title: Use of Osmotic Pumps to Establish the Pharmacokinetic-Pharmacodynamic Relationship and Define Desirable Human Performance Characteristics for Aggrecanase Inhibitors.
abstract: The 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.
authors.affiliation: Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wiley
authors.affiliation: Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Durham
authors.affiliation: Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Adams
authors.affiliation: Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Chambers
authors.affiliation: Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Chaohua
authors.initials: C
authors.lastname: Lin
authors.affiliation: Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Chin
authors.initials: C
authors.lastname: Liu
authors.affiliation: Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Jothirajah
authors.initials: J
authors.lastname: Marimuthu
authors.affiliation: Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Mitchell
authors.affiliation: Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Mudra
authors.affiliation: Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Swearingen
authors.affiliation: Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: James L
authors.initials: JL
authors.lastname: Toth
authors.affiliation: Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Weller
authors.affiliation: Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Kannan
authors.initials: K
authors.lastname: Thirunavukkarasu
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D009995:Osmosis / Q000187:drug effects; D010003:Osteoarthritis / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D006827:Hydantoins; D010450:Endopeptidases; C083641:aggrecanase