Physiologically Based Pharmacokinetic Study of Cefepime in Different Communities

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Computational Biology and Bioinformatics
• Clinical Pharmacology

Background:

• Cefepime, a fourth-generation cephalosporin, is crucial for treating moderate to severe infections.
• Renal clearance is the primary elimination pathway for cefepime.
• Physiologically based pharmacokinetic (PBPK) modeling offers a mechanistic approach for drug development and decision-making.

Purpose of the Study:

• To develop and validate a PBPK model for cefepime.
• To predict cefepime pharmacokinetics in healthy, chronic kidney disease (CKD), geriatric, and pregnant populations.
• To support cefepime dose optimization and personalized treatment strategies.

Main Methods:

• Developed a PBPK model for cefepime in healthy adults using IV doses.
• Evaluated model performance by comparing predicted and observed pharmacokinetic parameters.
• Simulated cefepime pharmacokinetics in virtual cohorts representing CKD, geriatric, and pregnant populations using PK-Sim, incorporating pathophysiological alterations.

Main Results:

• The cefepime PBPK model demonstrated accurate prediction of drug disposition across all studied populations (healthy, geriatric, CKD, pregnant).
• Model predictions closely aligned with available clinical data.
• Approximately 95% of predicted cefepime concentrations fell within a two-fold error margin of observed values, confirming model robustness.

Conclusions:

• PBPK modeling is effective for forecasting cefepime pharmacokinetics in diverse populations, especially where clinical trials are challenging.
• The validated PBPK model can guide cefepime dose adjustments and advance individualized therapy.
• This PBPK model complements therapeutic drug monitoring for initial dose selection and risk stratification in special populations with limited pharmacokinetic data.