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.

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.

Twice-daily administration of OPB-31121 was feasible up to doses of 300 mg. The pharmacokinetic profile was unfavorable, and no objective responses were observed.

The pharmacokinetic and pharmacodynamic interactions between tolvaptan and furosemide or hydrochlorothiazide (HCTZ) were determined in a single-center, randomized, open-label, parallel-arm, 3-period crossover study conducted in healthy white (Caucasian) men. A total of 12 subjects were enrolled in the study, with 6 subjects assigned to each of two treatment arms. Subjects in Arm 1 received 30 mg of tolvaptan, 80 mg of furosemide, and 30 mg of tolvaptan + 80 mg of furosemide. Subjects in Arm 2 received 30 mg of tolvaptan, 100 mg of HCTZ, and 30 mg pf tolvaptan + 100 mg of HCTZ. Doses were separated by a 48-hour washout. Blood and urine samples were collected at scheduled timepoints during the 24 hours after administration of study drug for the determination of pharmacokinetic and pharmacodynamic parameters. No clinically significant changes were noted in the pharmacokinetic profiles of tolvaptan and furosemide or tolvaptan and HCTZ when coadministered. Free water clearance, 24-hour urine volume, plasma sodium and argentine vasopressin concentrations, and plasma osmolality were higher, and urine osmolality was lower when tolvaptan was administered either alone or in combination with furosemide or HCTZ, compared with furosemide or HCTZ administered alone. At 24 hours postdose, plasma renin activity was increased after furosemide or HCTZ administered alone or with tolvaptan, but it was unchanged after tolvaptan alone. Tolvaptan did not significantly affect the natriuretic activity of furosemide or HCTZ. Furosemide and HCTZ did not significantly affect the aquaretic activity of tolvaptan. Tolvaptan administered alone or in combination with furosemide or HCTZ was safe and well tolerated at the given doses.