Pharmacokinetics and safety of single doses of tabalumab in subjects with rheumatoid arthritis or systemic lupus erythematosus

• Published in: British journal of clinical pharmacology Vol. 81; no. 5; pp. 908 - 917
• Main Authors: Witcher, Jennifer, Fleischmann, Roy, Chindalore, Vishala L., Hansen, Ryan J., Hu, Leijun, Radtke, David, Voelker, James, Gomez, Elisa, McColm, Juliet
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.05.2016
• Subjects: Adult; Aged; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal, Humanized; Antigens, CD20 - immunology; Arthritis, Rheumatoid - drug therapy; B-Cell Activating Factor - antagonists & inhibitors; B-Lymphocyte Subsets - drug effects; B-Lymphocyte Subsets - immunology; B‐cell activating factor; Female; Humans; Injections, Intravenous; Injections, Subcutaneous; Lupus Erythematosus, Systemic - drug therapy; Male; Middle Aged; Pharmacokinetics; rheumatoid arthritis; systemic lupus erythematosus; tabalumab; pharmacokinetics; B-cell activating factor; systemic lupus erythematosus; tabalumab; rheumatoid arthritis
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.12860

Aims Two phase 1 studies evaluated the pharmacokinetics (PK), safety and biological activity of tabalumab, a human monoclonal antibody against B‐cell activating factor (BAFF), administered intravenously (i.v.) or subcutaneously (s.c.) in subjects with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Methods In study A, subjects with RA (n = 23) or SLE (n = 6) received a single i.v. dose of tabalumab (RA 0.01, 0.04, 0.125, 0.5, 2.0, and 8.0 mg kg–1 and SLE 0.125 or 2.0 mg kg–1) or placebo. In study B, subjects with RA received a single tabalumab dose i.v. (10 mg) (n = 12) or s.c. (20 mg) (n = 12). Serum tabalumab and CD20+ B cells were evaluated and safety was assessed throughout both studies. Results Tabalumab PK were non‐linear across the 0.01 to 8.0 mg kg–1 dose range. Clearance (CL) decreased from 2.9 to 0.1 l day–1 and terminal half‐life (t1/2) increased from about 1.6 to 25 days. Subjects with RA or SLE had similar PK. After s.c. dosing, tabalumab time to maximal concentration (tmax) was 5.5 days. Absolute bioavailability (F) was approximately 62%. Following tabalumab dosing, CD20+ B cells transiently increased from baseline followed by a progressive decrease below baseline. Conclusion A single tabalumab dose administered i.v. or s.c. was well tolerated and had non‐linear CL over the dose range investigated in subjects with RA and SLE. The non‐linearity likely reflects target‐mediated CL due to binding to BAFF. Tabalumab showed biological activity based on changes in peripheral CD20+ lymphocyte numbers in both subjects with RA and SLE.