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

Abstract

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 Pseudomonas aeruginosa and Staphylococcus aureus infections. However, if ELF concentrations are a more accurate indicator, this dose is only effective for S. aureus pneumonia. For P. aeruginosa 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.

Keywords: fosfomycin; m-PBPK; pneumonia; repurposing; target attainment analysis.

Fig 1

Schematic diagram of the study design. The figure was created using BioRender.

Fig 2

The final proposed m-PBPK model structure following the administration of IV-infused fosfomycin includes plasma, lung (comprising lung tissues, interstitial fluid [ISF], epithelial lining fluid [ELF], and alveolar macrophages [AMs]), and residual (includes all the other organs). The plasma compartment (dashed line) on the left is identical to the plasma compartment on the right, and the lung receives full cardiac output (Q_C), while the tissues receive a fraction (fd). The figure was created using BioRender.

Fig 3

Observed (symbol) and model-predicted (line) concentration–time profiles for fosfomycin in (a) plasma (n = 37), (b) epithelial lining fluid (ELF), and (c) amacrophages (AMs). n = 6 at each sampling point in the ELF and AMs.

Fig 4

Goodness-of-fit plots for the population PK model of fosfomycin. (A) Observed versus population-predicted fosfomycin concentrations, (B) observed versus individual-predicted fosfomycin concentrations, (C) conditional weighted residuals versus population-predicted fosfomycin concentrations, (D) conditional weighted residuals versus time. Dotted black lines represent lines of identity in (A) and (B) and zero line in (C) and (D).

Fig 5

Pathophysiological changes during pneumonia and their impact on the PK profile in the ELF. (a) Increasing PS₁ and PS₂ due to enhanced membrane permeability lead to minor changes in the PK profile. (b) A decrease in the number of AMs, which reduces V_AMs, does not alter the PK profile. (c) Increasing V_ELF due to alveolar edema leads to a minor reduction in drug concentration in the ELF. (d) Decreasing Kp_ELF due to surfactant deactivation results in a reduction in ELF concentration. The solid line represents the base model, while the dashed line represents the modified model due to the pathophysiological conditions. The figure was created using BioRender.

Fig 6

Comparison of PTA% of fosfomycin in plasma and ELF for healthy and pneumonia for fosfomycin versus MIC for S. aureus following the administration of (a) 4 g q8h, (b) 5 g q8h, (c) 6 g q8h, (d) 8 g q12h, (e) 10 g q12h, and (f) 8 g q8h. The dashed line represents ≥90% of the population who achieved the PK/PD target.

Fig 7

Comparison of PTA% of fosfomycin in plasma and ELF for healthy and pneumonia for fosfomycin versus MIC for P. aeruginosa following the administration of (a) 4 g q8h, (b) 5 g q8h, (c) 6 g q8h, (d) 8 g q12h, (e) 10 g q12h, and (f) 8 g q8h. The dashed line represents ≥90% of the population who achieved the PK/PD target.