Csaba B. Kátai 1, Anke E. Kip 1, Manon M. M. Berns 1, Jeroen Elassaiss-Schaap 1
1 PD-value B.V. (Utrecht, The Netherlands)
Introduction: Over the last few decades physiology-based pharmacokinetic (PBPK) models have received increasingly more attention not just as an academic curiosity, but also as a useful tool in regulatory acceptance [1, 2]. Owing to their flexibility and modular nature they have been particularly well-suited to address both the specific and non-specific processes associated with antibody pharmacokinetics (PK). The salvage, recycling and non-specific elimination of antibodies mediated by the neonatal Fc receptor (FcRn) in PBPK models reported in the literature are often implemented in a similar way. A deep understanding of the effect of the various model parameters on antibody PK was offered by Kátai et al. [3, 4] using a three-tiered scaling framework and a set of sophisticated mathematical techniques. The analyses investigated the biological mechanisms themselves and showed how their characteristic behaviours arise mathematically. This is in contrast to most research papers in the literature that compute the behaviour of a model numerically. Nevertheless, similarly to many models reported in the literature (e.g. [5–7]), they chose not to include the competitive binding between therapeutic and endogenous antibodies to FcRn. To gain a more comprehensive picture of the FcRn mechanism, the inclusion of endogenous antibodies is necessary. Such a scenario is valuable not only to elucidate the dynamics for IVIG therapy, but also for patients with high or low baseline endogenous antibody levels such as in liver cirrhosis [8] or myotonic dystrophy [9], respectively.
Methods: The present work addresses the competitive binding of therapeutic and endogenous antibodies to FcRn, by extending the work of [3] by including an analogous FcRn interaction and a zeroth-order synthesis for endogenous antibodies. Crucially, the interaction scheme includes the dynamic binding, pinocytic uptake and recycling, and endosomal elimination of antibodies (cf. [10]). The analysis utilises the method of matched asymptotic expansions in the high antibody-FcRn binding limit and the three-tiered scaling framework of [3]. For the present work, both the simpler case of non-saturating doses (with respect to the baseline free FcRn) and an outline of the analysis for higher doses is presented.
Results: The analysis provides a detailed asymptotic description of the dynamics by deriving reduced models valid in each characteristic phase of the system. The multi-scale solution structures for low (non-saturating) and high (saturating) doses are identical to those in [3], but with the effect of endogenous antibodies incorporated. Owing to the long half life of antibodies, the production of endogenous antibodies is shown to be a leading-order effect only during the long ‘effective’ antibody elimination time scale. Apart from improving on the theory of [3], the work derives, as its main result, a set of coupled reduced equations governing the competition of the therapeutic and endogenous antibodies over the effective elimination time scale. The corresponding reduced system takes the form (cf. [3])
dC1/dt ~ – k1 * C1 / (Ftotal – s1 * C1 – s2 *C2) + production,
dC2/dt ~ – k2 * C2 / (Ftotal – s1 * C1 – s2 *C2),
where C1 and C2 are the endogenous and therapeutic antibody concentrations in the plasma, respectively, and k1, k2, s1, and s2 are (composite) parameters of the model, and Ftotal is the total FcRn concentration in the endosomal space (details included in [11]). The above equations describing the competitive binding can only be decoupled for sufficiently low endogenous antibody levels or therapeutic doses. Only the latter of these conditions guarantees linear PK, which corresponds to typical physiological parameter values and therapeutic doses (< 2 g for human). The system in this case relaxes to the results of [3], supporting the notion that in most cases the effect of endogenous antibodies is expected to be negligible. Conversely, when the therapeutic dose is sufficiently high, further competition develops during a rapid elimination phase responsible for the elimination of antibodies in ‘excess’ of FcRn. During this phase the relative binding affinity of the endogenous and therapeutic antibodies to FcRn drive the competition and determine the antibody composition leading up to the terminal phase. Conclusions: An asymptotic theory is presented that extends that of [3] by including the effect of endogenous antibodies. The analysis offers a deep understanding the effect of competitive binding on antibody PK and provides guidance for large-scale PBPK models. References: 1. M. Jamei. Recent advances in development and application of physiologically-based pharmacokinetic (PBPK) models: a transition from academic curiosity to regulatory acceptance. Curr. Pharmacol. Rep., 2(3):161–169, 2016. 2. P. Paul et al. Current use of physiologically based pharmacokinetic modeling in new medicinal product approvals at EMA. Clin. Pharmacol. Ther., 117(3):808–817, 2025. 3. C. B. Kátai et al.. An asymptotic description of a basic FcRn-regulated clearance mechanism and its implications for PBPK modelling of large antibodies. J. Pharmacokinet. Pharmacodyn., pages 1–25, 2024. 4. C. B. Kátai et al. On the coupling between a basic FcRn mechanism and target-mediated disposition of antibodies. J. Pharmacokinet. Pharmacodyn., 45(1):139–157, 2026 5. A. Garg and J. P. Balthasar. Physiologically-based pharmacokinetic (PBPK) model to predict IgG tissue kinetics in wild-type and FcRn-knockout mice. J. Pharmacokinet. Pharmacodyn., 34:687–09, 2007. 6. D. K. Shah and A. M. Betts. Towards a platform PBPK model to characterize the plasma and tissue disposition of monoclonal antibodies in preclinical species and human. J. Pharmacokinet. Pharmacodyn., 39(1):67–86, 2012. 7. P.-J. De Sutter et al. Comparison of monoclonal antibody disposition predictions using different physiologically based pharmacokinetic modelling platforms. J. Pharmacokinet. Pharmacodyn., 51(6):639–651, 2024. 8. D. Schuppan and N. H. Afdhal. Liver cirrhosis. Lancet, 371(9615):838–851, 2008. 9. R. D. Wochner et al. Accelerated breakdown of immunoglobulin G (IgG) in myotonic dystrophy: a hereditary error of immunoglobulin catabolism. J. Clin. Invest., 45(3):321–329, 1966. 10. S. Fuhrmann et al. Impact of altered endogenous IgG on unspecific mAb clearance. J. Pharmacokinet. Pharmacodyn., 44:351–374, 2017. 11. C. B. Kátai et al. An asymptotic theory on the competitive binding of therapeutic and endogenous antibodies to FcRn. (In preparation), 2026.
Reference: PAGE 34 (2026) Abstr 11871 [www.page-meeting.org/?abstract=11871]
Poster: Methodology - New Modelling Approaches