Target Mediated Drug Disposition Model to Describe the Expression and Kinetics of IL12 And IFNγ in Gene Therapy
Zinnia Parra Guillén(1), Rubén Hernández-Alcoceba(2), Gloria González-Aseguinolaza(2), Pedro Berraondo(2), Iñaki F. Trocóniz(1)
(1) Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra (Spain); (2) Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Spain
Objectives: Interleukin-12 (IL12) has shown to have a great therapeutical potential in the treatment of chronic hepatic diseases . Nevertheless its in vivo efficacy is hampered by a negative feedback mediated by the interferon γ (IFNγ) produced in response to this cytokine . A model able to describe the relationship between IL12 and IFNγ has already been developed when constant doses of mifepristone (RU, inductor of the gene expression of IL-12) were administered . The aim of the study is to challenge an improved the previously developed model when knock-out mice for the receptor of the IFNγ are used or when increasing doses of the mifepristone are administered under different dosing regimens.
Methods: Knock-out and wild type mice were infected with gutless adenoviral vectors containing a mifepristone (RU486)-inducible system for liver-specific expression of interleukin-12. Daily induction of constant or increasing doses of RU was performed and levels of IL12 and IFNγ were measured. Berkeley-Madonna, R and NONMEM VII softwares were used to develop the model.
Results: A target drug mediated disposition (TMDD) model for the IL12 successfully described the wild type mice observations when constant doses of RU were administered. However, simulations of the model, where decreasing elimination rates of IFNγ were used to emulate the knock-out mice conditions, were not able to describe the profiles of these mice. The introduction of a second TMDD  for the IFNγ, and an indirect response model mediated by the bound IFNγ instead of the free molecule, allowed a good description of the complete set of experimental data. Finally, an Emax model was introduced to account for those experiments where increasing doses of RU were administered.
Conclusions: A kinetic-pharmacodynamic model able to describe jointly the IL12 and IFNγ profiles observed both, in wild type and knock-out mice, through diverse experimental conditions has been developed.
 Berraondo P et al. Curr Gene Ther 9:62-71, 2009.
 Reboredo M et al. Gene Ther 15:277-288, 2008.
 Parra-Guillén et al. PAGE 19 (2010) Abstr 1899 [www.pagemeeting.org/?abstract=1899.
 Mager DE et al. J Pharmacokinet Pharmacodyn 28: 507-532, 2001.