Ertapenem (INVANZ) is a new once-a-day parenteral ␤-lactam antimicrobial shown to be effective as a single agent for treatment of various community-acquired and mixed infections. The single-and multiple-dose pharmacokinetics of ertapenem at doses up to 3 g were examined in healthy young men and women volunteers. Plasma and urine samples collected were analyzed using reversed-phase high-performance liquid chromatography with UV detection. Ertapenem is highly bound to plasma protein. The protein binding changes from ϳ95% bound at concentrations of <50 g/ml to ϳ92% bound at concentrations of 150 g/ml (concentration at the end of a 30-min infusion following the 1-g dose). The nonlinear protein binding of ertapenem resulted in a slightly less than dose proportional increase in the area under the curve from 0 h to infinity (AUC 0-ؕ ) of total ertapenem. The single-dose AUC 0-ؕ of unbound ertapenem was nearly dose proportional over the dose range of 0.5 to 2 g. The mean concentration of ertapenem in plasma ranged from ϳ145 to 175 g/ml at the end of a 30-min infusion, from ϳ30 to 34 g/ml at 6 h, and from ϳ9 to 11 g/ml at 12 h. The mean plasma t 1/2 ranged from 3.8 to 4.4 h. About 45% of the plasma clearance (CL P ) was via renal clearance. The remainder of the CL P was primarily via the formation of the ␤-lactam ring-opened metabolite that was excreted in urine. There were no clinically significant differences between the pharmacokinetics of ertapenem in men and women. Ertapenem does not accumulate after multiple once-daily dosing.Ertapenem (INVANZ; MK-0826; Merck & Co., Inc.) is a once-a-day parenteral ␤-lactam antimicrobial agent with excellent in vitro activity against gram-positive and gram-negative aerobic and anaerobic bacteria generally associated with community-acquired and mixed infections (1; C. J. Gill, J. J. Jackson, J. G. Sundelof, H. Rosen, and H. Kropp, Abstr. 36th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F125, p. 121, 1996). Moreover, ertapenem has been shown to be effective for treating several community-acquired and mixed infections, including intra-abdominal infections, skin and skinstructure infections, community-acquired pneumonia, acute pelvic infections, and urinary tract infections (3, 5; J. S. L-855, 2001). This structurally unique carbapenem (Fig. 1) exhibits a long plasma half-life (t 1/2 ) (about 4 h) due largely to its high plasma protein binding and stability against human renal dehydropeptidase.The objectives of this study were to (i) assess the dose proportionality of intravenous (i.v.) doses of ertapenem across the dose range of 0.5 to 3 g, (ii) evaluate the plasma protein MATERIALS AND METHODSStudy design. This report includes data from five clinical studies. The design of these studies are as follows. Study 1 was a two-part, double-blind, placebocontrolled study; part I was a two-panel, four-period single rising dose study with doses of 0.04, 0.25, 1, and 2 g in one panel and 0.1, 0.5, 1.5, and 3 g in the second panel. Pharmacokinetic analysis was performed for doses of...

The effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on ambulatory blood pressure was assessed in nondiabetic patients with mild to moderate hypertension in a randomized, double-blind, placebo-controlled, 3-period crossover study. Nineteen patients on stable treatment with antihypertensive agent(s) received sitagliptin 100 mg b.i.d., 50 mg b.i.d., or placebo for 5 days, with at least a 7-day washout interval between periods. Twenty-four-hour ambulatory blood pressure, including systolic blood pressure, diastolic blood pressure, and mean arterial pressure, were monitored on days 1 and 5. Relative to placebo on day 1, the mean difference in 24-hour systolic blood pressure was -0.9 mm Hg (90% confidence interval: -2.9 to 1.1; P = .46) with sitagliptin 50 mg b.i.d. and -2.8 mm Hg (90% confidence interval: -4.9 to -0.8; P < .05) with 100 mg b.i.d. On day 5, the mean difference in 24-hour systolic blood pressure was -2.0 mm Hg (90% confidence interval: -3.5 to -0.4; P < .05) with 50 mg b.i.d. and -2.2 mm Hg (90% confidence interval: -3.7 to -0.6; P < .05) with 100 mg b.i.d. relative to placebo. For 24-hour diastolic blood pressure, there were no between-group differences in mean 24-hour diastolic blood pressure on day 1. On day 5, sitagliptin 50 mg and 100 mg b.i.d significantly (P < .05) lowered mean 24-hour diastolic blood pressure by -1.8 mm Hg (90% confidence interval: -2.8 to -0.8) and -1.6 mm Hg (90% confidence interval: -2.6 to -0.7), respectively, relative to placebo. Sitagliptin produced small but statistically significant reductions of 2 mm Hg to 3 mm Hg in 24-hour ambulatory blood pressure measurements acutely (day 1) and at steady state (day 5), and was generally well tolerated in nondiabetic patients with mild to moderate hypertension.

The disposition of caspofungin, a parenteral antifungal drug, was investigated. Following a single, 1-h, intravenous infusion of 70 mg (200 Ci) of [ 3 H]caspofungin to healthy men, plasma, urine, and feces were collected over 27 days in study A (n ‫؍‬ 6) and plasma was collected over 26 weeks in study B (n ‫؍‬ 7). Supportive data were obtained from a single-dose [ 3 H]caspofungin tissue distribution study in rats (n ‫؍‬ 3 animals/time point). Over 27 days in humans, 75.4% of radioactivity was recovered in urine (40.7%) and feces (34.4%). A long terminal phase (t 1/2 ‫؍‬ 14.6 days) characterized much of the plasma drug profile of radioactivity, which remained quantifiable to 22.3 weeks. Mass balance calculations indicated that radioactivity in tissues peaked at 1.5 to 2 days at ϳ92% of the dose, and the rate of radioactivity excretion peaked at 6 to 7 days. Metabolism and excretion of caspofungin were very slow processes, and very little excretion or biotransformation occurred in the first 24 to 30 h postdose. Most of the area under the concentration-time curve of caspofungin was accounted for during this period, consistent with distribution-controlled clearance. The apparent distribution volume during this period indicated that this distribution process is uptake into tissue cells. Radioactivity was widely distributed in rats, with the highest concentrations in liver, kidney, lung, and spleen. Liver exhibited an extended uptake phase, peaking at 24 h with 35% of total dose in liver. The plasma profile of caspofungin is determined primarily by the rate of distribution of caspofungin from plasma into tissues.Caspofungin (CANCIDAS; MK-0991) is a parenteral antifungal agent that inhibits 1,3-␤-D-glucan synthesis, which forms a critical component of many fungal cell walls (4). Caspofungin is active against many clinically important fungal species, including Candida spp. and Aspergillus spp. (3,5,7,14), and in clinical trials it has been shown to be efficacious in the treatment of esophageal candidiasis (1, 15, 16), invasive candidiasis (9), and invasive aspergillosis (J. Maertens, I. Raad, G. Petrikkos, et al., Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-868, 2002). This paper describes results from two studies conducted in healthy human subjects to investigate the disposition of caspofungin following intravenous (i.v.) infusion of radiolabeled caspofungin and supportive studies of [ 3 H]caspofungin tissue distribution in rats, in vitro metabolism, and in vitro binding and partitioning in human plasma and blood. The metabolites of caspofungin, a cyclic hexapeptide, in humans have been previously reported (2). Caspofungin is the major component of radioactivity in plasma and urine in the first 24 to 30 h postdose, with a ring-opened form of caspofungin, M0, comprising a minor component. At time points of Ն5 days, M0 was the major component in plasma, and urine radioactivity was largely comprised of the synthetic amino acid dihydoxyhomotyrosine (M1) and its N-acetyl derivative (M2). Caspofungin...

Raltegravir is an HIV integrase inhibitor that is metabolized through glucuronidation by uridine diphosphate glucuronosyltransferase 1A1, and its use is anticipated in combination with atazanavir (a uridine diphosphate glucuronosyltransferase 1A1 inhibitor). Two pharmacokinetic studies of healthy subjects assessed the effect of multiple-dose atazanavir or ritonavir-boosted atazanavir on raltegravir levels in plasma. Atazanavir and atazanavir plus ritonavir modestly increase plasma levels of raltegravir.