Therapeutic drug monitoring · 2025
Optimizing the Clinical Exposure of Fosfomycin in Critically Ill Adult Septic Patients: A Physiologically Based Pharmacokinetic Modeling.
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Sherazi Abdul Wasay
Аннотация
BACKGROUND: Sepsis, a condition characterized by the excessive release of inflammatory mediators, significantly alters body composition and physiology and is potentially altered by intensive care therapy. The present study aimed to expand a comprehensive physiologically based pharmacokinetic (PBPK) model for healthy individuals based on physiological changes associated with conditions in critically ill adult patients with sepsis and to validate its accuracy using fosfomycin as a therapeutically relevant medication.
METHODS: A comprehensive literature search was conducted using various online databases, and pharmacokinetic (PK) data for fosfomycin were gathered. PKSim, a PBPK modeling program, was then used to construct and evaluate drug-specific and intravenous models. The robustness of the model was then evaluated for each of the crucial PK parameters using the average fold error, predicted/observed ratios, and visual predictive checks.
RESULTS: Analysis of the performance of the model showed that all PK parameters were within the 2-fold allowable error range. The average fold error value, which is an indication of how much model predictions normally differ from the reported value, was 0.81 after intravenous infusions in healthy individuals, which validates the proposed fosfomycin model. In patients with sepsis, the R Pre/obs ratio was predicted to be 310.2 mcg/mL, which is comparable to the value of 332.3 mcg/mL from the literature. In addition, the results were further analyzed to show how sepsis affects the area under the systemic concentration over a time curve from zero to infinity (AUC 0-∞ ). The results of this analysis serve as a reference for clinicians determining the optimal dosage of fosfomycin.
CONCLUSIONS: The proposed model, which is effective in predicting fosfomycin PK variations in both healthy and critically ill patients with sepsis, will aid in optimizing the dose of fosfomycin for critically ill patients.
METHODS: A comprehensive literature search was conducted using various online databases, and pharmacokinetic (PK) data for fosfomycin were gathered. PKSim, a PBPK modeling program, was then used to construct and evaluate drug-specific and intravenous models. The robustness of the model was then evaluated for each of the crucial PK parameters using the average fold error, predicted/observed ratios, and visual predictive checks.
RESULTS: Analysis of the performance of the model showed that all PK parameters were within the 2-fold allowable error range. The average fold error value, which is an indication of how much model predictions normally differ from the reported value, was 0.81 after intravenous infusions in healthy individuals, which validates the proposed fosfomycin model. In patients with sepsis, the R Pre/obs ratio was predicted to be 310.2 mcg/mL, which is comparable to the value of 332.3 mcg/mL from the literature. In addition, the results were further analyzed to show how sepsis affects the area under the systemic concentration over a time curve from zero to infinity (AUC 0-∞ ). The results of this analysis serve as a reference for clinicians determining the optimal dosage of fosfomycin.
CONCLUSIONS: The proposed model, which is effective in predicting fosfomycin PK variations in both healthy and critically ill patients with sepsis, will aid in optimizing the dose of fosfomycin for critically ill patients.