Monica Simeoni, Chao Chen
Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, London, UK
Objectives: One of the recognised functions of the neonatal Fc receptor (FcRn) is to protect IgG from catabolism by endosomal proteases, via FcRn-IgG binding in endosomes. The bound IgG is recycled back into circulation, escaping the catabolism. Successful quantification of this binding/recycling process can inform the understanding of the kinetics and effect level of an endogenous or exogenous IgG. The objective of the work presented here was to build a mathematical model that could be used to describe the circulating level of an endogenous or exogenous IgG under normal physiological conditions and to predict its level when the system would be perturbed by a number of causes such as disease conditions and pharmacological treatments.
Methods: A mechanistic model was constructed using literature knowledge, including alternative or component models, on the pharmacokinetics of IgG and the involvement of FcRn. The model was coded in ordinary differential equations; and the parameters were identified in literature reports or were derived by steady-state principles. Volume-related parameters were scaled cross species by direct proportion to body weight. To enhance computation speed, quasi equilibrium of the FcRn-IgG binding was assumed. We first conducted simulations to compare this model with alternative or component models that were found in the literature and to reconcile apparent differences. The model was then used to predict reported blood IgG levels in human and other species during various therapeutic interventions.
Results: The mechanistic model involving IgG and FcRn had three compartments. The IgG was produced in a blood compartment which was connected to a peripheral compartment through 2-way processes. Blood IgG was also distributed into an endosome compartment where IgG was eliminated; FcRn was produced and eliminated; and a reversible 1:1 binding between FcRn and IgG occurred. The IgG and the FcRn of the binding complex were recycled (instantly) to blood and to the endosome free FcRn pool, respectively. All processes were first-order, except for the syntheses of IgG and FcRn which were zero-order. The model was capable of reproducing simulations which were reported in the literature by alternative models. Preliminary simulations of changes in blood IgG level during various interventions were in broad agreement with those reported in the literature.
Conclusions: We have used literature findings to construct a versatile model to describe the FcRn involvement in the disposition of IgG in human. Emerging results showed that the model could successfully reproduce the reported changes in blood IgG during several types of system perturbation. Upon further development, the model can potentially be used to evaluate the pharmacological potential of certain therapeutic approaches.
Reference: PAGE 22 () Abstr 2755 [www.page-meeting.org/?abstract=2755]
Poster: Other Drug/Disease Modelling