title: Population pharmacokinetic modeling of LY2189102 after multiple intravenous and subcutaneous administrations.
abstract: Interleukin-1 beta (IL-1β) is an inflammatory mediator which may contribute to the pathophysiology of rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM). Population pharmacokinetics (PK) of LY2189102, a high affinity anti-IL-1β humanized monoclonal immunoglobulin G4 evaluated for efficacy in RA and T2DM, were characterized using data from 79 T2DM subjects (Study H9C-MC-BBDK) who received 13 weekly subcutaneous (SC) doses of LY2189102 (0.6, 18, and 180 mg) and 96 RA subjects (Study H9C-MC-BBDE) who received five weekly intravenous (IV) doses (0.02-2.5 mg/kg). Frequency of anti-drug antibody (ADA) development appears dose-dependent and is different between studies (36.7% in Study H9C-MC-BBDK vs. 2.1% in Study H9C-MC-BBDE), likely due to several factors, including differences in patient population and background medications, administration routes, and assays. A two-compartment model with dose-dependent bioavailability best characterizes LY2189102 PK following IV and SC administration. Typical elimination and distribution clearances, central and peripheral volumes of distribution are 0.222 L/day, 0.518 L/day, 3.08 L, and 1.94 L, resulting in a terminal half-life of 16.8 days. Elimination clearance increased linearly, yet modestly, with baseline creatinine clearance and appears 37.6% higher in subjects who developed ADA. Bioavailability (0.432-0.721) and absorption half-life (94.3-157 h) after SC administration are smaller with larger doses. Overall, LY2189102 PK is consistent with other therapeutic humanized monoclonal antibodies and is likely to support convenient SC dosing.
authors.affiliation: Cognigen Corporation, 1780 Wehrle Drive - Suite 110, Buffalo, NY, 14221-7000, USA.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bihorel
authors.forename: Jill
authors.initials: J
authors.lastname: Fiedler-Kelly
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ludwig
authors.forename: Joanne
authors.initials: J
authors.lastname: Sloan-Lancaster
authors.forename: Eyas
authors.initials: E
authors.lastname: Raddad
mesh_terms: D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D001682:Biological Availability; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D016014:Linear Models; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D007004:Hypoglycemic Agents; C586827:LY2189102