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) All Versions of this Article: 0091270008315312v1 48/4/406    most recent 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 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 Nestorov, I. Articles by Visich, J. Search for Related Content PubMed PubMed Citation Articles by Nestorov, I. Articles by Visich, J.

Pharmacokinetics and Biological Activity of Atacicept in Patients With Rheumatoid Arthritis

From ZymoGenetics, Seattle, Washington (Dr Nestorov, Dr Visich) and Merck Serono International S.A. (an affiliate of Merck KGaA, Darmstadt, Germany), Geneva, Switzerland (Dr Munafo, Dr Papasouliotis).

Atacicept is a recombinant fusion protein containing the extracellular ligand-binding portion of the transmembrane activator and CAML interactor (TACI, CD267) receptor and inhibits B lymphocyte stimulator (BLyS, CD257) and a proliferation-inducing ligand (APRIL, CD256), both potent stimulators of B cell maturation, proliferation, and survival. Atacicept pharmacokinetics and pharmacodynamics were assessed in a double-blind, placebo-controlled, phase I study in patients with active, moderate to severe rheumatoid arthritis receiving atacicept either as a single subcutaneous or repeated, every other week dose. Pharmacokinetic profiles were determined by measuring serum concentrations of free atacicept and its complex with BLyS. Nonspecific immunoglobulin (Ig)M, IgG, and IgA; IgM-RF (rheumatoid factor), IgG-RF, and IgA-RF antibody levels; and B cell profiles provided markers of biological activity. Pharmacokinetic, biological activity, and relationships between atacicept dose and Ig antibody response were evaluated. Pharmacokinetic profiles of atacicept were nonlinear, influenced by saturable binding with its ligands, but were consistent and predictable. Atacicept treatment reduced Ig and RF serum concentration. IgM antibody levels were most sensitive to atacicept, followed by IgA and IgG, underlining the biological activity of atacicept in patients with rheumatoid arthritis. These findings can be used to explore dosing regimen design scenarios in future studies.

Key Words: APRIL • atacicept • BLyS • pharmacokinetics • rheumatoid arthritis • TACI-Ig

Address for correspondence: Ivan Nestorov, ZymoGenetics, Inc, 1201 Eastlake Avenue East, Seattle, WA 98102; e-mail: intv{at}zgi.com.