Determining an appropriate fosfomycin (ZTI-01) dosing regimen in pneumonia patients by utilizing minimal PBPK modeling and target attainment analysis

Fosfomycin, a broad-spectrum antibiotic used for uncomplicated cystitis, represents a potential promising candidate in combating resistant pneumonia. To facilitate the transition of fosfomycin to broader indications, including pneumonia, a minimal physiologically based pharmacokinetics (m-PBPK) model for fosfomycin was developed based on data from plasma, epithelial lining fluid (ELF), and alveolar macrophages (AMs) obtained from 37 healthy participants in a recently completed intrapulmonary PK study. Utilizing this mechanistic m-PBPK model enabled us to predict drug concentrations at the infection site in pneumonia patients, taking into consideration the pathophysiological changes occurring during the infection. Our prediction shows that the drug concentrations at the infection site reduced, while plasma levels remain unchanged. Monte Carlo simulations were conducted to evaluate the probability of target attainment (PTA) for various dosing regimens infused over 1 h against major hospital-acquired pneumonia pathogens in plasma and ELF. Our PTA analysis suggested that if plasma concentrations are the appropriate efficacy indicator, a dose of 4 g q8h is sufficient for <i>Pseudomonas aeruginosa and Staphylococcus aureus</i> infections. However, if ELF concentrations are a more accurate indicator, this dose is only effective for <i>S. aureus</i> pneumonia. For <i>P. aeruginosa</i> pneumonia, a dose of 6 g q8h is recommended, with an even higher dose of 8 g q8h necessary for pneumonia patients. In conclusion, our model provides critical insights into fosfomycin dosing for pneumonia treatment, guiding clinical study design. Furthermore, it serves as a platform to evaluate intrapulmonary pharmacokinetics for other antibiotics.