Gatifloxacin was safe and well tolerated at intravenous doses of up to 800 mg/day for 14 days. Gatifloxacin pharmacokinetics were linear and time independent.

The safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of the angiotensin II (AII) AT1 blocker irbesartan were assessed in healthy subjects. In this single-center, placebo-controlled, double-blind within dose group, sequential, dose-ascending study, 48 men were randomized to receive irbesartan at doses of 150 mg, 300 mg, 600 mg, or 900 mg daily. Subjects received a single dose of irbesartan (n = 9 per group) or placebo (n = 3 per group), followed by 3 days of placebo, and then multiple doses of irbesartan or placebo once daily for 7 days. The values for plasma area under the concentration-time curve (AUC) of irbesartan were dose proportional up to 600 mg. There were no significant differences between the dose groups in time to maximum concentration (tmax) or half-life (t1/2) after single and multiple doses. After multiple doses, urinary recovery was significantly lower in the 600-mg and 900-mg dose groups compared with the 150-mg and 300-mg dose groups. Steady-state concentrations of irbesartan were achieved within 3 days of administration with no clinically important accumulation. Irbesartan produced dose-dependent increases in plasma renin activity and AII levels. Irbesartan was well tolerated at doses from 150 mg to 900 mg daily; a maximally tolerated dose was not reached. Modest decreases in blood pressure without orthostatic symptoms were observed at irbesartan doses of 300 mg or higher. These results demonstrated the dose-proportionality of irbesartan 150 mg to 600 mg and indicated that doses up to 900 mg daily were well tolerated.

A 21-day, open-label, multisite, dose escalation study comprising three demographic groups (children, adolescents, and adults) was performed to determine the pharmacokinetics and tolerability of orally administered buspirone. Thirteen children and 12 adolescents with anxiety disorder and 14 normal healthy adults were escalated from 5 to 30 mg buspirone bid over the 3-week study. Pharmacokinetic analysis revealed that buspirone was rapidly absorbed in all study groups, reaching peak levels at about 1 hour after administration. Peak plasma buspirone concentrations (Cmax) were highest in children and lowest in adults at all three dose levels (7.5, 15, 30 mg bid). However, 1-pyrimidinylpiperazine (1-PP), the primary metabolite of buspirone, exhibited a different plasma concentration-time profile; Cmax was significantly higher in children than in either adolescents or adults at all concentrations. In addition, TAUC0-T for 1-PP was significantly higher in the children cohort relative to adolescents and adults. Buspirone was generally safe and well tolerated at doses up to 30 mg bid in adolescents and adults and most of the children. The most frequently reported adverse events in children and adolescents were lightheadedness (68%), headache (48%), and dyspepsia (20%); 2 children withdrewfrom the study at the higher doses (15 mg and 30 mg bid) due to adverse effects. In adults, the most common adverse effect was somnolence (21.4%); lightheadedness, nausea, vomiting, and diarrhea were also reported, although these were mild in intensity.

Abstract. The metabolic clearance rate (MCR) and plasma disappearance rate (t1/2) ofhuman pancreatic tumor growth hormone releasing factor ] was determined in normal adult male subjects by single injection and constant infusion techniques. Single injections of 1, 3.3, and 10 ,Lg/kg hpGRF(l-40) were administered intravenously, plasma immunoreactive (IR) GRF levels were measured during the subsequent 180 min, and biexponential curve analysis was performed. Graded, dose-constant infusions of hpGRF(1-40) at rates of 1, 3.3, 10, and 33 ng/kg per min were administered and the MCR was calculated from measurement of steady state plasma IR-GRF levels at each infusion rate. The postinfusion disappearance rate was determined by linear regression analysis of plasma IR-GRF levels during the 120-min period after cessation of the infusion.The calculated MCR during the single injection study was 194±17.5 liters/M2 per d and was not significantly different from the calculated value during the constant infusion study (202±16 liters/M2 per d). The disappearance rate during the single injection study was subdivided into two linear phases: an initial equilibration phase (7.6±1.2 min) and a subsequent elimination phase (51.8±5.4 min). The latter was similar to the linear disappearance rate observed (41.3±3.0 min) after cessation of the constant infusion. The chromatographic and bi-

Aims To determine the pharmacokinetics, pharmacodynamics and tolerability of omapatrilat, a vasopeptidase inhibitor, in healthy subjects. Methods The effects of oral omapatrilat were evaluated in healthy men in two double-blind, placebo-controlled, dose-escalation trials. In a single-dose study, subjects received omapatrilat in doses of 2.5, 7.5, 25, 50, 125, 250, or 500 mg. In a multiple-dose study, subjects received doses of 10, 25, 50, 75, or 125 mg daily for 10 days. Results In the multiple-dose study, peak plasma concentrations ( C max = 10-895 ng ml -1 ; t max = 0.5-2 h) of omapatrilat were attained rapidly. Omapatrilat exhibited a long effective half-life (14-19 h), attaining steady state in 3-4 days. In the single-dose study, C max (1-1009 ng ml -1 ) and AUC(0, t ) (0.4-1891 ng ml -1 h) were linear but not dose proportional. In the multiple-dose study, based on weighted least-squares linear regression analyses vs dose, C max but not AUC(0, t ) was linear at the lower doses on day 10. The lowest dose of omapatrilat (2.5 mg) almost completely inhibited ( > 97%) serum angiotensin converting enzyme activity at 2 h after dosing. In the multiple dose study, angiotensin converting enzyme activity was inhibited by more than 80% 24 h after all doses of omapatrilat. Inhibition of neutral endopeptidase activity was shown by increases in the daily urinary excretion of atrial natriuretic peptide and cyclic guanosine monophosphate at doses of more than 7.5 and 25 mg, respectively. In the single dose study, omapatrilat increased the daily urinary excretion of atrial natriuretic peptide dose-dependently from 10.8 ± 4.1 ( ± SD) ng 24 h -1 in the placebo group to 60.0 ± 18.2 ng 24 h -1 in the 500 mg group. Omapatrilat did not affect sodium and potassium excretion or urinary volume. Compared with placebo, omapatrilat produced a decrease in mean arterial pressure at 3 h after all doses in both the single-and multiple-dose studies. Conclusions Omapatrilat was generally well tolerated. The pharmacokinetic and pharmacodynamic effects of omapatrilat are consistent with once-daily dosing.