Pharmacokinetics and immunoglobulin response of subcutaneous and intravenous atacicept in patients with systemic lupus erythematosus.

Abstract

Atacicept, a recombinant fusion protein of the TACI receptor and human IgG, is an inhibitor of B-Lymphocyte Stimulator (BLyS) and APRIL, potent stimulators of B cell maturation, proliferation, and survival. Pharmacokinetics (PKs) and biological activity of intravenous (iv) and subcutaneous (sc) atacicept are described here for patients with systemic lupus erythematosus in two randomized, double-blind, placebo-controlled, Phase Ib studies. Study 1: Six cohorts of eight patients received sc atacicept (single dose: 0.3, 1, 3, or 9 mg/kg; four weekly doses: 1 or 3 mg/kg), or placebo (3:1 ratio). Study 2: Four cohorts of six patients received iv atacicept (single dose: 3, 9, or 18 mg/kg; multiple dose: 2 x 9 mg/kg), or matching placebo (5:1 ratio). PK profiles were determined through serum atacicept and atacicept-BLyS complex, and biological activity through IgA, IgG, and IgM levels. PK profiles of atacicept were influenced by saturable binding between atacicept and its ligands, and were consistent and predictable across doses and regimens. Atacicept's biological activity was compatible with its presumed mechanism of action. Bioavailability was approximately 30-40% following sc or iv administration and similar doses yielded similar biological activity irrespective of administration route. This observation may have a mechanistic foundation and may inform dosing regimen design for future studies.

• Authors: I Nestorov, O Papasouliotis, C Pena Rossi, A Munafo
• Journal: Journal of pharmaceutical sciences (J Pharm Sci) Vol. 99 Issue 1 Pg. 524-38 (Jan 2010) ISSN: 1520-6017 [Electronic] United States
• PMID: 19743503 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Biomarkers
• Immunoglobulins
• Recombinant Fusion Proteins
• TACI receptor-IgG Fc fragment fusion protein

Topics

• Adult
• Biomarkers (blood)
• Cohort Studies
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Enzyme-Linked Immunosorbent Assay
• Female
• Humans
• Immunoglobulins (blood)
• Injections, Intravenous
• Injections, Subcutaneous
• Lupus Erythematosus, Systemic (blood, drug therapy, immunology)
• Male
• Middle Aged
• Recombinant Fusion Proteins (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Young Adult