Population pharmacokinetics and Monte Carlo simulation of Cefepime in paediatric and Young adult bone marrow transplant patients.

AIMS: To develop a population pharmacokinetic (PopPK) model of cefepime in paediatric and young adult BMT patients, identify clinical predictors of variability in cefepime clearance and simulate dosing strategies to optimize therapeutic target attainment.

METHODS

This PopPK analysis pooled data from two prospective studies, including 97 BMT patients aged 1 month to 30 years with 252 cefepime plasma concentrations. The final model was validated with goodness-of-fit plots, bootstrap analysis and prediction-corrected visual predictive checks. Monte Carlo simulations assessed the probability of target attainment (PTA) for various dosing regimens, targeting 100% of the dosing interval during which free drug concentrations exceed the minimum inhibitory concentration (100% fT>MIC), across a range of estimated glomerular filtration rates (eGFR) and MICs.

RESULTS

A two-compartment model with first-order elimination best described the data. The most predictive covariate for cefepime clearance was eGFR estimated using a combined creatinine-cystatin C equation (eGFRcr-cys). Simulations suggested that standard cefepime dosing (50 mg/kg every 8 h over 30 min) often failed to achieve ≥90% PTA, particularly at MICs ≥2-8 mg/L in patients with normal or augmented renal clearance. Extended (3-hour) or continuous infusions substantially improved PTA.

CONCLUSIONS

This study presents the first cefepime PopPK model tailored to paediatric and young adult BMT recipients, identifying eGFRcr-cys as a key determinant of cefepime clearance. Prolonging the infusion duration or shortening the dosing interval may be required to enhance target attainment with initial dosing regimens. This PopPK model provides a foundation for individualized dosing adjustments through model-informed precision dosing.