Physiologically Based Pharmacokinetic Study of Cefepime in Different Communities.

Abstract

Introduction/objective: Cefepime, a fourth-generation cephalosporin, is commonly prescribed in clinical practice for the treatment of moderate to severe infections and is primarily eliminated by renal clearance. PBPK modeling, a mechanistic and innovative approach with substantial implications for decision-making and drug development. The current study aimed to develop and validate a PBPK model of cefepime in healthy, CKD, geriatric, and pregnant populations to support dose optimization and promote personalized, safer treatment strategies.

Methods: The model was first developed in a healthy adult population using different intravenous doses of cefepime, and its performance was evaluated using observed-to-predicted ratios of pharmacokinetic parameters. A virtual cohort of 100 subjects was then created in PK-Sim, and cefepime pharmacokinetics in CKD, geriatric, and pregnant populations was simulated after incorporating the relevant pathophysiological alterations.

Results: The cefepime PBPK model accurately predicted drug disposition across healthy, geriatric, CKD, and pregnant populations, aligning with reported clinical data.

Discussion: The findings underscore the effectiveness of PBPK modeling in forecasting cefepime pharmacokinetics across diverse populations, particularly where conducting clinical trials may be difficult. This predictive accuracy highlights its importance in guiding dose adjustments and advancing individualized therapy.

Conclusion: Approximately 95% of observed versus predicted cefepime concentrations fell within a two-fold error margin, demonstrating the robustness of the PBPK model. This PBPK model is intended to complement, not replace, therapeutic drug monitoring by supporting initial dose selection and pharmacokinetic risk stratification in special populations, particularly in clinical settings where routine monitoring or population-specific pharmacokinetic data are limited.