Pharmacokinetics of ceftobiprole following single and multiple intravenous infusions administered to healthy subjects

Abstract number: 1733_277

Murthy B., Skee D., Wexler D., Balis D., Chang I., Desai-Kreiger D., Noel G.

Objectives: Ceftobiprole, an investigational broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci, is currently in late stage clinical development. The purpose of this study was to evaluate the single- and multiple-dose pharmacokinetics (PK) of ceftobiprole 500 mg q8h given as a 2-h infusion.

Methods: This was a single-centre, open-label study in 28 healthy adult males and females. Subjects received a single infusion on Day 1 and multiple infusions on Days 3 through 5. Serial blood and urine samples were collected through 24 h after the start of infusion on Days 1 and 5 for estimation of ceftobiprole medocaril (prodrug), ceftobiprole, and open-ring metabolite (M1) via an LC-MS/MS method. PK parameters were estimated using model-independent methods.

Results: PK parameter estimates for ceftobiprole and M1 are shown in the table. Plasma concentrations of the prodrug were measurable only during the infusion, indicating instantaneous conversion to ceftobiprole. Systemic exposure of ceftobiprole was comparable between Days 1 and 5 with minimal accumulation. Clearance (CL) remained unchanged from Day 1 to Day 5. Ceftobiprole was primarily excreted unchanged in the urine (≥83%). Systemic exposure of M1 increased from Day 1 to 5 with an accumulation index of 1.5. Elimination half-life of M1 was 5–6 h. Less than 7% of ceftobiprole is excreted in the urine as the open-ring metabolite. Systemic exposure of ceftobiprole and M1 was higher in females compared to males, which normalised upon correction for body weight. On Day 5, approximately 100% of the dose was excreted in the urine as the prodrug, ceftobiprole, and M1. No subject had a serious adverse event. No subjects were withdrawn from the study due to an adverse event.

Day 1Day 5Day 1Day 5  
Cmax (mg/L)29.2 (5.52)33.0 (4.83)0.804 (0.214)1.07 (0.254)
AUC0–8 h (mg·h/L)90.0 (12.4)102 (11.9)3.68 (0.882)5.45 (1.35)
t1/2 (h)3.1 (0.3)3.3 (0.3)4.7 (0.8)5.8 (0.9)
CL (L/h)4.89 (0.687)4.98 (0.582)

Conclusion: The pharmacokinetics of the ceftobiprole 500 mg q8h regimen given as a 2-h infusion are similar to results previously reported with no accumulation observed. The majority of the administered dose was recovered in the urine. This regimen was safe and well tolerated.

Session Details

Date: 31/03/2007
Time: 00:00-00:00
Session name: European Society of Clinical Microbiology and Infectious Diseases
Location: ICC, Munich, Germany
Presentation type:
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