Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination for the treatment of serious infections caused by resistant gram-negative pathogens. Population pharmacokinetic (PopPK) models were built to incorporate pharmacokinetic (PK) data from five phase III trials in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), or nosocomial (including ventilator-associated) pneumonia. Ceftazidime and avibactam pharmacokinetics were well-described by two-compartment disposition models, with creatinine clearance (CrCL) the key covariate determining clearance variability. Steady-state ceftazidime and avibactam exposure for most patient subgroups differed by ≤ 20% vs. healthy volunteers. Probability of PK/pharmacodynamic (PD) target attainment (free plasma ceftazidime > 8 mg/L and avibactam > 1 mg/L for ≥ 50% of dosing interval) was ≥ 94.9% in simulations for all patient subgroups, including indication and renal function categories. No exposure-microbiological response relationship was identified because target exposures were achieved in almost all patients. These modeling results support the approved ceftazidime-avibactam dosage regimens (2000-500 mg every 8 hours, adjusted for CrCL ≤ 50 mL/min).
© 2018 University of Liverpool. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.