Frances N. (1), Richter W. F. (1), Grimm H. P. (1), Walz A. (1), Roopenian D. (2)
(1) F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, Non-clinical Safety, CH-4070 Basel, Switzerland, (2) The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Objectives: To characterize the observed PK profiles of mAbX after IV and SC administration in variants of human FcRn transgenic mice in a mathematical model incorporating physiological elements of FcRn salvage.
Methods: Transgenic mice deficient of mouse FcRn and expressing human FcRn (hFcRn) were provided by Jackson Laboratory in Bar Harbor, Maine (USA) where also all in vivo PK studies were performed (presented at AAPS Annual Meeting in October 2012 [1]). In short, the PK of mAb X, a humanized IgG1 antibody, not cross reactive with the murine target, was investigated after administration of 10 mg/kg iv and sc administration. Mice expressing human FcRn either in somatic cells, in bone-marrow derived cells, in both cell types or none (4 groups, 8 animals per group and per route of administration) were prepared as described elsewhere for wild-type mice [2]. Compartmental PK models were developed to describe the PK in in all groups and route of administration simultaneously. Model parameters were estimated using Monolix and simulations performed with Matlab. Model comparisons were based on the Akaike criterion.
Results: Observed IV PK profiles were adequately described by a model involving plasma, extravascular compartments and two endosomal compartments representing somatic and bone marrow-derived cells. In this model, antibodies are eliminated uniquely from the endosomal compartments. FcRn knock-in variants were modeled by permitting recycling from the corresponding endosomal compartment and thereby salvaging them from degradation. Similarly, observed SC PK profiles were adequately described by transferring the drug from a compartment representing the SC administration site to compartments of the IV model structure.
Conclusions: Contribution of both somatic and bone marrow derived cells in FcRn salvage from catabolism [3] is adequately described in the presented novel mathematical model, which reflects the various localizations of FcRn and associated salvage processes. It is an alternative to other models incorporating similar mechanism [4, 5, 6].
References:
[1] W. F. Richter, G. Proetzel, G. J. Christianson, D. C. Roopenian; Bone marrow derived cells as sites of first pass catabolism of monoclonal antibodies after SC administration, Poster 2012 AAPS Annual meeting and exposition, Chicago.
[2] S. Akilesh, G. J. Christianson, D. C. Roopenian and A. S. Shaw; Neonatal FcR Expression in Bone Marrow-Derived Cells Functions to Protect Serum IgG from Catabolism, The Journal of Immunology, 2007.
[3] D. C. Roopenian, S. Akilesh; FcRn: the neonatal Fc receptor comes of age, Nature reviews, Immunology, Sept 2007.
[4] R. Deng, Y. G. Meng, K. Hoyte, J. Lutman, Y. Lu, S. Iyer, L. E. DeForge, F-P. Theil, P. J. Fielder, S. Prabhu; Subcutaneous bioavailability of therapeutic antibodies as a function of FcRn binding affinity in mice, mAbs, Feb 2012.
[5] J. J. Xiao; Pharmacokinetic models for FcRn-mediated IgG disposition, Journal of Biomedicine and Biotechnology, Feb 2012.
[6] L. Kagan, D. E. Mager; Mechanism of subcutaneous absorption of Rituximab in rats, Drug metabolism and disposition, Jan 2013.
Reference: PAGE 22 (2013) Abstr 2855 [www.page-meeting.org/?abstract=2855]
Poster: New Modelling Approaches