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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.

The pharmacokinetics of toborinone was studied in subjects with congestive heart failure (CHF) and concomitant renal and/or hepatic disease. At the time of admission, subjects were grouped based on estimated creatinine clearance and serum bilirubin. Glomerular filtration rate was assessed using iothalamate clearance. Hepatic function was assessed using the caffeine metabolism test and indocyanine green clearance. No significant differences were observed in mean toborinone pharmacokinetic parameters among the four study groups. Positive correlations were observed between toborinone clearance and the measured indices of renal and hepatic function: creatinine clearance, iothalamate renal clearance, paraxanthine/caffeine ratio, and indocyanine green clearance. Toborinone clearance decreased with decreasing creatinine clearance, decreasing glomerular filtration rate, decreasing demethylation metabolic activity, and decreasing hepatic bloodflow, although no significant differences were observed in any mean toborinone pharmacokinetic parameters evaluated among the four study groups.

This study investigated the effects of the concomitant administration of theophylline and toborinone on the pharmacokinetics of both compounds in poor and extensive metabolizers via CYP2D6. In period 1, a single dose of 3.5 mg/kg theophylline was administered orally. In period 2, a single dose of 1.0 microg/kg/min toborinone was infused over 6 hours. In period 3, 3.5 mg/kg theophylline was coadministered with 1.0 microg/kg/min toborinone. Serial blood and pooled urine samples were collected before and after toborinone administration for the quantification of toborinone and its metabolites in plasma and urine. Serial blood samples were collected before and after theophylline administration for the quantification of theophylline and its metabolites in plasma. No significant differences were observed in toborinone pharmacokinetics between poor and extensive metabolizers via CYP2D6. Toborinone coadministration with theophylline did not result in a substantive effect on the disposition of theophylline and vice versa.

Vesnarinone is an orally administered inotropic agent that is metabolized in vitro by the cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1. The purpose of this study was to assess the contribution of CYP2E1 activity to the disposition of vesnarinone in humans by characterizing the pharmacokinetics before and after disulfiram-mediated CYP2E1 inhibition. The pharmacokinetics of vesnarinone 60 mg were determined in normal healthy volunteers (N = 7) before and after daily disulfiram administration (250 mg). Chlorzoxazone 250 mg was also administered before, during, and after disulfiram administration to serve as a positive control for CYP2E1 inhibition. Disulfiram treatment decreased 6-hydroxychlorzoxazone formation clearance by nearly 95% but effected only a modest decrease in vesnarinone apparent oral clearance (5.7 +/- 1.0 vs. 5.0 +/- 0.5 ml/min; p = 0.022). In contrast to the modest effect on the parent drug, disulfiram treatment substantially increased plasma concentrations of the primary metabolite OPC-18692. The Cmax of OPC-18692 was increased approximately 7-fold, and the area under the plasma concentration-time curve was increased 18-fold (2.9 +/- 0.9 vs. 53.7 +/- 33.2 micrograms.h/ml; p = 0.006). The results indicate that CYP2E1 inhibition has only a modest, clinically insignificant effect on vesnarinone disposition but markedly increases plasma concentrations of the OPC-18692 metabolite. The pharmacological properties of this metabolite have not been fully defined; thus, the clinical importance of this observation depends on whether this metabolite contributes to any of the toxicity associated with vesnarinone administration.

The effect of famotidine, an H2 receptor blocker, on the oral absorption and pharmacokinetics of the novel agent vesnarinone was investigated after oral administration of 60 mg vesnarinone with and without pretreatment with intravenous famotidine. The single-blind, randomized, two-way crossover study was conducted in 12 volunteers, with a washout period of 7 days between the two treatments. A pH monitor was used to ensure that gastric pH of the subjects was < or = 3 in the absence of and > or = 5 in the presence of famotidine. A significant decrease in maximum concentration (Cmax) and increase in time to Cmax (tmax) was observed for vesnarinone during treatment with famotidine, whereas area under the concentration-time curve (AUC) was similar for both treatments. The physicochemical properties of the drug support the above observations. Therefore, therapies that increase gastric pH will affect the rate but not the extent of absorption of vesnarinone or the safety or efficacy profile of vesnarinone.

Cilostazol is being developed for the treatment of intermittent claudication due to peripheral arterial disease (PAD). This study was conducted to investigate the effects of age and gender on the pharmacokinetics of cilostazol after multiple-dose administration. It was an open label, multiple-dose study of cilostazol administered to male and female subjects 50 years of age and older at a dose of 100 mg (oral tablet) twice daily for 7 days. Equal numbers of healthy male and female (7 per group), nonsmoking subjects stratified into age groups of 50 to 59 years, 60 to 69 years, and 70 years or older were enrolled. Serial plasma samples were obtained. Data were analyzed by model-independent methods. Cilostazol was absorbed at a moderate rate, with peak plasma concentrations occurring at an overall mean of 2.4 hours after administration. Cilostazol is extensively bound (95%), primarily to albumin. A trend toward increasing cilostazol free fraction with age was observed in the male subjects, which was explained by a decrease in plasma albumin concentration with age. Differences in plasma protein binding between age and gender groups (less than 15%) are not expected to have any clinical significance. Plasma cilostazol concentrations reached steady state by day 4. The pharmacokinetic characteristics of cilostazol were not affected by age or gender.