2011 - Athens - Greece

PAGE 2011: Absorption and physiology-based PK
Thomas Wendl

Development of a physiologically-based pharmacokinetic (PBPK) model for Moxifloxacin and its metabolites in healthy adults

Thomas Eissing(1), Thomas Wendl(1), Katrin Cob÷ken(1), Michael Block(1), Kirstin Thelen(1), Corina Becker(2), Heino Sta▀(2), Rolf Burghaus(2), J÷rg Lippert(1), Stefan Willmann(1)

(1) Bayer Technology Services GmbH, Competence Center Systems Biology and Computational Solutions, D-51368 Leverkusen, Germany; (2) Bayer HealthCare AG, Clinical Pharmacology / Clinical Pharmacokinetics, D-42096 Wuppertal, Germany

Objectives: The objective of this study was to establish a PBPK model for Moxifloxacin and its two main metabolites in healthy adults after intravenous (IV) and per oral (PO) administration with and without charcoal co-administration in order to get a detailed understanding of the metabolic processes and parent-metabolite interrelationships.

Methods: Starting from an established Moxifloxacin PBPK model [1], a coupled whole-body PBPK model for Moxifloxacin and its two major metabolites, i.e. the sulfated metabolite 1 (M1 Sulfate) and the glucuronidated metabolite 2 (M2 Glucuronide), after IV and PO administration with and without co-administration of charcoal was built using the software tools PK-Sim«, MoBi« and the MoBi« toolbox for Matlab« [2]. A new physiologically-based compartmental absorption model allowing for the mechanistic description of gut wall metabolism, enterohepatic recycling, and binding to charcoal according clinical studies was included into the whole-body PBPK model [3]. Physicochemical data, demographic data, mass balance information and plasma concentration time profiles obtained in clinical studies [4, 5] were used for model establishment and model validation.

Results: The established PBPK model describes the PK of Moxifloxacin, M1, and M2 in a very accurate manner, after both, Moxifloxacin IV and PO administration and with and without charcoal co-administration as evidenced by a visual predictive check. The model provides a detailed understanding of the interrelationship of Moxifloxacin and its metabolites with respect to metabolism in the gastro-intestinal tract and the liver. Furthermore, metabolic processes like glucuronidation and deglucuronidation in the gut which are difficult to measure in-vivo were successfully tested in the model.

Conclusions: The model was successfully established and validated and, hence, can be used to simulate the pharmacokinetics of Moxifloxacin, M1, and M2 in different scenarios or under modified conditions. In particular, the model is suitable for scaling to pediatric populations and planning of clinical studies.

References:
[1] Edginton, A. N., G. Ahr, et al. (2009). Defining the role of macrophages in local moxifloxacin tissue concentrations using biopsy data and whole-body physiologically based pharmacokinetic modelling. Clin Pharmacokinet 48(3): 181-7.
[2] Eissing T, Kuepfer L, Becker C, Block M, Coboeken K, Gaub T, Goerlitz L, Jaeger J, Loosen R, Ludewig B, Meyer M, Niederalt C, Sevestre M, Siegmund H, Solodenko J, Thelen K, Telle U, Weiss W, Wendl T, Willmann S and Lippert J (2011). A Computational Systems Biology Software Platform for Multiscale Modeling and Simulation: Integrating Whole-Body Physiology, Disease Biology, and Molecular Reaction Networks. Front. Physio. 2:4.
[3] K. Thelen, K. Coboeken, S. Willmann, J.B. Dressman, J. Lippert. A novel physiological model to simulate gastrointestinal fluid dynamics, transit of luminal contents, absorption, and pre-systemic metabolism of orally administered drugs in humans, Poster PAGE 2010.
[4] Stass H, Kubitza D, Schuhly U. Pharmacokinetics, safety and tolerability of moxifloxacin, a novel 8-methoxyfluoroquinolone, after repeated oral administration. Clin Pharmacokinet 2001;40 Suppl 1:1-9.
[5] Stass H, Kubitza D. Pharmacokinetics and elimination of moxifloxacin after oral and intravenous administration in man. J Antimicrob Chemother 1999;43 Suppl B:83-90.




Reference: PAGE 20 (2011) Abstr 2196 [www.page-meeting.org/?abstract=2196]
Poster: Absorption and physiology-based PK
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