Estevan Zimmermann(1,2); Camila Neris (1); Stephan Schmidt (2); Chakradhar Lagishetty (2); Teresa Dalla Costa (1)
(1) Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, Brazil; (2) Center for Pharmacometrics & Systems Pharmacology, School of Pharmacy, University of Florida at Lake Nona, Orlando, USA
Objectives: To evaluate levofloxacin (LEV) lung and prostate interstitial fluid (ISF) concentrations with and without tariquidar (TAR), a P-gp inhibitor, viewing to elucidate this fluoroquinolone penetration mechanism and to develop a population pharmacokinetic (POPPK) model able to describe experimental data simultaneously.
Methods: Wistar rats (300-400 g) were randomly distributed in eight groups (n = 6/groups). For each dose/route of administration, one group was used for total plasma sampling and one for ISF concentrations sampling. Animals received LEV 7 mg/kg intravenously (i.v.) or intratracheally (i.t.) alone or 30 min after TAR 15 mg/kg i.v. dosing. Experiments approved by CEUA/UFRGS 21169. CMA/20 microdialysis probes (4 mm, cutoff 20 kDa), flushed with Ringer´s solution 1.5 µL/min, were used to collect ISF free concentrations in both tissues. Throughout the experiment, animals were kept anesthetized with urethane and under mechanical ventilation. Total LEV concentrations in plasma and free lung and prostate were investigated up to 12 h. A semi-mechanistic population pharmacokinetic model was developed using NONMEM version 7.2 to simultaneously characterize total plasma and free ISF tissues (lung and prostate) concentrations.
Results: A four compartment model was appropriate to simultaneously characterize and predict concentrations in total plasma and in the ISF of prostrate and lung, target infected tissues treated with this drug [1,2]. Statistically significant differences were observed for three parameters for TAR group compared to control group (lung penetration, prostrate penetration and kidney active secretion). The final model was best in terms of curve fitting, precision of parameter estimates and model stability. The interindividual variabilities were reasonably small for the parameters in the model. The intravenous model was extended and adapted to describe the intratracheal route of administration. The intratracheal model was adequate to fit simultaneously plasma and lung levels in presence and absence of TAR.
Conclusions: A semi-mechanistic POPPK model was successfully developed to describe LEV total plasma and free ISF concentrations in lung and prostate. The results indicate P-gp impact on LEV renal active secretion. Efflux transporters are relevant to pulmonary penetration only after intratracheal dosing. In the prostate, our findings strongly support the role of efflux transporters besides P-gp participating in LEV tissue penetration.
References:
[1] F. Bambeke et al., Clin. Microbiol. Infect. 11, 4 (2005).
[2] J. Mouton et al., J. Antimicrob. Chemother. 61, 2 (2008). Financial support from FAPERGS/Brazil and CNPq/Brazil. E. Zimmermann PhD scholarship from CAPES/Brazil.
Reference: PAGE 24 (2015) Abstr 3562 [www.page-meeting.org/?abstract=3562]
Poster: Drug/Disease modeling - Absorption & PBPK