Nonlinear Pharmacokinetic Model For Interleukin-12 Gene Therapy
Parra-Guillen ZP(1), Hernandez-Alcoceba R(2), Gonzalez-Aseguinolaza G(2), Berraondo P(2), Troconiz IF(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: Several animal and human clinical studies have shown the therapeutic potential of interleukin-12 (IL-12) for the treatment of cancer and chronic viral hepatitis, although an adaptive response that down-regulated the levels of IL-12 was observed in long-term treatments. Pharmacokinetic modelling is a useful tool to understand the mechanisms of the different biological processes involved in this therapeutic response. The aim of the study is to develop a pharmacokinetic model that describes the behaviour of IL-12 and IFNγ at different doses in mice.
Methods: Mice were infected with two doses (2x1e8 and 5x1e8 iu) of a viral vector that codified for the interleukin gene. Interleukin expression was induced daily by the administration of mifepristone (RU) and levels of IL-12 and IFNγ were measured for 10 days. Berkeley-Madonna and Nonmem 6 software programmes were used to develop a semi-mechanistic model able to describe the data obtained.
Results: A three compartmental model was initially developed to describe the kinetic of IL-12 and the negative feedback of the IFNγ at low dose, but it was not able to describe the results obtained at higher doses. Receptor mediated endocytosis is known to play an important role in cellular uptake and disposition. The nonlinear pharmacokinetic behaviour previously observed was explained by incorporating the concept of receptor mediated endocytosis to the pharmacokinetic model.
Conclusions: Berkeley-Madonna was used to explore and improved the pharmacokinetic model developed by incorporating the concept of receptor mediated endocytosis. This model will be further explored using knock-out mice for the IFNγ receptor.
References:
[1] Berraondo P, Prieto J and Gonzalez-Aseguinolaza G. Advances in Interleukin-12:Therapy for Acquired liver diseases. Curr Gene Ther 2009, 9: 62-71.
[2] Krippendorf BF, Kuester K, Kloft C, Huisinga W. Nonlinear pharmacokinetics of therapeutic proteins resulting from receptor mediated endocytosis. J Pharmacokinet Pharmacodyn 2009, 36: 239-260.
