HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Sign In to gain access to subscriptions and/or personal tools.

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Roy, A. Articles by Pfister, M. Search for Related Content PubMed PubMed Citation Articles by Roy, A. Articles by Pfister, M.

Modeling and Simulation of Abatacept Exposure and Interleukin-6 Response in Support of Recommended Doses for Rheumatoid Arthritis

From Bristol-Myers Squibb, Princeton, New Jersey (Dr Roy, Dr Wang, Dr Tay, Mr Raymond, Dr Pfister) and Projections Research, Inc, Phoenixville, Pennsylvania (Dr Mould). Dr Wang is a former Bristol-Myers Squibb employee and contributed to the analysis and interpretation of the data while affiliated with Bristol-Myers Squibb.

Abatacept is a recombinant soluble fusion protein that inhibits the CD80/CD86:CD28 costimulatory signal required for T cell activation and has demonstrated efficacy in the treatment of rheumatoid arthritis. The objectives of this analysis were to provide support for a body weight-tiered dosing regimen approximating 10 mg/kg by (1) quantifying the effect of body weight on exposure and (2) characterizing the relationship between exposure and serum interleukin (IL)-6 concentration. The abatacept exposure and exposure-response models were developed with 2148 abatacept serum concentrations (from 388 subjects) and 1894 IL-6 serum concentrations (from 799 subjects), respectively, followed by simulation with these models to address the above objectives. Abatacept exposure was characterized by a linear 2-compartmental model, in which clearance was linearly related to body weight. The IL-6 response was characterized by an indirect-response model, in which the IL-6 production rate increased with baseline C-reactive protein levels. Model-based simulations demonstrated that body weight-tiered dosing was desirable to ensure consistent steady-state abatacept trough concentrations across a range of body weights; doses approximating 10 mg/kg (500, 750, 1000 mg for subjects weighing <60, 60-100, and >100 kg, respectively) provided consistent exposure across the body weight groups. In addition, doses >10 mg/kg did not result in further increases in IL-6 suppression. These modeling and simulation results indicate that the body weight-tiered abatacept therapeutic doses approximating 10 mg/kg will ensure consistent abatacept exposure and optimal IL-6 suppression.

Key Words: Population pharmacokinetics • exposure response • abatacept • rheumatoid arthritis • IL-6

Address for correspondence: Dr Amit Roy, Clinical Discovery, Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543-4000; e-mail: amit.roy{at}bms.com.