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

Abstract

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.

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“…The combined dataset was used to update the PK model and run simulations demonstrating that the exposure and probability of target attainment in pediatric patients with normal or mildly impaired renal function were comparable to those observed in adults. Using a similar methodology, a subsequent PK population modeling study based on an extensive adult and pediatric database was conducted [ 90 ]. The results supported the recommended 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.…”