Safety, tolerability, pharmacokinetics and pharmacodynamics of belimumab in Japanese patients with mild-to-moderate systemic lupus erythematosus

Abstract

Objectives: Belimumab, an anti-B lymphocyte stimulator (BLyS) human monoclonal antibody, was approved in the United States, Canada and European Union for the treatment of the patients with systemic lupus erythematosus (SLE). However, belimumab had not been evaluated in Japanese patients. The objectives of this study were to evaluate the safety and tolerability of belimumab in Japanese patients with SLE, as well as to investigate the pharmacokinetics (PK) and biological activity of belimumab in this population.

Methods: A total of 12 Japanese patients were enrolled in a randomized, single-blind, placebo-controlled, dose-ascending design study. A dosing regimen of a single intravenous infusion over 1 hour of belimumab (1 mg/kg and 10 mg/kg) was employed. Patients were followed for 84 days after dosing to assess adverse events, pharmacokinetics, biomarkers and SLE disease activity.

Clinical trial registration number: ClinicalTrials.gov identifier is NCT01381536.

Results: Belimumab (1 mg/kg and 10 mg/kg) demonstrated a favorable clinical safety and tolerability profile in Japanese patients with SLE. The incidence of adverse events was similar among the two belimumab groups and placebo group. The PK profile of single-dose belimumab was approximately dose proportional, and the long terminal elimination half-life (12.4-15.7 days), low clearance (3.55-4.65 mL/day/kg), and small volume of distribution (76.2-80.1 mL/kg) were consistent with a fully humanized antibody. Effects of belimumab on B cells suggested biological activity effects expected as an inhibitor of BLyS.

Limitation: The small sample size and single dose design of this study prevent definitive conclusions regarding the safety, pharmacokinetics or pharmacodynamics of belimumab in a Japanese population being made.

Conclusions: The preliminary safety, PK profile, and observed biological activity of belimumab support further evaluation of its safety and efficacy in Japanese patient with SLE.

Keywords: Belimumab; Pharmacodynamics; Pharmacokinetics; Safety; Systemic lupus erythematosus.

Figures

Figure 1.

Serum concentration of belimumab after a single intravenous dose in individual patients; 1 mg/kg (n = 4), 10 mg/kg (n = 4). Serum concentrations of belimumab were determined using an electrochemiluminescence (ECL)-based assay. The lower limit of quantitation of the assay was 100 ng/mL of belimumab in 100% human serum, which was determined by multiplying 0.25 ng/mL by 400, the lowest dilution factor used in the assay.

Figure 2.

Median percentage change from baseline in CD20+, naïve, activated and memory B cells after a single intravenous dose; 1 mg/kg (n = 4), 10 mg/kg (n = 4) and placebo (n = 4).

Figure 3.

Median percentage change from baseline in complements (C3, C4) after a single intravenous dose; 1 mg/kg (n = 4), 10 mg/kg (n = 4) and placebo (n = 4).