Translational Model to Predict Lung and Prostate Distribution of Levofloxacin in Humans

TL;DR

This study uses a pharmacokinetic model to predict how levofloxacin distributes in lung and prostate tissues in humans, helping to optimize antibiotic dosing.

Contribution

A translational PBPK model is developed to predict tissue-specific drug distribution of levofloxacin in lung and prostate.

Findings

Levofloxacin shows similar penetration into lung and prostate tissues with unbound partition coefficients of 0.79 and 0.72, respectively.

Efflux transporters influence drug distribution to prostate but not lung tissue.

The model can help refine dosing regimens based on pathogen susceptibility and tissue exposure.

Abstract

Background/Objectives: Levofloxacin (LVX) is a fluoroquinolone approved for the treatment of bacterial pneumonia, sinusitis, and prostatitis. Emerging in vitro and preclinical evidence suggests that efflux transporters are involved in LVX’s target tissue site distribution. Methods: The objective of this research was to characterize tissue exposure using a physiologically based pharmacokinetic (PBPK) model to be able to make more educated choices for optimal doses using target site pharmacokinetics data. Results: The final PBPK model in humans was applied to simulate free target site concentrations of LVX in lung and prostate, linking to minimum inhibitory concentrations (MIC) to assess appropriateness of currently approved dosing regimens for infections in both tissues. The clinical PBPK model was able to reproduce total plasma as well as free lung and prostate exposure of LVX in humans. Efflux transporters participate in LVX distribution to prostatic but not pulmonary tissue. Our results show a good penetration of LVX in both tissues with unbound partition coefficient (Kp,uu) equal to 0.79 and 0.72 for lung and prostate, respectively. Since LVX penetration in lung and prostate is similar, different sensitivities of the pathogens to LVX will dictate the effectiveness of the approved therapeutic regimen in the treatment of bacterial pneumonia, sinusitis, and prostatitis. Conclusions: Our research provides relevant insight into LVX’s target site exposure in lung and prostate. When integrated with pathogen-specific susceptibility data, these findings can be applied to refine current dosing regimens and help optimize the pharmacological treatment outcomes.

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