Iñaki F. Trocóniz, Zinnia P Parra-Guillén, Álvaro Janda
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra; Pamplona 31080 (Spain)
Objectives: Interleukin-12 (IL12) has shown to have a great therapeutical potential for the treatment of chronic hepatic diseases [1]. Nevertheless its in vivo efficacy is hampered by a negative feedback mediated by the interferon γ (IFNγ) produced in response to this cytokine [2]. A target mediated drug disposition model [3,4] able to describe the relationship between IL12 and IFNγ, after administration of a viral vector (DNA) codifying for the IL12 gene under the control of Mifepristone (RU) inducible promoter, has been developed for wild type mice (WT) and knock-out mice for the IFNγ receptor (KO). The aim of this work is to explore the role and importance of the different processes considered in the model to increase the understanding of the system.
Methods: The impact of the different model processes on free and bound IL12 and IFNγ, as well as on their receptors was evaluated by temporal modification of different model parameters. Different initial viral loads and daily administration of a single RU dose (250µg/kg) were explored. The implementation and evaluation has been performed by Matlab® software.
Results: The analysis of the model has revealed an important coupling between the different kinetics involved in the processes. Because of this feature, the changes on some parameters reveal behaviours which are hard to extrapolate without this exploration. Moreover, the results show a great influence of the parameters related to the bound IL12 and IFNγ on the dynamics of the system.
Conclusions: A better understanding of the role of the different model processes has been obtained. This approach can be used to propose new therapeutic goals to achieve sustained levels of IL12 minimizing the negative feedback triggered by IFNγ.
References:
[1] Berraondo P et al. Curr Gene Ther 9:62-71, 2009.
[2] Reboredo M et al. Gene Ther 15:277-288, 2008.
[3] Mager DE et al. J Pharmacokinet Pharmacodyn 28: 507-532, 2001.
[4] Gibiansky L. PAGE 20 (2011) Abstr 1966 [www.page-meeting.org/?abstract=1966].
Reference: PAGE 21 () Abstr 2579 [www.page-meeting.org/?abstract=2579]
Poster: Model evaluation