NDLI: Population Pharmacokinetic Modeling of LY2189102 after Multiple Intravenous and Subcutaneous Administrations

Content Provider	Springer Nature Link
Author	Bihorel, Sébastien Fiedler Kelly, Jill Ludwig, Elizabeth Sloan Lancaster, Joanne Raddad, Eyas
Copyright Year	2014
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.
Starting Page	1009
Ending Page	1017
Page Count	9
File Format	PDF
ISSN	12341234
Journal	The AAPS Journal
Volume Number	16
Issue Number	5
e-ISSN	15507416
Language	English
Publisher	Springer US
Publisher Date	2014-06-11
Publisher Institution	American Association of Pharmaceutical Scientists
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacology/Toxicology Biochemistry Biotechnology Pharmacy
Content Type	Text
Resource Type	Article

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