Leonid Gibiansky, Ekaterina Gibiansky
QuantPharm LLC, North Potomac, MD
Objectives: FcRn recycling plays an important role in non-specific clearance of endogenous and therapeutic antibodies [1]. A compartmental model of IgG turnover was proposed to describe the process [2-5]. However, use of different data and techniques used for calibration of the model resulted in several different sets of parameter estimates [5]. Recent studies of therapeutic antibodies targeting the FcRn receptor provided longitudinal data of IgG suppression resulting from blocking FcRn recycling [6]. We aim to use these data to evaluate the proposed models of endogenous IgG kinetics and provide the parameter estimates consistent with the observed data.
Methods:
The compartmental model of IgG turnover describes IgG pharmacokinetics by the two-compartment model with the Michaelis-Menten term [5]:
dA1/dt = I0 – (k10 + k12 – Vmax/(KM+A1/VC))*A1+ k21*A2, (1)
dA2/dt = k12*A1 – k21*A2,
where A1 and A2 are IgG amounts in the central and peripheral compartments, I0 is zero-order IgG production rate, k12=Q/VC, k21=Q/VP are inter-compartment rate constants; Q, VC, and VP are inter-compartment clearance, central volume, and peripheral volume, respectively; k10 is IgG non-specific elimination rate in absence of FcRn recycling, and VM and KM are Michaelis-Menten parameters.
Unlike the target-mediated drug disposition model, the Michaelis-Menten term describes the FcRn-mediated IgG recycling from the intra-cellular space to the central compartment rather than IgG elimination. Three different sets of IgG PK parameters were previously suggested [2-5]. The newly available data of FcRn receptor occupancy and IgG concentrations following administration of a monoclonal antibody targeting FcRn receptor [7] allowed to evaluate model predictions the for these sets of parameters. Specifically, assuming that FcRn recycling is proportional to fraction of unbound FcRn receptors, IgG suppression time course was predicted and compared with the observed data. Then, the new set of model parameters was proposed. It was assumed that VC, VP, and Q are similar to the typical values of monoclonal antibodies (VC=VP=3L, Q=0.38 L/day); IgG elimination rate [k10 – Vmax/(KM+IgG0)] at typical IgG concentration of IgG0=80 µmol/L is 0.07 1/day (corresponding to a typical clearance of 0.21 L/day); maximum IgG decrease from baseline following complete FcRn receptor suppression is 80% (resulting in k10 = 5*0.07=0.35 1/day; Vmax=0.28*(KM+IgG0) ). These assumptions allowed to compute all parameters if KM is known. We assumed that KM = 170 µmol/L, in the range of values reported in [3-5].
Results: Simulations assuming the parameter values as reported in [3, 5] resulted in maximum predicted IgG suppression of only about 50%. The parameters reported in [4] also resulted in predictions incompatible with the observed data, but those parameters were obtained using data from transplant patients and may not be applicable. The simulations using the new proposed set of parameters were in an agreement with the observed time course of IgG suppression (e.g. time to 50% suppression, time and % of maximum suppression, time to return to baseline).
Conclusions: Parameters of the mechanistic compartmental IgG turnover model should be consistent with the data observed following administration of therapeutic antibodies targeting the FcRn receptor. Joint modeling of the antibody kinetics, FcRn receptor occupancy, and IgG suppression can further improve the description of IgG turnover.
References:
[1] Ryman JT, Meibohm B. Pharmacokinetics of Monoclonal Antibodies. CPT Pharmacometrics Syst Pharmacol. 2017;6(9):576–588. doi:10.1002/psp4.12224.
[2] Waldmann, T. A., and Strober,W. (1969). Metabolism of immunoglobulins. Prog. Allergy 13, 1–110
[3] Jonghan Kim, William L. Hayton, John M. Robinson, and Clark L. Anderson, Kinetics of FcRn-mediated recycling of IgG and albumin in human: Pathophysiology and therapeutic implications using a simplified mechanism-based model, Clin Immunol. 2007 February ; 122(2): 146–155. doi:10.1016/j.clim.2006.09.001
[4] Hattersley, J. G., Chappell, M. J., Zehnder, D., Higgins, R. M., and Evans, N. D. (2013). Describing the effectiveness of immunosuppression drugs and apheresis in the treatment of transplant patients. Comput. Methods Programs Biomed. 109, 126–133. doi: 10.1016/j.cmpb.2011.12.013
[5] Kendrick Felicity, Evans Neil D., Arnulf Bertrand, Avet-Loiseau Hervé, Decaux Olivier, Dejoie Thomas, Fouquet Guillemette, Guidez Stéphanie, Harel Stéphanie, Hebraud Benjamin, Javaugue Vincent, Richez Valentine, Schraen Susanna, Touzeau Cyrille, Moreau Philippe, Leleu Xavier, Harding Stephen, Chappell Michael J., Analysis of a Compartmental Model of Endogenous Immunoglobulin G Metabolism with Application to Multiple Myeloma, Front. Physiol., 17 March 2017 | https://doi.org/10.3389/fphys.2017.00149
[6] Gable Karissa L., Guptill Jeffrey T., Antagonism of the Neonatal Fc Receptor as an Emerging Treatment for Myasthenia Gravis, Frontiers in Immunology, 2020, volume 20, page 3052, DOI=10.3389/fimmu.2019.03052
[7] Ling, LE, Hillson JL, Tiessen RG, Bosje, T, van, Iersel MP, Nix, D.J., Markowitz, L., Cilfone, N.A., Duffner, J., Streisand, J.B., Manning, A.M. and Arroyo, S. (2019), M281, an Anti‐FcRn Antibody: Pharmacodynamics, Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First‐in‐Human Study. Clin. Pharmacol. Ther., 105: 1031-1039. doi:10.1002/cpt.1276
Reference: PAGE () Abstr 9562 [www.page-meeting.org/?abstract=9562]
Poster: Drug/Disease Modelling - Other Topics