LAUSR

Increasing prevalence of infections caused by antimicrobial-resistant Gram-negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination approved for adults and children 3 months and older with complicated intra-abdominal infection, and urinary tract infection (cUTI) or hospital-acquired/ventilator-associated pneumonia (adults only in the US) caused by susceptible Gram-negative bacteria. Extensive population pharmacokinetic (PK) datasets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2000-500 mg by 2-hour intravenous [IV] infusion every 8 hours [q8h], with adjustments for renal function). Following the completion of one phase I (NCT01893346) and two phase II ceftazidime-avibactam studies (NCT02475733 and NCT02497781) in children, adult PK datasets were updated with pediatric PK data. This paper describes the development of updated combined adult and pediatric population PK models and their application in characterizing the population PK of ceftazidime and avibactam in children, and in dose selection for further pediatric evaluation. The updated models supported the approval of ceftazidime-avibactam pediatric dosage regimens (all by 2-hour IV infusion) of 50-12.5 mg/kg (maximum 2000-500 mg) q8h for those ≥6 months to 18 years old, and 40-10 mg/kg q8h for those ≥3 to 6 months old with creatinine clearance >50 mL/min/1.73 m2 .