Ignacio Gonzalez-Garcia (1) (2), Itziar Irurzun-Arana (1), Leire Ruiz-Cerdá (1), Chuanpu Hu (3), Honghui Zhou (3), An Vermeulen (4), Iñaki F. Trocóniz (1), José David Gómez-Mantilla (1)
(1) Pharmacometrics and Systems Pharmacology. Pharmacy and Pharmaceutical Technology Department. University of Navarra, Pamplona 31080, Spain. (2) Pharmacy and Pharmaceutical Technology Department. University of Valencia. Valencia, Spain. (3) Janssen Research and Development, LLC, Spring House, PA 19477, USA (4) Janssen Research and Development, a division of Janssen Pharmaceutica NV, Beerse B-2340, Belgium
Objectives: Inflammatory Bowel Disease (IBD) is a gastrointestinal tract (GIT) disorder characterized by processes of remission and relapse producing a functional impairment[HZ1] [VA[2] of the gut wall. It includes Crohn Disease (CD) and Ulcerative Colitis (UC) [1, 2]. The objective of the current work was to develop a systems pharmacology model for CD and UC integrating the main known components and reactions.
Material and Methods: The development of the theoretical disease network is based on the information obtained from the literature. Once the most relevant relationships were identified, the network was built using Boolean functions. Network validation was carried out by comparing the results reported in literature for selected nodes and the corresponding relative expression simulated profiles obtained by 10,000 simulations.
Results: The network contains information about 5 kinds of immune cells, different membrane and cytosol receptors, and several cytokines, resulting in 45 nodes and more than 100 interactions. The network model was able to simulate the GIT state in healthy subjects and patients with active disease condition. The simulation exercise allowed identification of model elements, which, once their status with respect to the healthy condition was modified, allowed recreation of disease conditions.
Conclusions: A systems pharmacology model integrating the main known pathways in IBD, and discrimination between CD and UC was constructed and validated. The model has shown its applicability in identifying altered pathways, which resembled different statuses of the disease, opening up the potential to identify therapeutic targets.
References:
[1] Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361(21):2066–78.
[2] Yarur AJ, Abreu MT, Deshpande AR, Kerman DH, Sussman D a. Therapeutic drug monitoring in patients with inflammatory bowel disease. World J Gastroenterol. 2014;20(13):3475–84.
Reference: PAGE 24 (2015) Abstr 3375 [www.page-meeting.org/?abstract=3375]
Poster: Drug/Disease modeling - Other topics