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Target-Mediated Disposition Model Describing the Dynamics of IL12 and IFNγ after Administration of a Mifepristone-Inducible Adenoviral Vector for IL-12 Expression in Mice

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Abstract

Interleukin-12 (IL12) is a cytokine with potential applications in the treatment of cancer given the potent immune response that it triggers, in part due to its ability to stimulate expression of interferon-γ (IFNγ). To avoid the toxicity associated with systemic exposure to IL12, a high-capacity adenoviral vector carrying a liver-specific, mifepristone-inducible IL12 expression system (HC-Ad/RUmIL12) has been developed. However, the maintenance of IL12 expression at therapeutic levels is compromised by the inhibitory effect of IFNγ on inducible systems. The aim of this work is to develop a semi-mechanistic model to characterize the relationship between IL12 and IFNγ in wild-type and knock-out mice for the IFNγ receptor treated with HC-Ad/RUmIL12 under different dosing regimens in order to better understand the key mechanisms controlling the system. Rapid binding was considered to account for target-mediated disposition exhibited by both cytokines (equilibrium dissociation constant were 18 and 2.28 pM for IL12 and IFNγ, respectively). The final model included: (1) IFNγ receptor turnover, (2) irreversible free cytokine elimination from the serum compartment, (3) internalization of the IL12 receptor complex, (4) IL12 expression upregulated by the co-administration of the adenoviral vector and mifepristone and downregulated by the IFNγ receptor, and (5) synthesis of IFNγ controlled by the relative increments in the bound IL12. In conclusion, a model simultaneously describing the kinetics of IL12 and IFNγ in the context of gene therapy was developed and validated with additional data. The model was applied to design an experimental dosing protocol intended to maintain sustained therapeutic IL12 levels.

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Notes

  1. http://getdata-graph-digitizer.com/

Abbreviations

−2LL:

−2 × log (likelihood)

E MAX :

Maximum effect

IFNγ:

Interferon-γ

IL12:

Interleukin-12

HC-Ad/RUmIL12:

Adenoviral vector carrying a liver-specific, mifepristone-inducible IL12 expression system

KO:

Knock-out

mIL12:

Mouse interleukin-12

NK:

Natural killers

REG:

Regulator compartment

RU:

Mifepristone

RU50 :

Mifepristone concentration needed to achieve 50% of the maximum effect

TMDD:

Target-mediated drug disposition

WT:

Wild-type

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Acknowledgments

This work was supported by: (1) grant SAF2009-11324 from the Spanish Department of Science and the UTE project CIMA and the agreement FIMA, the “UTE project CIMA”, Fondo de Investigacion Sanitaria (FIS PI10/00264) and (2) from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115156, resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution. The DDMoRe project is also supported by financial contribution from Academic and SME partners. This work does not necessarily represent the view of all DDMoRe partners. Additionally, ZPP-G was supported by FPU fellowship from the Spanish Ministerio de Educacion, Cultura y Deporte. PB was supported by a Miguel Servet contract from Spanish Fondo de Investigacion Sanitaria

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Authors and Affiliations

  1. Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, C/ Irunlarrea 1, 31008, Pamplona, Navarra, Spain

    Zinnia Patricia Parra-Guillen, Alvaro Janda & Iñaki F. Troconiz

  2. Division of Hepatology and Gene Therapy, Centre for Applied Medical Research (CIMA), Pamplona, Navarra, Spain

    Pilar Alzuguren, Pedro Berraondo & Ruben Hernandez-Alcoceba

Authors
  1. Zinnia Patricia Parra-Guillen
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  2. Alvaro Janda
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  3. Pilar Alzuguren
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  4. Pedro Berraondo
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  5. Ruben Hernandez-Alcoceba
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  6. Iñaki F. Troconiz
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Corresponding author

Correspondence to Iñaki F. Troconiz.

ELECTRONIC SUPPLEMENTARY MATERIALs

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Supplemental Materials

Pharmacokinetic model developed for mifepristone and computational model developed for wild-type mice (DOC 78 kb)

Supplementary Fig. 1

Wild-type mice models. a Schematic representation of the Push-and-pull model, b together with the corresponding IL12 observed (Obs) and model predicted concentrations (Pred) vs time profiles obtained for the low and high viral dose in experiment 1. c Schematic representation of the TMDD model developed for wild-type mice along with the d IL12 observed and model predicted concentrations vs time profiles for the low and high viral dose corresponding to experiment 1 (upper panel) and the IL12 observed and predicted levels measured 10 h after the first administration of mifepristone vs the RU dose (lower panel) from experiments 1–4. Terms and parameters are described in the text (JPEG 75 kb)

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Parra-Guillen, Z.P., Janda, A., Alzuguren, P. et al. Target-Mediated Disposition Model Describing the Dynamics of IL12 and IFNγ after Administration of a Mifepristone-Inducible Adenoviral Vector for IL-12 Expression in Mice. AAPS J 15, 183–194 (2013). https://doi.org/10.1208/s12248-012-9423-9

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