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

Abstract

ObjectivesBelimumab, 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.MethodsA 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 numberClinicalTrials.gov identifier is NCT01381536.ResultsBelimumab (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.LimitationThe 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.ConclusionsThe preliminary safety, PK profile, and observed biological activity of belimumab support further evaluation of its safety and efficacy in Japanese patient with SLE.

Pharmacokinetics, Pharmacodynamics and Safety of Belimumab in Chinese Patients with Systemic Lupus Erythematosus: A Phase I, Open-Label Study

“…After a single 10 mg/kg IV dose of belimumab, geometric mean t 1/2 , CL, V z , C max , and AUC 0-t were 14.6 days, 4.06 mL/day/kg, 85.7 mL/kg, 221 lg/ mL, and 2395 dayÁlg/mL, respectively. These results are consistent with PK values for Japanese patients in a previous study [9], who demonstrated geometric mean t 1/2 , CL, V z , C max , and AUC 0-t values of 15.7 days, 3.6 mL/day/kg, 76.2 mL/kg, 223 lg/mL, and 2814 dayÁlg/mL, respectively [9]. The values from Chinese and Japanese patients differ slightly from those of patients in a US study, who showed a slightly higher mean CL (6.9 mL/day/kg), a lower t 1/2 (10.6 days), C max (192 lg/mL), and AUC 0-t (1510 dayÁlg/mL), and a similar V z (86.3 mL/kg) [10].…”

“…The safety profile of belimumab in this study was consistent with that in the phase 3 study conducted in Northeast Asia in which patients received belimumab for 48 weeks [8], with upper respiratory tract infection and nasopharyngitis being the most commonly reported AEs. These findings are in keeping with those of other clinical studies of belimumab in patients with SLE, in AE adverse event, IV intravenous, SLE systemic lupus erythematosus which it was well tolerated when one or two doses of up to 20 mg/kg, or multiple doses of 1 or 10 mg/kg, were administered for up to 76 weeks [9,10,14].…”

“…PK samples were collected from patients for 84 days after dosing (i.e., more than 5 half-lives of belimumab) to enable a comprehensive PK profile to be determined following a single IV dose. Although the PK of belimumab 10 mg/kg IV has not been assessed in healthy volunteers, it has been assessed in patients with mild-tomoderate SLE from Japan [9] and the USA [10]. Therefore, Chinese patients with SLE, rather than healthy Chinese volunteers, were recruited into this study to allow unbiased comparison between Chinese and non-Chinese patients.…”

“…The pharmacokinetics (PK) and pharmacodynamics (PD) of IV administration of belimumab have previously been investigated in patients with SLE from Japan [9] and the USA (white or African-American) [10], and were generally similar across these populations. After administration of a single dose of belimumab 10 mg/kg IV in Japanese or American patients with SLE, the terminal half-life (t 1/2 ) was 15.7 and 10.6 days, the volume of distribution (V z ) was 76.2 and 86.3 mL/kg, and mean clearance (CL) was 3.6 and 6.9 mL/day/kg, respectively [9,10].…”

The pharmacokinetics and safety profiles of belimumab after single subcutaneous and intravenous doses in healthy Japanese volunteers

“…2,8 However, such treatments provide insufficient efficacy and are associated with significant toxicity. 4,7,8 In Japan, the safety and pharmacokinetics of a single-dose belimumab (1 and 10 mg/kg, intravenous (IV) administration in Japanese patients with SLE) has been evaluated, 9 and a phase 3 study to evaluate its efficacy and safety in Northeast Asian patients (10 mg/kg IV every 2 weeks for 3 doses and every 4 weeks thereafter) is ongoing. Once-weekly subcutaneous (SC) injections, if shown to be feasible and effective, would be more convenient for patients than the IV regimen.…”