2010 - Berlin - Germany

PAGE 2010: Methodology- PBPK
Kirstin Thelen

A novel physiological model to simulate gastrointestinal fluid dynamics, transit of luminal contents, absorption, and pre-systemic metabolism of orally administered drugs in humans

K. Thelen (1), K. Coboeken (2), S. Willmann (2), J.B. Dressman (1), J. Lippert (2)

(1) Institute of Pharmaceutical Technology, Johann Wolfgang Goethe University Frankfurt, Frankfurt am Main, Germany; (2) Systems Biology and Computational Solutions, Bayer Technology Services GmbH, Leverkusen, Germany

Objectives: To allow for a precise prediction of oral drug absorption, drug-drug interactions within the gut wall, and the effects of active transport and gut wall metabolism, a new compartmental absorption model was developed. This model reflects detailed knowledge of human gastrointestinal (GI) physiology such as anatomical dimensions, local pH profiles, fluid secretion as well as absorption rates and GI transit rates of solid and liquid components. Furthermore, the model comprises a detailed representation of the mucosa, which is particularly involved in oral drug absorption and intestinal first pass metabolism. The GI model will be integrated into the whole-body physiology based pharmacokinetic (PBPK) software tool PK-Sim®.

Methods: Physiological information regarding GI anatomy and physiology of humans was collected from the literature. The alimentary canal from the stomach to the rectum was divided into 12 compartments each representing a particular segment of the GI tract. In parallel to each luminal compartment the respective mucosal compartment was added and connected with the respective luminal compartment and the portal vein blood flow via ordinary differential equations according to their physiology. The intestinal permeability coefficient can be calculated based on physicochemical information of the drug to be modelled using a semi-empirical equation [1]. A data set of 111 compounds with reported human fractions of dose absorbed [2] was used to determine an optimal set of parameters for this equation. The new gut model was subsequently validated using experimental plasma concentration time profiles of 8 test compounds with diverse physicochemical properties obtained after oral administration.

Results: A good correlation between the predicted and known fractions of dose absorbed was obtained for the passively absorbed compounds under permeability-limited conditions. Plasma concentration time profiles of the 8 test compounds from different BCS classes were very well predicted by the model.

Conclusions: A novel physiological multicompartmental model for GI transit and absorption was presented. Oral drug absorption of permeability-limited drugs could be very well simulated with the new model. The detailed physiological model can help to better understand the complex processes of oral drug absorption and pre-systemic metabolism in the gut wall and will be useful during the drug research and developmental process.

[1] Leahy, D.E. et al. (1989) In Novel Drug Delivery and Its Therapeutic Application; Prescott, F.F., Nimmo, W.S., Eds., John Wiley & Sons: New York, 33-44
[2] Willmann, S. et al. (2004) J. Med. Chem. 47, 4022-4031

Reference: PAGE 19 (2010) Abstr 1857 [www.page-meeting.org/?abstract=1857]
Poster: Methodology- PBPK