Dataset Information

Population pharmacokinetic modeling of LY2189102 after multiple intravenous and subcutaneous administrations.

ABSTRACT: Interleukin-1 beta (IL-1?) 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-1? 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.

SUBMITTER: Bihorel S

PROVIDER: S-EPMC4147062 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Population pharmacokinetic modeling of LY2189102 after multiple intravenous and subcutaneous administrations.

Bihorel Sébastien S Fiedler-Kelly Jill J Ludwig Elizabeth E Sloan-Lancaster Joanne J Raddad Eyas E

The AAPS journal 20140611 5

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 ...[more]

PMID: 24912797

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Dataset Information

Population pharmacokinetic modeling of LY2189102 after multiple intravenous and subcutaneous administrations.

Publications

Population pharmacokinetic modeling of LY2189102 after multiple intravenous and subcutaneous administrations.

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