Biomarker-informed PBPK modelling of meropenem in paediatric severe pneumonia: implications for target-site PK/PD
Yao Liu1,2, Sa-Sa Zhang1, Ji-Hui Chen3
1State Key Laboratory of Natural Medicine, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Insights
Optimizing meropenem dosing for pneumonia requires focusing on epithelial lining fluid (ELF) concentrations, not just plasma levels. This approach improves therapeutic efficacy and patient survival, especially in pediatric cases.
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Infectious Diseases
- Pediatric Pharmacology
Background:
- Meropenem efficacy in pneumonia hinges on optimal antimicrobial exposure in epithelial lining fluid (ELF).
- Limited ELF pharmacokinetic data, particularly in children, hinders effective dosing strategies.
- Understanding drug penetration into the lung is crucial for meropenem treatment success.
Purpose of the Study:
- To develop a physiologically based pharmacokinetic (PBPK) model for predicting meropenem concentrations in plasma and ELF.
- To evaluate pharmacodynamic target attainment under various clinical dosing strategies.
- To assess the relationship between meropenem exposure and survival in pneumonia patients.
Main Methods:
- Developed a PBPK model to simulate unbound meropenem concentrations in plasma and ELF.
- Incorporated an empirical penetration coefficient to link lung and ELF concentrations.
- Related meropenem exposure (e.g., %ƒT > MIC) to in-hospital mortality using Monte Carlo simulations.
Main Results:
- The PBPK model accurately predicted meropenem plasma and ELF concentrations.
- Epithelial lining fluid (ELF) penetration was influenced by physiological and pathological factors.
- ELF %ƒT > MIC demonstrated higher variability and stronger correlation with survival than plasma concentrations in both adults and children.
Conclusions:
- Targeting infection-site pharmacokinetics (ELF) is superior to plasma exposure for meropenem efficacy in pneumonia.
- The developed PBPK model can guide optimization of meropenem dosing regimens.
- Prolonged infusions may improve target attainment but are insufficient for high-MIC pathogens or poor lung penetration scenarios.
Objectives:
Optimal antimicrobial exposure in epithelial lining fluid (ELF) is critical for meropenem efficacy in pneumonia, yet ELF pharmacokinetic data remain scarce, particularly in children. To address this, we aimed to develop a model capable of predicting meropenem concentrations in both plasma and ELF for evaluating pharmacodynamic target attainment under clinical dosing strategies.
Methods:
A physiologically based pharmacokinetic (PBPK) model was developed to simulate unbound meropenem concentrations in plasma and ELF. An empirical penetration coefficient (ρ) was incorporated to link lung intracellular concentrations to ELF concentrations, modelled as a function of clinical and inflammatory covariates. Following validation, the percentage of time over a dosing interval that the free drug concentration remains above the MIC(%ƒT > MIC), of meropenem plasma and ELF were related to in-hospital mortality. Monte Carlo simulations were conducted to assess the PTA for 40%ƒT > MIC under varying regimens, MIC ranges (0.25-16 mg/L) and penetration scenarios.
Results:
The PBPK model accurately predicted meropenem exposures in both plasma and ELF. ELF penetration was significantly influenced by physiological and pathological factors. ELF %ƒT > MIC showed higher interindividual variability compared with that of plasma and was more strongly correlated with survival in both adult (P = 0.073) and paediatric patients (P = 0.013). Although prolonging the infusion improved ELF target attainment for susceptible pathogens (MIC ≤4 mg/L) with adequate penetration, it failed against high-MIC strains or with poor lung penetration.
Conclusions:
These findings underscore the importance of targeting infection-site pharmacokinetics over plasma exposure for better therapeutic efficacy in pneumonia. The model can be used to optimize dosing strategies.
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