 200mg were below the therapeutic range and pharmacokinetic parameters were not proportional to the administered dose compared with the 300 mg and 400mg doses. Treatment with aripiprazole once-monthly, at any dose, did not result in any clinically meaningful changes from baseline in extrapyramidal symptom scales, clinical laboratory tests, vital signs, or electrocardiogram parameters. The most common treatment-emergent adverse events were vomiting (13.3%, 300 mg; 14.3%, 400mg), injection site pain (28.6%, 400mg), upper respiratory tract infection (10%, 200mg; 6.7% 300 mg; 14.3%, 400mg) and tremor (6.7%, 300 mg; 21.4%, 400mg). In conclusion, aripiprazole once-monthly at doses of 300 and 400mg is a viable formulation for treatment of adults with schizophrenia.