Monoclonal Antibody Disposition beyond Target Binding: Impact of FcRn on Clearance and Derivation of Mechanistic Compartment Models
Ludivine Fronton (1,3), Sabine Pilari (2,3) and Wilhelm Huisinga (1)
(1) Institute of Mathematics, Potsdam University, Germany; (2) Department of Mathematics and Computer Science, Freie University, Germany; (3) Graduate Research Training Program PharMetrX: Pharmacometrics and Computational Disease Modeling, Martin-Luther-University, Freie University and Potsdam University, Germany
Objectives: Despite the detailed knowledge of the molecular processes involved in the disposition of monoclonal antibodies (mAbs), the development of compartment models to describe mAbs pharmacokinetic data is largely empirical. There is no established strategy to translate the mechanistic understanding into design criteria that guarantee consistency of the structural model with the current knowledge. The objective of this work is to transpose the mechanisms involved in mAbs disposition, when the target is not expressed, from a detailed physiologically-based pharmacokinetic (PBPK) model into a low-dimensional compartment model while retaining a mechanistic interpretation of the pharmacokinetic parameters. The mechanistic nature of the PBPK model allows oneself to assess the relation between the saturation level of the neonatal Fc Receptor (FcRn) and endogenous immunoglobulins type G (IgGendo) and its impact on mAbs disposition.
Methods: The experimental venous plasma data of the mAb (7E3), administered intravenously at 8 mg/Kg, were extracted from [1] for FcRn-knockout and wild-type mice using the software DigitizeIt, version 1.5.8a. The steady-state plasma concentration of total IgGendo was reported in [2]. MATLAB R2009a was used for modelling and simulations (ode15s solver with default options). To reduce the dimensionality of the PBPK model we extended the lumping approach presented in [3].
Results: The lumping of the PBPK model resulted in a 2-compartment model. The central compartment comprised the plasma and the interstitial spaces of all tissues/organs of the PBPK model, while the peripheral compartment included all the endosomal spaces where the non-linear FcRn-mediated salvage of IgGendo and mAb occurs. We observed that the steady-state (SS) level of IgGendo was not perturbed by the administration of the mAb. Consequently, the SS-IgGendo concentration solely determined the level of saturation of FcRn so that the mAb clearance in the endosomal space appeared to be linear.
Conclusions: Based on the extension of the lumping approach presented in [3], we reduced the 35-compartment PBPK model to a mechanistic 2-compartment model which successfully described the experimental plasma concentration-time profiles of the mAb 7E3 in mice. The therapeutic mAb exhibited a linear clearance from the endosomal compartment, even if the FcRn system is not fully saturated.
References:
[1] R.J. Hansen and J.P. Balthasar. J Pharm Sci, 92:1206-1215, 2003. [2] R.P. Junghans and C.L. Anderson. Proc Natl Acad Sci U S A, 93:5512-5516, 1996. [3] S. Pilari and W. Huisinga. J Pharmacokinet Pharmacodyn, 37:1-41, 2010.
