Clinical Pharmacokinetics and Pharmacodynamics of Ceftazidime-Avibactam Combination: A Model-Informed Strategy for its Clinical Development

Avibactam is a non--lactam, -lactamase inhibitor of the diazabicyclooctane class that covalently acylates its -lactamase targets, encompassing extended spectrum of activities that cover serine -lactamases but not metallo--lactamases. Ceftazidime and avibactam have complementary pharmacokinetic (PK) profiles. Both drugs have a half-life of approximately 2 h, making them suitable to be combined in a fixed-dose combination ratio of 4:1 (ceftazidime:avibactam). Renal clearance is the primary elimination pathway of both ceftazidime and avibactam, and dose adjustment is required in patients with moderate and severe renal impairment. Population PK models of ceftazidime and avibactam were developed separately and incorporated body weight, disease state, ethnicity, and renal function (creatinine clearance) as covariates of clearance and volume of distribution. The clinical dosing regimen of ceftazidime/avibactam combination was determined from population PK model simulations in the patient population for dosing regimens that can achieve sufficient joint probability of target attainment for ceftazidime minimum inhibitory concentration (MIC) of 8mg/L at a fixed 4mg/L avibactam concentration (MIC 8/4mg/L); 8mg/L is the breakpoint of ceftazidime in Enterobacteriaceae and Pseudomonas aeruginosa for the target pharmacodynamic indices of ceftazidime and avibactam of 50% time at which the free ceftazidime concentration is above the MIC (fT>MIC) and 50% time at which the free avibactam is above a threshold concentration of 1mg/L (fT>C-T). Whereas the static index approach does not take into account the changing potency of ceftazidime in the presence of changing avibactam concentration, a mathematical model based on kill-curve kinetics was utilized to validate the dose selection in humans. The clinical dosing regimen of 2/0.5g ceftazidime/avibactam administered every 8h as a 2-h intravenous infusion in patients with normal renal function, with dose adjustment in renal impairment, demonstrated statistical non-inferiority to carbapenem in phase III studies on the treatment of complicated intra-abdominal infection, complicated urinary tract infection, and nosocomial pneumonia, including ceftazidime non-susceptible Gram-negative pathogens. The success of the phase III studies validated the dose selection and exposure target that were associated with efficacy based on a model-informed approach.