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 complicated urinary tract infection or hospital‐acquired ventilator‐associated pneumonia (adults only in the United States) caused by susceptible gram‐negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000–500 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 data sets 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 2,000–500 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.

Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?☑ Ceftazidime-avibactam dosage regimens for pediatric patients with normal renal function or mild renal impairment have been developed using combined adult and pediatric population pharmacokinetic (PK) models and exposure and probability of target attainment (PTA) simulations in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), or hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP). Approved ceftazidime-avibactam doses for adults include adjustments for patients with moderate or severe renal impairment or end-stage renal disease (ESRD). WHAT QUESTION DID THIS STUDY ADDRESS?☑ Using the existing combined adult and pediatric population PK models for ceftazidime and avibactam, additional simulations were conducted to evaluate dose adjustments for pediatric patients ≥ 2 to < 18 years old with moderate, severe, or very severe renal impairment or ESRD and cIAI, cUTI, or HAP/VAP, and for those ≥ 3 months to < 2 years old with moderate or severe renal impairment. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?☑ These analyses support the recommended ceftazidimeavibactam pediatric dose adjustments for renal function included in European and US labeling. The approved pediatric dosing recommendations use the same proportional dose adjustments or dose interval adjustments (vs. the corresponding age group with normal renal function) as those for adults with renal impairment. HOW MIGHT THIS CHANGE CLINICAL PHARMA-COLOGY OR TRANSLATIONAL SCIENCE?☑ This work demonstrates the use of modeling and simulation to develop pediatric dosing recommendations across a range of age and renal function groups and patient populations based on exposure-matching and extrapolation from adult data.