Population Pharmacokinetic Modeling and Probability of Pharmacodynamic Target Attainment for Ceftazidime‐Avibactam in Pediatric Patients Aged 3 Months and Older

Abstract

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.

All Roads Lead to Rome: Enhancing the Probability of Target Attainment with Different Pharmacokinetic/Pharmacodynamic Modelling Approaches

“…They calculated the PTA based on the dosing regimens used in pediatric populations in previous clinical trials [ 85 , 86 ] and proved that the doses were sufficient to reach PTA in pediatric populations with normal renal function or mild renal impairment. Thus, the modelling results supported the current dosing scheme in clinical practice [ 84 ].…”

“…Moreover, it gave guidance for dose adjustments in the case of renal insufficiency [ 80 ]. In addition to this study in adults, Franzese et al addressed the question of PTA in pediatric patients older than three months [ 84 ]. They calculated the PTA based on the dosing regimens used in pediatric populations in previous clinical trials [ 85 , 86 ] and proved that the doses were sufficient to reach PTA in pediatric populations with normal renal function or mild renal impairment.…”

Population Pharmacokinetic Modeling for Ceftazidime‐Avibactam Renal Dose Adjustments in Pediatric Patients 3 months and Older

“…The dose was assumed to be 930 mg (i.e., 15 mg/kg × 62 kg); a body weight of 62 kg was chosen as the mid‐point of the reported range of 41–83 kg 20 Single‐dose AUC 0‐inf is equivalent to simulated AUC ss over a dose interval. Linear kinetics for dose normalization (from 930 to 750 mg). The maximum effect ( E max ) body weight covariate function in the ceftazidime model 9 applies to patients in the Leroy study 20 …”

“…other antibiotics) in both adult and pediatric populations, including in patients with pneumonia. 28,29 Completion of the ceftazidime-avibactam phase II pediatric cIAI and cUTI trials, and the associated population PK analyses demonstrating that the evaluated pediatric dosages achieved exposures and PTA generally comparable to those in adults, 9,10,12 supported extension of the existing adult approvals of ceftazidime-avibactam in Europe and the United States to include pediatric patients ≥ 3 months old (cIAI and cUTI only in the United States). 1,2 The simulation results for pediatric patients with estimated CrCL ≥ 51 mL/min/1.73 m 2 (i.e., normal renal function or mild impairment) have been published.…”

Use of Antibiotics in Preterm Newborns

“…CAZAVI is licensed for use in infants > 3 months [ 161 ]. PK behavior in children was already evaluated in a phase I study and two phase II studies [ 162 , 163 ]. A dose of 10–40 mg/kg q8h for those ≥ 3 to 6 months old with creatinine clearance > 50 mL/min/1.73 m 2 was suggested.…”