Characterization of binding between OSM and mAb in RA patient study: an extension to TMDD models
Roberto Bizzotto (1) and Stefano Zamuner (2)
(1) Institute of Biomedical Engineering, National Resource Council, Padua, Italy; (2) Clinical Pharmacology - Modelling and Simulation, GlaxoSmithKline, Stockley Park, UK
Objectives: A humanised IgG1 monoclonal antibody (mAb) against human Oncostatin M (OSM) is being developed for the treatment of rheumatoid arthritis (RA) . Oncostatin M is a member of the interleukin (IL)-6 family of secreted cytokines and is present in the inflamed synovium and blood of patients with RA. This works aims to describe and explain the relationship between mAb and OSM plasma levels and to characterize the in vivo equilibrium dissociation constant.
Methods: Plasma levels of free drug (mAb), and free and total OSM (free + mAb-OSM complex) were measured after intravenous and subcutaneous administration of various drug amounts. Using Monolix 4.1.4 software, a mixed-effect model for mAb pharmacokinetics (PK) was developed and estimated on the available measures to discard possible non linearity in the kinetics due to the binding of the drug with the target. The individual estimates of the PK parameters were included in a binding model implemented to fit the observed kinetics of free and total OSM. The target-meditated drug disposition (TMDD) model  was not able to contemporary fit the two sets of measures, and the equilibrium dissociation constant (KD) value estimated from the total OSM measures (less noisy than the free OSM measures) was far from the in vitro value (~ 1 nM). Berkeley Madonna 8.3.18 software was then used to explore more elaborated models able to describe all the data together.
Results: Drug kinetics was found to be linear. The best model able to reproduce the relationship between drug level, free and total plasma OSM includes the activation of a gradient-related OSM release in plasma from a separated OSM pool. Such hypothesis is supported by consequent KD estimates similar to the in vitro measure, and by the existence of intracellular preformed stocks of OSM in human neutrophils from which the cytokine is released besides being synthesised de novo .
Conclusions: Understanding antibody interaction with its target at physiological level is essential in better predicting clinical outcomes and TMDD models are generally adopted for this purpose. This analysis provides a real case in which TMDD models have been extended with the inclusion of a pool compartment to successfully describe the kinetics of drug and target and to provide in vivo estimates of their binding rates.
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This study has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115156, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. The DDMoRe project is also financially supported by contributions from Academic and SME partners.