Population Pharmacokinetic Modeling as a Tool to Characterize the Decrease in Ciprofloxacin free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats [PublishAheadOfPrint]

Biofilm formation plays an important role in the persistence of pulmonary infections, for example in cystic fibrosis patients. So far, little is known about antimicrobials lung disposition in biofilm-associated pneumonia. This study aimed to evaluate, by microdialysis, ciprofloxacin (CIP) penetration into the lungs of healthy and Pseudomonas aeruginosa biofilm infected rats and to develop a comprehensive model to describe the CIP disposition in both conditions. P. aeruginosa was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg). Plasma and microdialysate were sampled in different animal groups and the observations were evaluated by noncompartmental analysis (NCA) and population pharmacokinetic (popPK) analysis. The final model, that successfully described all data, consisted of an arterial and a venous central compartment, two peripheral distribution compartments and lung disposition was modeled as a two-compartment model structure linked to the venous compartment. Plasma clearance was approximately 32% lower in infected animals leading to a significant higher plasma CIP exposure (AUC_0- 27.3 ± 12.1 μg⋅h/mL and 13.3 ± 3.5 μg⋅h/mL, infected and healthy, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue/plasma ratio (fT = 0.44 and fT = 1.69, infected and healthy, respectively), a lung clearance was added to the model for these animals (CL_lung = 0.643 L h^-1 kg^-1) to explain the lower tissue concentrations. Our results indicate that P. aeruginosa biofilm infection reduces CIP free interstitial lung concentrations and increases plasma exposure, suggesting that plasma concentrations alone are not a good surrogate of lung concentrations.

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