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Int J Antimicrob Agents. 2010 Feb;35(2):182-5. doi: 10.1016/j.ijantimicag.2009.10.013. Epub 2009 Dec 16.

Novel antimicrobial lipopeptides with long in vivo half-lives.

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1
MIGENIX Inc., 102-2389 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3.

Abstract

The pharmacokinetic (PK) properties of novel lipopeptides (semi-synthetic amphomycin analogues) with potent activity against Gram-positive organisms were evaluated in mice and rats following single intravenous (i.v.) and oral administration. Following oral administration at 50mg/kg, plasma concentrations of amphomycin analogues were <0.3-0.9microg/mL, suggesting that oral availability was low. Following i.v. administration (5-10mg/kg), the majority of lipopeptides demonstrated a long half-life (5.2-8.0h in mice and 4.6-7.1h in rats), low clearance (0.005-0.016mL/min in mice and 0.050-0.084mL/min in rats) and a volume of distribution indicative of extracellular penetration (0.118-0.339L/kg in mice and 0.121-0.133L/kg in rats). The area under the plasma concentration-time curve extrapolated to infinity (AUC(0-infinity)) for a 10mg/kg i.v. dose was determined to be 601.7-791.7microgh/mL in mice and 511.1-850.2microgh/mL in rats. The long half-life and low clearance observed with these novel lipopeptides indicate that drug serum concentrations will remain above the target minimal inhibitory concentration (MIC) levels for significant periods of time. When combined with the potent efficacy of these agents against Gram-positive organisms, the results of the present study support further development of these lipopeptide analogues towards clinical evaluation.

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