Caspofungin, a glucan synthesis inhibitor, is being developed as a parenteral antifungal agent. The pharmacokinetics of caspofungin following 1-h intravenous infusions in healthy men was investigated in four phase I studies. In an alternating two-panel (six men each), rising-single-dose study, plasma drug concentrations increased proportionally with the dose following infusions of 5 to 100 mg. The ␤-phase half-life was 9 to 10 h. The plasma drug clearance rate averaged 10 to 12 ml/min. Renal clearance of unchanged drug was a minor pathway of elimination (ϳ2% of the dose). Multiple-dose pharmacokinetics were investigated in a 2-week, serial-panel (5 or 6 men per panel) study of doses of 15, 35, and 70 mg administered daily; a 3-week, single-panel (10 men) study of a dose of 70 mg administered daily; and a parallel panel study (8 men) of a dose of 50 mg administered daily with or without a 70-mg loading dose on day 1. Moderate accumulation was observed with daily dosing. The degree of drug accumulation and the time to steady state were somewhat dose dependent. Accumulation averaged 24% at 15 mg daily and ϳ50% at 50 and 70 mg daily. Mean plasma drug concentrations were maintained above 1.0 g/ml, a target selected to exceed the MIC at which 90% of the isolates of the most clinically relevant species of Candida were inhibited, throughout therapy with daily treatments of 70 or 50 mg plus the loading dose, while they fell below the target for the first 2 days of a daily treatment of 50 mg without the loading dose. Caspofungin infused intravenously as a single dose or as multiple doses was generally well tolerated. In conclusion, the pharmacokinetics of caspofungin supports the clinical evaluation of once-daily dosing regimens for efficacy against fungal infections.Caspofungin (Cancidas; MK-0991) is an echinocandin that was recently approved by the U.S. Food and Drug Administration for patients with invasive aspergillosis who are refractory to or intolerant of standard therapy. Caspofungin inhibits the synthesis of 1,3-␤-D-glucan, which forms a critical component of many fungal cell walls (3). It has been shown to have potent activity in vitro against many clinically important fungi, including Candida spp. and Aspergillus spp. (2, 7, 9; M. Del Poeta, W. A. Schell, and J. R. Perfect, Abstr. 36th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F33, 1996). In in vivo studies with healthy and immunocompromised animals, prolonged survival in models of disseminated aspergillosis and candidiasis and clearance of Candida spp. from a target organ have been demonstrated with caspofungin treatment (1,5,6 , abstr. 1103, p. 371, 2000).Caspofungin has been developed as a parenteral agent due to its high molecular weight, unfavorable log P (partition coefficient), and extremely poor oral bioavailability in animals. In all the clinical studies, caspofungin has been administered as a constant-rate, 1-h intravenous (i.v.) infusion. This paper describes the results from four phase I studies conducted with healthy male subjects to ...

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...

Consumption of typical quantities of grapefruit juice (GFJ) increases the oral bioavailability of several CYP3A4 substrates without affecting their elimination, consistent with selective inhibition of intestinal but not hepatic CYP3A4. However, increases in the AUCs of CYP3A4 substrates recently associated with the consumption of large amounts of GFJ were similar to those observed with potent inhibitors of hepatic CYP3A4. The current study compared the effects of consuming large quantities and more typical amounts of GFJ on the activity of hepatic and intestinal cytochrome P450 3A4 in vivo, employing the erythromycin breath test (EBT) and oral midazolam pharmacokinetics. This was a two-phase, randomized, placebo-controlled crossover study, with each phase conducted with a separate panel of subjects. In Phase I, 8 male volunteers were randomized to the order of receiving one glass (240 mL) of water (placebo) or double-strength (DS) GFJ tid for 2 days and then 90, 60, and 30 minutes prior to administration of probe drugs on the 3rd day. In Phase II, 16 male volunteers were randomized to the order of receiving one glass of (1) single-strength (SS) GFJ, (2) DS GFJ, and (3) water (placebo). All treatments were administered in a fasted state. There was at least a 7-day washout period between treatments. Probe drugs, administered 30 minutes or 1 hour following each treatment in Phase I or II, respectively, consisted of oral midazolam (2 mg) coadministered with IV [14G N-methyl] erythromycin (0.03 mg). The EBT was performed 20 minutes following erythromycin administration. Blood was collected during the 24 hours following probe drug administration for the analysis of midazolam pharmacokinetics. In Phase I, consumption of one glass of DS GFJ tid for 3 days increased the Cmax of midazolam 3-fold, the AUC 6-fold, and the t1/2 2-fold and decreased the amount of exhaled 14CO2 in all 8 subjects, with a mean decrease in EBT of 18%. In Phase II, consumption of one glass of DS GFJ significantly increased the AUC and Cmax of midazolam approximately 2-fold without a significant effect on the t1/2 of midazolam or the EBT. The effects of consuming one glass of SS GFJ on midazolam pharmacokinetics and the EBT were not significantly different from those of one glass of DS GFJ. It was concluded that consumption of one glass of DS GFJ tid for 3 days significantly increased the AUC, Cmax, and t1/2 of midazolam and reduced EBT values, reflecting inhibition of both hepatic and intestinal CYP3A4. In contrast, consumption of one glass of SS or DS GFJ increased midazolam AUC and Cmax, with little effect on the midazolam t1/2 and EBT values, reflecting preferential inhibition of intestinal CYP3A4. Alterations of midazolam AUC and Cmax induced by nine glasses of DS GFJ were significantly greater than those produced by one glass of SS or DS GFJ. These data suggest that GFJ inhibits intestinal and hepatic CYP3A4 in an exposure-dependent fashion and that patients taking medications that are CYP3A4 substrates are at risk for developing drug-related ...

Aprepitant is the first NK1 receptor antagonist approved for use with corticosteroids and 5HT3 receptor antagonists to prevent chemotherapy-induced nausea and vomiting (CINV). The effective dose to prevent CINV is a 125-mg capsule on day 1 followed by an 80-mg capsule on days 2 and 3. Study 1 evaluated the bioavailability of the capsules and estimated the effect of food. The mean (95% confidence interval [CI]) bioavailabilities of 125-mg and 80-mg final market composition (FMC) capsules, as assessed by simultaneous administration of stable isotope-labeled intravenous (i.v.) aprepitant (2 mg) and FMC capsules, were 0.59 (0.53, 0.65) and 0.67 (0.62, 0.73), respectively. The geometric mean (90% CI) area under the plasma concentration time curve (AUC) ratios (fed/fasted) were 1.2 (1.10, 1.30) and 1.09 (1.00, 1.18) for the 125-mg and 80-mg capsule, respectively, demonstrating that aprepitant can be administered independently of food. Study 2 defined the pharmacokinetics of aprepitant administered following the 3-day regimen recommended to prevent CINV (125 mg/80 mg/80 mg). Consistent daily plasma exposures of aprepitant were obtained following this regimen, which was generally well tolerated.

Background: Circadian (diurnal) rhythm is an integral part of the physiology of the body; specifically, sleep, feeding behavior and metabolism are tightly linked to the light-dark cycle dictated by earth's rotation.