2561. Population Pharmacokinetic Analyses for Ceftobiprole Using Data from Phase 1 and 3 Studies

Abstract Background Ceftobiprole medocaril is an intravenously administered cephalosporin prodrug that is rapidly converted in vivo to ceftobiprole which has activity against Gram-positive and -negative organisms. A population pharmacokinetic (PK) model was constructed from nine Phase 1 studies and three Phase 3 studies in patients with acute bacterial skin and skin structure infections (ABSSSI) or hospital- or community-acquired bacterial pneumonia (HABP or CABP) and refined using Phase 3 data from patients with Staphylococcus aureus bacteremia (SAB). Methods Structural PK models for systemic compartments and linear vs. non-linear elimination were considered. Covariate analyses were carried out. Model evaluation involved goodness-of-fit and prediction-corrected visual predictive check plots and a sampling-importance-resampling procedure. The model was externally qualified and refined using Phase 3 SAB PK data. Results The initial dataset included 4890 plasma concentrations from 773 healthy subjects or patients with ABSSSI, HABP, or CABP. This dataset was expanded to include 1134 plasma concentrations from 180 patients with SAB. External qualification showed that the model predicted data from patients with SAB well but the model was refined to best capture data from these patients. The refined model (three-compartment model with linear elimination) provided a robust fit to the pooled data (Figure 1). Model-based simulations to predict exposure in subgroups (i.e., renal function, body size, sex, and infection type) showed that renal function is the most clinically relevant covariate, consistent with the predominance of renal elimination for ceftobiprole (Figure 2). While model-based simulations showed that predicted exposure in subjects with extreme body weight (120 kg) fall below the bioequivalence reference range of healthy subjects weighing 75 kg, these weight-based differences are unlikely to be clinically significant. Neither sex nor infection type are expected to have a clinically relevant impact. Conclusion A population PK model that described the plasma PK of ceftobiprole well in healthy and infected patients was developed. The derived measures of plasma exposure are expected to be both accurate and precise. Disclosures Anthony P. Cammarata, M.S., Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Gr