An asymptotic description of a basic FcRn-regulated clearance mechanism and its implications for PBPK modelling of large antibodies.

Abstract

A basic FcRn-regulated clearance mechanism is investigated using the method of matched asymptotic expansions. The broader aim of the work is to obtain further insight on the mechanism, thereby providing theoretical support for future pharmacologically-based pharmacokinetic modelling efforts. The corresponding governing equations are first non-dimensionalised and the order of magnitudes of the model parameters are assessed based on their values reported in the literature. Under the assumption of high FcRn-binding affinity, analytical approximations are derived that are valid over the characteristic phases of the problem. Additionally, relatively simple equations relating clearance and AUC to physiological model parameters are derived, which are valid over the longest characteristic time scale of the problem. For lower to moderate doses clearance is effectively linear, whereas for higher doses it is nonlinear. It is shown that for all doses sufficiently high the leading-order approximation for the IgG concentration in plasma, over the longest characteristic time scale, is independent of the initial dose. This is because IgG that is in 'excess' of FcRn is eliminated over a time scale much shorter than that of the terminal phase. In conclusion, analytical approximations of the basic FcRn mechanism have been derived using matched asymptotic expansions, leading to a simple equation relating clearance to FcRn binding affinity, the ratio of degradation and FcRn concentration, and the volumes of the system.