Pharmacokinetics of Ertapenem in Healthy Young Volunteers

Abstract

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...

β-Lactams Enhance Daptomycin Activity against Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium in In Vitro Pharmacokinetic/Pharmacodynamic Models

“…Fresh medium (MHB) was continuously supplied and removed from the compartment along with the drug via a peristaltic pump (Masterflex; Cole-Parmer Instrument Company, Chicago, IL) at an appropriate rate to simulate the average human clearance and half-lives (t 1/2 ) of the antimicrobials. The antimicrobial regimens evaluated were simulations of 10 mg/kg DAP every 24 h (q24h) (targeted maximum free-drug concentration in serum [fC max ], 11.3 g/ ml; t 1/2 , 8 h; protein binding, 92%; area under the concentration-time curve for the free, unbound fraction of a drug over 24 h [fAUC 0 -24 ], 114.8 g · h/ml), 600 mg CPT every 8 h (fC max , 17.04 g/ml; t 1/2 , 2.66 h; protein binding, 20%), 1 g ERT every 24 h (fC max , 15.5 g/ml; t 1/2 , 4 h; protein binding, 90%), 2 g AMP every 4 h (fC max ,70 g/ml; t 1/2 , 1.9 h; protein binding, 20%), 10 mg/kg DAP q24h plus 600 mg CPT q8h, 10 mg/kg DAP q24h plus 1 g ERT q24h, and 10 mg/kg DAP q24h plus 2 g AMP q4h (29)(30)(31)(32)(33)(34). The models were performed in duplicate to ensure reproducibility.…”

β-Lactams and β-Lactamase Inhibitors: An Overview

“…Doripenem, a carbapenem with somewhat higher chemical stability than imipenem or meropenem (Prescott et al 2011), follows the antibacterial profile of meropenem, but is slightly more potent against Gram-negative organisms (Nordmann et al 2011). Ertapenem, recognized for its long elimination half-life in humans because of its high protein binding (95%) (Majumdar et al 2002), may be effectively administered once daily (Kattan et al 2008) in contrast to the other carbapenems that are dosed most commonly two or three times a day. Although its antibacterial spectrum is similar to the other carbapenems against Enterobacteriaceae, ertapenem differs from imipenem, meropenem, and doripenem in that it has no useful activity against P. aeruginosa (Kohler et al 1999).…”

Design, Synthesis, and Evaluation of Prodrugs of Ertapenem

“…This is the only carbapenem antibiotic that is dosed once daily. 1,7,8 While the core structures of ertapenem and tebipenem is common, they are differentiated by the structure of their side chain substituents at C-2. Tebipenem possesses a basic side chain consisting of azetidino-thiazolidine, whereas ertapenem consists of a prolyl-3-aminobenzoic acid.…”