Eduardo AsÃn-Prieto (1,2), Zinnia P Parra-Guillen (1,2), Jose David Gomez Mantilla (1,2,#), Joris Vandenbossche (3), Kym Stuykens (3), Xavier Woot de Trixhe (3), Juan José Perez-Ruixo (3), Iñaki F. Troconiz (1,2)
(1) Pharmacometrics & Systems Pharmacology Research Unit, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Spain; (2) IdiSNA, Navarra Institute for Health Research, Pamplona, Spain, (3) Janssen R&D, Beerse, Belgium. # Current affiliation: Boehringer Ingelheim. Ingelheim am Rhein, Germany
Objectives: Hepatitis B is an infectious disease caused by the hepatitis B virus (HBV) that affects the liver, a known organ for its capability to develop tolerogenic immune responses [1]. After infection in adults, approximately 95% of the subjects developed an acute infection (AHB ) and are capable to mount an adequate immune response that leads to the subsequent resolution of the infection within 1 – 3 months [2]. However, the other 5% of patients experience a more tolerogenic immune response leading to chronicity of the infection. The CHB patients tend to develop complications such as cirrhosis and hepatocellular carcinoma, and finally, death.
A topological model representing the interaction between the key elements of the HBV and the immune system –in terms of location, causality and nature of the relationship- was recently developed by our group [3]. This representation provides a comprehensive overview of the system, but it does not account for the magnitude of the response nor the temporality. Consequently, the objective of this work is to build a multiscale quantitative system pharmacology (QSP) model able to characterize the immune response against HBV.
Methods: The topological model was used as the basis for the QSP model in terms of entities and processes. Ordinary differential equations (ODE) describing the temporal changes of the identified components were implemented in Matlab/Simbiology R2017a using zero-, first-, and second-order processes. Inhibitory and stimulatory effects were integrated using standard pharmacodynamic models. Model parameters were obtained directly from the literature or computed from human in vivo or in vitro studies where the interactions between components had been quantitatively characterized. When needed, data were digitalized using WebPlotDigitalizer v3.8 and analyzed in R v3.3.2 and NONMEM7.3. Simulations were confronted with data from AHB patients obtained from the literature [4-7]. Finally, a sensitivity analysis was performed varying the different model parameters +/- 10% and exploring its impact on clinically relevant markers such as time to cure (HBVDNA < 2000 IU/mL) and maximal HBVDNA or ALT levels.
Results: An ODE-based model (35 equations, 86 parameters) representing the temporal evolution of the HBV-related immune response across 3 different compartments – liver, plasma and lymph node- has been successfully developed. The framework included the key element from the viral dynamics together with the innate, adaptive, and regulatory immune response identified from the topological model from a molecular (e.g cytokines) to cellular (lymphocytes) level.
The model was able to reproduce the HBV-related immune response in terms of chronology and plausibility of component levels during an acute process. Simulations highlight the limited contribution of the innate response to the control of the disease, but its central role triggering the adaptive response, together with the role of the immunoregulatory system in the establisment of a chronic infection. Indeed, changes of only 10% in model parameters controlling the tolerogenic response were sufficient to switch from an acute to a chronic viral response. The sensitivity analysis revealed that the cytotoxic lymphocytes proliferation rate constant, the cytokine levels, and the degradation of the HBV had the larger impact on maximum achieved levels of HBVDNA in plasma, while the duration of the acute disease was meanly controlled by parameters related to the viral dynamics (infectivity capability and virus degradation rate).
Conclusions: A multiscale QSP model characterising the HBV immune-related response has been developed. The model developed provides an adequate quantitative framework to (i) understand the role and contribution of the innate, cellular and humoral immune response to the viral erradication, and (ii) explore the mechanism of action of different agents and their effects in terms of efficacy and safety.
References:
[1] Bogdanos D, et al. Compr. Physiol. 3(2): 567-598, 2013.
[2] Dunn et al. Gastroenterol. 137:1289-1300, 2009.
[3] Asin-Prieto et al. PAGE 26 (2017) Abstr 7327.
[4] Webster et al. Hepatol. 32:1117-1124, 2000.
[5] Dunn et al. J Exp Med. 204:667-680, 2007.
[6] Fisicaro et al. Gut. 58: 974-982, 2009.
[7] Yoshikawa et al. Transfusion. 47: 1162-1171, 2007.
Reference: PAGE 27 (2018) Abstr 8718 [www.page-meeting.org/?abstract=8718]
Poster: Drug/Disease Modelling - Infection