jm6b00398_si_001.pdf (242.2 kB)
Use of Osmotic Pumps to Establish the Pharmacokinetic–Pharmacodynamic Relationship and Define Desirable Human Performance Characteristics for Aggrecanase Inhibitors
journal contribution
posted on 2016-05-19, 00:00 authored by Michael R. Wiley, Timothy B. Durham, Lisa A. Adams, Mark G. Chambers, Chaohua Lin, Chin Liu, Jothirajah Marimuthu, Peter
G. Mitchell, Daniel R. Mudra, Craig A. Swearingen, James L. Toth, Jennifer M. Weller, Kannan ThirunavukkarasuThe development of
reliable relationships between in vivo target
engagement, pharmacodynamic activity, and efficacy in chronic disease
models is beneficial for enabling hypothesis-driven drug discovery
and facilitating the development of patient-focused candidate selection
criteria. Toward those ends, osmotic infusion pumps can be useful
for overcoming limitations in the PK properties of proof-of-concept
(POC) compounds to accelerate the development of such relationships.
In this report, we describe the application of this strategy to the
development of hydantoin-derived aggrecanase inhibitors (eg, 3) for the treatment of osteoarthiritis (OA). Potent, selective
inhibitors were efficacious in both chemical and surgical models of
OA when exposures were sustained in excess of 10 times the plasma
IC50. The use of these data for establishing patient-focused
candidate selection criteria is exemplified with the characterization
of compound 8, which is projected to sustain the desired
level of target engagement at a dose of 45 mg qd.