X. Hu and I. Nestorov
Biogen Idec Inc, sponsor of the study.
Objectives: Seven tolerance models were compared to describe neopterin response as a pharmacodynamic marker and to explore the mechanisms of tolerance development in Rhesus monkeys after administration of interferon beta-1a (IFN) or PEGylated IFN.
Methods: PEG-IFN and IFN concentration data and neopterin concentration data were collected in two single-dose PK/PD studies and one multiple-dose toxicity study, from a total of 76 monkeys. A two-compartment PK model and an indirect stimulatory PD model were developed [1]. Seven tolerance models were compared, including indirect moderator tolerance model, direct moderator model, tolerance pool model, tolerance adaptive model, partial agonist model, competitive antagonist model, and noncompetitive antagonist model [2], to select the best model to describe the data. The analysis was performed using nonlinear mixed effect modeling tool, NONMEM 7.2.
Results: All tolerance models fit the data better than the base model which did not include tolerance, with the indirect moderator tolerance model providing the best fit and the tolerance pool model the least fit. Based on the indirect moderator tolerance model, BASE (neopterin baseline) was 2.88 ng/mL, the LOSS (first-order elimination rate) was 0.0095 h-1, the MRT (mean resident time for the delayed neopterin response) was 8.24 h for IFN and 7.85 for PEG-IFN, the KTOL (the rate constant for tolerance compartment) was 0.0593 h-1, the TC50 (concentration in tolerant compartment to achieve 50% of tolerance) was 0.0261, the Emax (maximum stimulating effect) was 1710, the EC50 (concentration to achieve 50% of Emax) was 574 pg/mL for IFN and was 8220 pg/mL for PEG-IFN. The results suggest that the development of tolerance, which resulted in similar neopterin response between PEG-IFN and IFN, is more likely due to negative feedback of neopterin or down-regulation of IFN receptors than due to exhausted neopterin precursor pool.
Conclusion: An indirect moderator tolerance model was selected as the best model from seven tolerance models to describe the development of tolerance in neopterin elevation following IFN or PEG-IFN treatment in Rhesus monkeys.
References:
[1] X. Hu, K. Olivier, E. Polack, M. Crossman, K. Zokowski, R.S. Gronke, S. Parker, Z. Li, I. Nestorov, D.P. Baker, J. Clarke, M. Subramanyam, In vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a, JPET, 2011, 338:984-996.
[2] M. Gårdmark M, L. Brynne, M. Hammarlund-Udenaes, M.O. Karlsson, Interchangeability and predictive performance of empirical tolerance models, Clin Pharmacokinet, 1999, 36:145-67. Review.
Reference: PAGE 21 () Abstr 2457 [www.page-meeting.org/?abstract=2457]
Poster: Model evaluation