Session: Poster Session: Human Pharmacokinetics/Dynamics
Monday, October 27, 2008: 12:00 AM
Room: Hall C
Background: Cephalosporins are a main stay of treatment for both community- (CAP) and hospital-acquired pneumonia (HAP). BPR is an investigational cephalosporin with activity against MRSA that has been studied in patients with complicated skin infections, CAP and HAP. In support of the HAP and CAP clinical studies the penetration of BPR into ELF was assessed in HVs into ELF. Methods: 25 HVs received 4 doses of BPR 500 mg Q8h (2h infusion). Around dose4, 9 plasma samples were obtained. HVs had a timed bronchoscopy for ELF, obtaining blood for BPR & urea determination then. Concentrations for BPR were determined by LC/MS/MS, urea by kit. PK analysis was by BigNPAG. Monte Carlo simulation was performed with ADAPT II to estimate penetration and T>MIC in plasma & ELF after 1 dose. Results: BPR CL was 5.16 L/h; VCentral was 2.85 L; VELF 39.1 L. A 9,999 subject simulation (Log-N) showed Mean, Median, 25th PCTLE and 75th PCTLE AUCPlasma (mg*h/L), AUCELF (mg*h/L), and Penetration (%) of 94.5, 94.0, 86.0, 102; 43.1, 20.6, 9.20, 46.3; 45.6, 21.8, 0.098, 49.3, respectively. fTime>MIC for plasma was 97.5% & 95.9% for targets of 40% & 50% at 2 mg/L. These values were 87.0% and 79.8% at 4 mg/L. In ELF, 40% & 50% target attainment were 94.3% and 90.5% at 0.25 mg/L, 86.6% & 81.3% at 0.5 mg/L and 72.6% & 65.7% at 1.0 mg/L. At 2.0 mg/L & above, target attainments were < 50%. Conclusions: At this dose and schedule, BPR provides robust protection for the plasma (T>MIC) for pathogens with MIC values <4 mg/L. Overall penetration into ELF approximated that seen earlier with ceftazidime in patients (median ELF/plasma ratio = 0.22). These results need correlation with clinical data.