Target-site cefiderocol pharmacokinetics in soft tissues of healthy volunteers

Abstract

Background: Cefiderocol may potentially be used to treat skin and soft tissue infections (SSTIs). However, the pharmacokinetics of cefiderocol in human soft tissues have not yet been determined. The objective of the present PK study was to investigate whether target-site concentrations of cefiderocol are sufficiently high for the treatment of SSTIs.

Methods: In this pharmacokinetic study, a single intravenous dose of 2 g cefiderocol was administered to eight healthy male volunteers. Drug concentrations were determined in plasma, muscle and subcutis over 8 h. Free plasma concentrations were calculated using the plasma protein binding determined with ultrafiltration. Free tissue concentrations were obtained using microdialysis. Penetration ratios were calculated as AUC0-8h_free_tissue/AUC0-8h_free_plasma. A population pharmacokinetic model was developed, and the probability of target attainment (PTA) was determined using Monte Carlo simulations.

Results: Cefiderocol showed good tissue penetration, with mean penetration ratios ± standard deviation of 0.99 ± 0.33 and 0.92 ± 0.30 for subcutis and muscle, respectively. Cefiderocol pharmacokinetics in plasma were best described with a two-compartment model, and tissue concentrations were described by scaling the tissue concentrations to concentrations in the peripheral compartment of the plasma model. For a thrice-daily regimen with 2 g doses intravenously infused over 3 h, PTA was ≥90% for MIC values up to 4 mg/L, both based on free plasma and soft tissue pharmacokinetics.

Conclusions: This study indicates that a dose of 2 g cefiderocol achieves concentrations in plasma considered sufficient for treating relevant bacterial species. Assuming a comparable PK/PD target for soft tissues, sufficiently high concentrations would also be achieved in soft tissues.

Figure 1.

Concentration–time profile of cefiderocol after a single intravenous dose of 2 g (mean ± SD). Tissue concentrations are plotted at the mid-point of the microdialysate collection interval. The dotted horizontal lines indicate an MIC of 4 and 8 mg/L. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 2.

Visual predictive check for the population pharmacokinetic model. Open circles represent observations, and the solid line indicate the median of observed concentrations. The dashed lines represent the 10th, 50th and 90th percentiles of the simulated data (n = 1000). The shaded areas indicate the 95% confidence interval around the simulated median. Note that the confidence intervals around the 10th and 90th percentiles of the simulated data are not plotted given the small population size.

Figure 3.

Probability of target attainment (PTA) based on cefiderocol pharmacokinetics in plasma, subcutaneous adipose tissue and skeletal muscle tissue over 24 h following a 2 g q8h dosing regimen given as an intravenous infusion over 3 h. PTA was calculated using a fT_>MIC target of 75% and 95%. The dotted line indicates 90% PTA. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.