Bruna G. S. Torres (1), Alexandre Macedo (1), Elisabet Nielsen (2), Lena E. Friberg (2), Teresa Dalla Costa (1)
(1) Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, Porto Alegre, Brazil, (2) Department of Pharmaceutical Biosciences, Uppsala University, Sweden.
Objectives: Biofilm is an important virulence factor that allows bacteria to resist host responses and antimicrobials [1]. Although several pharmacodynamic studies have been conducted showing the intrinsic resistance of a bacteria growing in biofilms [2], little is known about antimicrobials disposition in biofilm infections. The purpose of this study was to develop a comprehensive model able to describe the disposition of total plasma and unbound lung ciprofloxacin (CIP) concentrations in healthy and biofilm infected rats leading to a better understanding of the lung penetration in both conditions.
Methods: Study was approved by UFRGS Ethics in Animal Use Committee (24140). A rat model of lung biofilm infection proposed by Johansen & Høiby was used [3]. CIP lung penetration in healthy and infected rats was investigated after the administration of a single i.v. bolus dose of 20 mg/kg. Arterial blood and microdialysis (MD) samples were collected at predetermined time points up to 12 h (total of 30 animals and 526 observations). Data were analyzed with nonlinear mixed effect modeling in NONMEM, version 7.3. Microdialysate samples were described by the integral over each collection interval [4] instead using mid point approach, therefore, no assumptions regarding collection time were made.
Results: The model was built in steps, first plasma data was fitted and found to be well described with a three-compartment model with first-order elimination. Infected animals showed a 34% lower plasma clearance. Unbound lung data were thereafter added and the model was expanded to also describe lung penetration. The central compartment was separated into arterial and venous compartments to explain high initial CIP levels achieved in the lung. Lung penetration and distribution was modeled as a two-compartment model structure linked to the venous compartment. Unbound fraction in plasma was fixed to 0.7 (in house MD data) and separate residual error models were used for total plasma and lung data. All parameters were allometrically scaled with the individual rat body weights. Acceptable predictive performance of the final model was confirmed by VPC.
Conclusions: The PK model developed successfully described the plasma and microdialysis data from healthy and infected rats. The inclusion of the separate arterial and venous compartment could account for the discrepancies between plasma and lung concentrations.
Acknowledgements: CNPq and CAPES/Brazil for financial support.
References:
[1] Parra-Ruiz, J. et al., Antimicrob. Agents Chemother., 54, 4329 (2010).
[2] Hengzhuang, W., et al., Antimicrob. Agents Chemother., 55, 4469 (2011).
[3] Johansen, H. K., HØiby, N. Handbook of Animal Models of Infection, 517 (1999).
[4] Tunblad, K., Hammarlund-Udenaes, M., Jonsson, E. N. Pharmaceutical Research, 21, 1698 (2004).
Reference: PAGE 25 (2016) Abstr 5958 [www.page-meeting.org/?abstract=5958]
Poster: Drug/Disease modeling - Infection