Population Pharmacokinetic Analysis To Support Dosing Regimens Of Ceftobiprole
Hui Kimko, Steven Xu, Bindu Murthy, Mahesh Samtani, Partha Nandy, Richard Strauss, Gary Noel
Johnson & Johnson Pharmaceutical Research & Development; Raritan, NJ; Titusville, NJ
Objectives: Ceftobiprole is a first-in-class broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci. Dosage adjustment strategy was supported by a population analysis approach.
Methods: Ceftobiprole plasma pharmacokinetic (PK) data from healthy volunteers and patients in eight phase 1 (n=162), one phase 2 (n=27) and two phase 3 (n=414) clinical trials were combined to identify factors contributing towards inter-individual variability in PK of ceftobiprole. NONMEM was used to develop a PK model with statistically significant covariates. To test clinical relevance of the covariates, the percentage of time the concentrations of ceftobiprole above MIC during a dosing interval (%T>MIC) was estimated, which is the PK/PD index of ceftobiprole.
Results: A three-compartment model with first-order elimination provided the best fit for the ceftobiprole plasma- concentration time-profile. In the final population PK model, clearance (CL) was a function of creatinine clearance and health status (healthy volunteers vs. patients); volume of distribution in the central compartment (V1) was a function of body weight and health status; volume of distribution in a shallow peripheral compartment (V2) was a function of gender and health status; volume of distribution in a deep peripheral compartment (V3) was a function of gender. Of these covariates, only the renal function was identified as the clinically relevant factor using %T>MIC. Age (i.e., ³ 18 years old) was neither statistically nor clinically influential when creatinine clearance was included as a covariate. The influence of other statistically significant covariates such as gender and body weight on PK was negligible with suggested dosing regimen adjustments based on degree of renal function. Exploratory analyses with race and concomitant medications as covariates suggested no change in PK of ceftobiprole due to these factors.
Conclusion: The population PK analyses support the proposed labeling dosing for ceftobiprole and dosing adjustments based on creatinine clearance only. No adjustments to ceftobiprole dosing appear to be warranted for age, race, gender, body weight or the assessed concomitant medications.