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.

Trial registration: ClinicalTrials.gov NCT00380744 NCT00942188.

Figures

Fig. 1

LY2189102 dose-normalized serum concentrations versus time since the previous dose stratified by study and dose a, and LY2189102 concentration versus time since first dose in Study BBDK stratified by antidrug antibody status b

Fig. 2

goodness-of-fit plots for the final model for LY2189102 pharmacokinetics

Fig. 3

Prediction-corrected visual predictive check of the final model for LY2189102 pharmacokinetics

Fig. 4

Influence of creatinine clearance on steady-state LY2189102 exposures. Lines delimit the 80% prediction intervals of the steady-state exposure versus dose relationship predicted from the final LY2189102 model at the 5th, 50th, and 95th percentiles of creatinine clearance in the study population. Inset represents the same data for the 0 to 3 mg dose range