Semi-mechanistic model-based drug development of EMD 525797 (DI17E6), a novel anti-αv integrin monoclonal antibody
B. Meibohm (1), B. Brockhaus (2), M. Zühlsdorf (2), A. Kovar (2)
(1) The University of Tennessee Health Science Center, Memphis, TN, USA, (2) Merck Serono, Darmstadt, Germany
Objectives: The objective of this analysis was to develop a semi-mechanistic population PK model for EMD 525797 incorporating receptor occupancy that forms the basis of a model-guided dose rationale.
Methods: A stepwise approach was used to develop and iteratively refine a population PK/PD model throughout clinical development of EMD 525797 using nonlinear mixed effect modeling with NONMEM. The model was initially derived for describing the PK data in a dose-escalation study in Cynomolgus monkeys, and was subsequently refined with human concentration-time data. At the current iteration of model refinement, 815 serum concentrations of 51 subjects have been included in the analysis: 37 healthy volunteers receiving EMD 525797 single doses of 35, 100, 250, 500, 1000, and 1500 mg, and 14 patients with metastatic castrate-resistant prostate cancer (mCRPC) receiving EMD 525797 250 or 500 mg every 2 weeks. EMD 525797 was administered as intravenous infusion over 1 hour.
Results: The disposition of EMD 525797 was best described by a 2-compartment model with 2 parallel elimination pathways, an unspecific proteolytic pathway, and a saturable, target-mediated process with Michaelis-Menten-type kinetics, which is an approximation of the target-mediated drug disposition model (TMDD) [1]. A disease modifier function was included for Vmax based on disease status. The obtained parameter point estimates and their between-subject variability (% CV) were: Vmax=493 µg/hr (21.4%), with a 35.3% increase in mCRPC patients, Km=0.571 µg/mL, V1=4.41 L (22.0%), V2=3.44 L (40.4%), Q=0.0444 L/hr (56.9%), and CLproteolytic=0.00857 L/hr (25.8%). Saturation of the saturable elimination process was assumed to be indicative of receptor occupancy for the targeted αv integrins, and IC90, IC95, and IC99 of αv integrin inhibition could be derived from Km. Model-based stochastic simulations were performed to explore dosing regimens with regard to their likelihood to achieve steady-state trough concentration exceeding these landmarks.
Conclusions: Modeling and simulation provides a rational basis for EMD 525797 dose selection. Next steps are to use the model to compare between different populations and to test whether other TMDD model approximations could fit better the data [2].
References:
[1] Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinet Pharmacodyn 2001;28:507-32.
[2] Gibiansky L, Gibiansky E. Target-mediated drug disposition model: approximations, identifiability of model parameters and applications to the population pharmacokinetic-pharmacodynamic modeling of biologics. Expert Opinion Drug Metab Toxicol 2009;5:803-12.