Biofilm formation plays an important role in the persistence of pulmonary infections, for example, in cystic fibrosis patients. So far, little is known about the antimicrobial 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 under both conditions. P. aeruginosa was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg of body weight). Plasma and microdialysate were sampled from 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 and two peripheral distribution compartments, and the disposition in the lung 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 significantly higher level of plasma CIP exposure (area under the concentration-time curve from time zero to infinity, 27.3 Ϯ 12.1 g · h/ml and 13.3 Ϯ 3.5 g · h/ml in infected and healthy rats, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue concentration/plasma concentration ratio (lung penetration factor ϭ 0.44 and 1.69 in infected and healthy rats, respectively), and lung clearance (CL lung ) was added to the model for these animals (CL lung ϭ 0.643 liters/h/kg) to explain the lower tissue concentrations. Our results indicate that P. aeruginosa biofilm infection reduces the 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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Ceftaroline, approved to treat skin infections and pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA), has been considered for the treatment of central nervous system (CNS) infections. A population pharmacokinetic (popPK) model was developed to describe ceftaroline soft tissue and cerebrospinal fluid (CSF) distributions and investigate the probability of target attainment (PTA) of the percentage of the dosing interval that the unbound drug concentration exceeded the MIC (% fT >MIC ) to treat MRSA infections.

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This study investigated plasma and brain disposition of quetiapine lipid core nanocapsules (QLNC) in naïve and schizophrenic (SCZ-like) rats and developed a semi-mechanistic model to describe changes in both compartments following administration of drug in solution (FQ) or nanoencapsulated. QLNC (1 mg/mL) presented 166 ± 39 nm, low polydispersity, and high encapsulation (93.0 ± 1.4%). Model building using experimental data from total and unbound plasma and unbound brain concentrations obtained by microdialysis after administration of single i.v. bolus dose of FQ or QLNC to naïve and SCZ-like rats. A two-compartment model was identifiable both in blood and in brain with a bi-directional drug transport across the blood-brain barrier (CL in and CL out ). SCZ-like rats significant decrease in brain exposure with FQ (decrease in CL in ) was reverted by QLNC showing that nanocarriers govern quetiapine tissue distribution. Model simulations allowed exploring the potential of LCN for brain delivery. SIGNIFICANCE STATEMENTA population approach was used to simultaneously model total and unbound plasma and unbound brain quetiapine concentrations allowing for quantification of the rate and extent of drug's brain distribution following administration of both free drug in solution or as nanoformulation to naïve and SCZ-like rats. The model-based approach is useful to better understand the possibilities and limitations of this nanoformulation for drug delivering to the brain, opening the opportunity to use this approach to improve SCZ-treatment limited response rates.