Quantitative modelling to assess target engagement and pharmacology in early clinical development of an anti-OSM humanised mAb
Chiara Zecchin (1), Stefano Zamuner (1)
(1) GlaxoSmithKline, Stevenage, UK
Objectives: GSK2330811 is a humanized IgG1κ monoclonal antibody (mAb) that functionally blocks human oncostatin M (OSM) from binding to the gp130 receptor. It is being developed for the treatment of systemic sclerosis and other immune-mediated diseases. The aim of this analysis is 1) to develop a PKPD model to describe target engagement (TE) with GSK2330811, 2) to simulate TE with repeat dosing and 3) to optimise the design of the Proof-of-Mechanism (PoM) study.
Methods: Data collected during the Phase I single ascending dose study 201246 were available. Doses of 0.1, 0.3, 1, 3 and 6 mg/kg were given subcutaneously to healthy volunteers. Serial PK and OSM samples were taken for all cohorts. This information was used to develop PKPD models [1] to describe total drug and target concentration values in plasma and in blister fluid.
Simulations of TE during repeat dosing based on parameters uncertainty were performed to support dose selection, dosing schedule and sample size to enhance probability of success in the planned PoM study.
Results: The mPBPK model [1] with target mediated drug disposition (TMDD) in plasma and in leaky tissues best described drug and OSM concentration in plasma and blister fluid. The median estimated in vivo mAb/OSM affinity equilibrium constant was 630 pM and the estimated degradation rate of mAb+OSM complex was 0.0478 hr-1 in plasma and 0.0864 hr-1 in leaky tissue. The quasi-steady-state (QSS) [2] approximation was used to describe TE. PKPD model parameters were estimated simultaneously with the IMP estimation method in NONMEM 7.3 [3].
Virtual trials were simulated using parameter estimated values and their uncertainty to assess the probability of success based on TE criteria. Different study designs (sample size, dose and frequency) were tested. Success was defined as the lower bound of the 95% CI of TE above 85% at steady state (day 56). The optimal dose for the PoM trial was 300 mg every other week.
Conclusions: Mechanistic PKPD modelling and simulation was used to predict TE in human for repeat dosing of GSK2330811 based on data observed in a FTIH study.
These predictions helped to select optimal doses, dosing interval and sample size in the PoM study.
References:
[1] Cao Y and Jusko WJ. "Incorporating target-mediated drug disposition in a minimal physiologically-based pharmacokinetic model for monoclonal antibodies." J pharmacokinet pharmacodyn 41.4 (2014): 375-387.
[2] Gibiansky L, et al. "Approximations of the target-mediated drug disposition model and identifiability of model parameters." J pharmacokinet pharmacodyn 35.5 (2008): 573-591.
[3] Beal SL., et al. "NONMEM 7.3. 0 Users Guides. (1989–2013)." ICON Development Solutions, Hanover, MD.
This study was funded by GSK.
