Pharmacokinetic-Pharmacodynamic Assessment of Faropenem in a Lethal Murine Bacillus anthracis Inhalation Postexposure Prophylaxis Model
Abstract
There are few options for prophylaxis after exposure to Bacillus anthracis, especially in children and women of childbearing potential. Faropenem is a -lactam in the penem subclass that is being developed as an oral prodrug, faropenem medoxomil, for the treatment of respiratory tract infections. Faropenem was shown to have in vitro activity against B. anthracis strains that variably express the bla1 -lactamase (MIC range, <0.06 to 1 micrograms/ml). In this study we evaluated the pharmacokinetic-pharmacodynamic (PK-PD) relationships between the plasma faropenem free-drug (f) concentrations and efficacy against B. anthracis in a murine postexposure prophylaxis inhalation model. The plasma PKs and PKs-PDs of faropenem were evaluated in BALB/c mice following the intraperitoneal (i.p.) administration of doses ranging from 2.5 to 160 mg/kg of body weight. For the evaluation of efficacy, mice received by inhalation aerosol doses of B. anthracis (Ames strain; faropenem MIC, 0.06 g/ml) at 100 times the 50% lethal dose. The faropenem dosing regimens (10, 20, 40, and 80 mg/kg/day) were administered i.p. at 24 h postchallenge at 4-, 6-, and 12-h intervals for 14 days. The sigmoid maximum-threshold-of-efficacy (Emax) model fit the survival data, in which the free-drug area under the concentration-time curve (fAUC)/MIC ratio, the maximum concentration of free drug in plasma (fCmax)/MIC ratio, and the cumulative percentage of a 24-h period that the free-drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (f %TMIC) were each evaluated. Assessment of f %TMIC demonstrated the strongest correlation with survival (R2 0.967) compared to the correlations achieved by assessment of fAUC/MIC or fCmax/MIC, for which minimal correlations were observed. The 50% effective dose (ED50), ED90, and ED99 corresponded to f %TMIC values of 10.6, 13.4, and 16.4%
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2010
- Accession Number
- ADA519565
Entities
People
- Amber Beaudry
- Christopher M. Rubino
- Henry S. Heine
- Ian Critchley
- Jennifer Bassett
- Jinfang Li
- Kimberly C. Stone
- Lynda Miller
- Nebojsa Janjic
- Paul G. Ambrose
- Stanley C. Gill
- Sujata M. Bhavnani