Rodrigues, C.L. (1) , I. Gueorguieva (2), Marylore Chenel (3), D. A. Berk (4) and L. Aarons (1)
(1) Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, UK; (2) Global PK/PD, Lilly Research Centre, Erl Wood Manor, Surrey, UK; (3) Clinical Pharmacokinetics Department, Institut de Recherches Internationales Servier, France; (4) School of Pharmacy and Pharmaceutical Sciences, University of Manchester, UK.
Objectives: The extent of tissue penetration, distribution and the size of the therapeutic window of antibiotics are among the most important issues confronting antibiotic therapies. Modelling is an important applied tool in drug discovery and development for the prediction and interpretation of drug pharmacokinetics. Whole body physiologically based pharmacokinetic (WBPBPK) models are increasingly used to predict pharmacokinetic behaviour of drugs. Norfloxacin is a widely distributed fluoroquinolone antibiotic used mainly in genitourinary infections. The aim of this study is to develop a WBPBPK model to study norfloxacin kinetics in rats.
Methods: Using tissue concentration and arterial blood data, a WBPBPK model for norfloxacin is derived. Initially, it is assumed that each tissue is represented by a single, well-stirred compartment and tissue affinities were estimated from the model. Permeability versus perfusion rate limitation of the norfloxacin distribution process for each tissue was tested. These alternative assumptions were judged based on fits of the tissue concentration data to the WBPBPK model by using nonlinear least squares regression[1]. Additionally, data were available following the administration of three different doses – 25, 50 and 100 mg/kg. It has been reported that norfloxacin has dose-ranging pharmacokinetics, which was investigated using the developed WBPBPK model.
Norfloxacin is known to be cleared via 2 routes in rats – renal clearance and faecal clearance. Renal clearance has been previously calculated as being responsible for 15% of the total clearance[2]. NONMEM was then used to estimate the total plasma clearance of the system for each dose level and 15% of each clearance value was then fixed as the renal clearance in the open-loop optimisation of the model. This allowed the gut clearance to be estimated.
Results: It was observed that the percentage of the extrapolated AUC lying after the last measured time point was high in the gut and skin. Steady state Kps and area Kps were found to be generally similar to each other across the 3 dose levels, showing that the steady state measurements were able to accurately reflect the dynamic situation in the tissues. The open- and closed-loop optimisations produced fits which are closest to the measured concentration points, whereas the area ratio Kps tend to over-predict concentrations. This was true for all 3 doses.
Conclusion: The study suggests that open- and closed-loop optimisations are the best ways of predicting Kps by data fitting and that the tissues in this model are likely to be perfusion rate limited. The model is also able to reflect the actual physiological situation realistically, allowing reasonable estimations to be made.
References:
[1] Gueorguieva, I., et al., Development of a whole body physiologically based model to characterise the pharmacokinetics of benzodiazepines. 1: Estimation of rat tissue-plasma partition ratios. J Pharmacokinet Pharmacodyn, 2004. 31(4): p. 269-98.
[2] Davis, J.D., L. Aarons, and J.B. Houston, Effect of norfloxacin on theophylline disposition: a comparison with other fluoroquinolones. Pharm Res, 1995. 12(2): p. 257-62.
Reference: PAGE 15 (2006) Abstr 975 [www.page-meeting.org/?abstract=975]
Poster: Methodology- PBPK