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

Clin Pharmacol Ther. 2023 Jan;113(1):182-195. doi: 10.1002/cpt.2764. Epub 2022 Nov 16.

Abstract

Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination developed to treat serious Gram-negative bacterial infections; approved indications include complicated urinary tract infection, complicated intra-abdominal infection, and hospital-acquired pneumonia including ventilator-associated pneumonia in patients ≥ 3 months old. Because of the predominantly renal clearance of ceftazidime and avibactam, dose adjustments (reductions) are required for patients with estimated creatinine clearance (CrCL) ≤ 50 mL/min. We describe the application of combined adult and pediatric population pharmacokinetic models in developing ceftazidime-avibactam dose recommendations for pediatric patients ≥ 2 to < 18 years old with body surface area-normalized CrCL ≤ 50 mL/min/1.73 m2 , including moderate, severe, or very severe renal impairment, or end-stage renal disease requiring hemodialysis, and for patients ≥ 3 months to < 2 years old with mild, moderate, or severe renal impairment. Models included allometric scaling for all subjects and simulations (1,000 subjects per age group, renal function group, and indication) were performed nonparametrically using post hoc random effects. Doses were selected based on simulated pediatric patients achieving steady-state exposures similar to adults and high probability of target attainment (using a simultaneous joint target for both ceftazidime and avibactam). Because there were few children with renal impairment in the ceftazidime-avibactam clinical trials, selected pediatric doses were guided by extrapolation and matching of adult exposures associated with efficacy and within established safety margins. The recommended doses for pediatric patients with estimated CrCL ≤ 50 mL/min/1.73 m2 use equivalent adjustments in dose quantity and/or administration interval (vs. the corresponding age group with normal renal function) as those for adults.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Anti-Bacterial Agents / adverse effects
  • Ceftazidime* / pharmacokinetics
  • Child
  • Drug Combinations
  • Humans
  • Infant
  • Kidney / physiology
  • Monobactams
  • Renal Insufficiency*
  • beta-Lactamase Inhibitors / therapeutic use

Substances

  • avibactam, ceftazidime drug combination
  • Ceftazidime
  • Anti-Bacterial Agents
  • avibactam
  • Drug Combinations
  • beta-Lactamase Inhibitors
  • Monobactams