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Physiologically Based Pharmacokinetic Modeling of Meropenem in Preterm and Term Infants

Samit Ganguly1,2, Andrea N Edginton3, Jacqueline G Gerhart1

  • 1Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, 301 Pharmacy Lane, Campus Box #7569, Chapel Hill, NC, 27599-7569, USA.

Clinical Pharmacokinetics
|June 22, 2021
PubMed

Insights

Physiologically based pharmacokinetic (PBPK) modeling confirms meropenem dosing for infants under 3 months. The model accurately predicts drug concentrations, supporting current product label recommendations for treating infections.

Area of Science:

  • Pharmacokinetics and Drug Metabolism
  • Pediatric Pharmacology
  • Computational Modeling in Medicine

Background:

  • Meropenem, a broad-spectrum antibiotic, is FDA-approved for pediatric use, including complicated intra-abdominal infections in infants <3 months.
  • The influence of renal maturation on meropenem pharmacokinetics and optimal dosing in neonates and infants remains unclear.
  • Physiologically based pharmacokinetic (PBPK) modeling was employed to investigate meropenem disposition in preterm and term infants.

Purpose of the Study:

  • To characterize meropenem pharmacokinetics in infants using PBPK modeling.
  • To evaluate the impact of renal maturation on meropenem disposition and dosing in pediatric patients.
  • To assess the adequacy of current meropenem dosing regimens for infants <3 months.

Main Methods:

  • An adult meropenem PBPK model was adapted for infants, incorporating maturation of glomerular filtration rate and renal transporters.
  • The PBPK model's accuracy was validated against 645 plasma concentrations from 181 infants (23-40 weeks gestational age; 1-95 days postnatal age).
  • Simulations were conducted to evaluate meropenem dosing as per the product label for complicated intra-abdominal infections in infants.

Main Results:

  • The PBPK model accurately predicted infant plasma concentrations, with an average fold error of 0.90.
  • Model-predicted clearance in a virtual infant population aligned with previous estimations.
  • Recommended product label dosing achieved a target meropenem plasma concentration (4 mg/L) for over 50% of the dosing interval in 90% of virtual infants.

Conclusions:

  • The developed PBPK model provides robust support for the meropenem dosing regimens currently recommended in the product label for infants under 3 months of age.
  • This modeling approach aids in understanding drug disposition in immature renal systems.
  • The findings reinforce the safe and effective use of meropenem in the target pediatric population.
Abstract

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