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

Abstract

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.

Translational in vitro and in vivo PKPD modelling for apramycin against Gram-negative lung pathogens to facilitate prediction of human efficacious dose in pneumonia

“…We observed a reduced clearance of apramycin in infected animals. While it was beyond the scope of this study to find the cause; it is in line with previous results by Torres et al [31] where reduced ciprofloxacin clearance was shown in infected animals.…”

Model-Based Drug Development in Pulmonary Delivery: Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection

“…Lung PK are typically investigated by collecting either lung homogenates from small animals for total lung exposures, fluids from the airways (e.g., BAL or sputum) as an indication of the amount of drug in the epithelial lining fluid, or microdialysis for drug concentrations at a specific site in the lung 13, 15, 16, 31, 32, 33, 34. While total lung concentrations provide an estimate of overall lung exposure, they might not always represent the most relevant therapeutic exposure, since the amounts of intracellular and extracellular drugs are indistinguishable from each other.…”

“…In the literature, antibiotic concentrations in the lung have been measured in samples collected from bronchoalveolar lavage (BAL), sputum, microdialysis, and lung tissue homogenates 13, 14, 15, 16, 17, 18. However, these different sampling methods do not necessarily provide the same information.…”

Probability of Target Attainment of Tobramycin Treatment in Acute and Chronic Pseudomonas aeruginosa Lung Infection Based on Preclinical Population Pharmacokinetic Modeling

“…Chronic infection was developed to mimic the chronic infection observed in CF patients following previously reported protocols [16][17][18][19]. In order to produce a chronic infection, bacteria was impregnated in alginate beads according to Torres et al (2017) [20] based on Johansen & Høiby (1999) [21]. Briefly, 1 mL from a bacterial suspension, prepared as previously described, containing 10 9 CFU/mL of P. aeruginosa ATCC 27,853 was mixed with 9 mL of sterile alginate solution (1 mg/mL) and sprayed into a constant-stirring 0.1 M CaCl 2 solution in tris-HCL buffer (0.1 M, pH 7.0).…”