Population Pharmacokinetic Modelling of Ceftazidime and Avibactam in the Plasma and Epithelial Lining Fluid of Healthy Volunteers

OBJECTIVES: Our objective was to develop population pharmacokinetic (PK) models for ceftazidime and avibactam in the plasma and epithelial lining fluid (ELF) of healthy volunteers and to compare ELF concentrations to plasma PK/pharmacodynamic (PD) targets. METHODS: Plasma and ELF population PK models were developed for ceftazidime and avibactam concentration data from 42 subjects (NCT01395420). Two- and three-compartment plasma PK models were fitted to ceftazidime and avibactam plasma PK data, and different plasma–ELF linked models were evaluated. Using best-fitting models, plasma and ELF concentration–time profiles were simulated for 1000 subjects. ELF concentration–time profiles for ceftazidime/avibactam 2000–500 mg every 8 h were compared with plasma PK/PD targets for ceftazidime (50% of time above [fT >] 8 mg/l) and avibactam (50% fT > 1 mg/l). RESULTS: Three-compartment PK models best fitted the plasma concentration data for ceftazidime and avibactam. ELF data for both drugs were best described by a direct response (instantaneous equilibrium) model. Ceftazidime plasma–ELF relationships were best described by a saturable Michaelis–Menten model. For avibactam, departure from plasma–ELF relationship linearity was more modest than for ceftazidime. ELF:plasma penetration ratios of both ceftazidime (52%) and avibactam (42%) at plasma concentrations relevant for efficacy (~ 8 mg/l for ceftazidime and ~ 1 mg/l for avibactam) were greater than previously calculated using non-compartmental area under the curve (AUC) methods, which average across the entire concentration range. Ceftazidime and avibactam ELF exposures exceeded their respective plasma PK/PD time-above-threshold targets by the dosing interval mid-point in most subjects. CONCLUSIONS: This compartmental modelling analysis suggests ELF exposures of both ceftazidime and avibactam exceed levels required for efficacy in plasma.