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

Jing Zhang, Weiguo Wan, Liyan Miao, Jian Wu, Jun Dong, Yinghua Shen, Cui Xiong, Chao Li, Yu Xue, Guoying Cao, Peiming Ma, Jing Zhang, Weiguo Wan, Liyan Miao, Jian Wu, Jun Dong, Yinghua Shen, Cui Xiong, Chao Li, Yu Xue, Guoying Cao, Peiming Ma

Abstract

Introduction: The B cell survival factor B lymphocyte stimulator (BLyS) is elevated in patients with systemic lupus erythematosus (SLE) and associated with disease activity. Belimumab, a monoclonal antibody specific for soluble BLyS, is approved for the treatment of adults with active, autoantibody-positive SLE receiving standard therapy. Ethnicity is one of the factors that can potentially affect the pharmacokinetics (PK) of therapeutic monoclonal antibodies, and therefore their efficacy and safety.

Methods: This phase 1, open-label study (200909) evaluated the pharmacokinetics (PK, primary objective), pharmacodynamics (PD), and safety (secondary objectives) of belimumab in Chinese patients with SLE (N = 20). Blood samples were taken up to 84 days after a single intravenous (IV) dose of belimumab 10 mg/kg.

Results: Peak serum concentrations of belimumab (Cmax) were obtained within the 1-h infusion. Geometric mean Cmax, area under the concentration-time curve (time 0 to last quantifiable concentration), terminal half-life, systemic clearance, and volume of distribution were 221 μg/mL, 2395 day·μg/mL, 14.6 days, 4.06 mL/day/kg, and 85.7 mL/kg, respectively. Decreases in CD20+, CD20+/CD27- naïve, CD20+/CD69+ active, CD20+/CD138+ plasmacytoid, CD19+/CD27BRIGHT/CD38BRIGHT SLE subset, and CD20-/CD138+ plasma B Cells post-dose were accompanied by an increase in CD20+/CD27+ memory B cells. Four cases of upper respiratory tract infection (three mild, one moderate) and one case of mild pharyngitis were possibly drug-related; all resolved during the study.

Conclusion: PK of a single belimumab 10 mg/kg IV dose in Chinese patients with SLE were similar to those observed previously in Japanese and American (white and African-American) patients with SLE. PD results were consistent with belimumab inhibiting BLyS, and belimumab was well tolerated. These data support the use of belimumab in Chinese patients with SLE.

Trial registration: ClinicalTrials.gov identifier, NCT02880852.

Keywords: Belimumab; Chinese ethnicity; Pharmacodynamics; Pharmacokinetics; Systemic lupus erythematosus.

Figures

Fig. 1
Fig. 1
Mean (SD) serum concentration–time profile of belimumab after a single IV dose (10 mg/kg) in Chinese patients with SLE (N = 20), depicted on a linear and b semilogarithmic scales. IV intravenous, SD standard deviation, SLE systemic lupus erythematosus
Fig. 2
Fig. 2
Percentage change from baseline in B cell subsets in Chinese patients with SLE who received a single dose of belimumab 10 mg/kg IV (N = 20). IV intravenous, SLE systemic lupus erythematosus, CD, cluster of differentiation

References

    1. Di Battista M, Marcucci E, Elefante E, et al. One year in review 2018: systemic lupus erythematosus. Clin Exp Rheumatol. 2018;36:763–777.
    1. Mok CC. Epidemiology and survival of systemic lupus erythematosus in Hong Kong Chinese. Lupus. 2011;20:767–771. doi: 10.1177/0961203310388447.
    1. Mok CC, To CH, Ho LY, Yu KL. Incidence and mortality of systemic lupus erythematosus in a southern Chinese population, 2000–2006. J Rheumatol. 2008;35:1978–1982.
    1. Rees F, Doherty M, Grainge MJ, Lanyon P, Zhang W. The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies. Rheumatology (Oxford) 2017;56:1945–1961. doi: 10.1093/rheumatology/kex260.
    1. Wang Z, Wang Y, Zhu R, et al. Long-term survival and death causes of systemic lupus erythematosus in China: a systemic review of observational studies. Medicine (Baltimore) 2015;94:e794. doi: 10.1097/MD.0000000000000794.
    1. GlaxoSmithKline. Belimumab US prescribing information. . Accessed 1 Jul 2019.
    1. FDA. News release. FDA approves first treatment for paediatric patients with lupus. 2019. . Accessed 1 Jul 2019.
    1. Zhang F, Bae SC, Bass D, et al. A pivotal phase III, randomised, placebo-controlled study of belimumab in patients with systemic lupus erythematosus located in China, Japan and South Korea. Ann Rheum Dis. 2018;77:355–363. doi: 10.1136/annrheumdis-2017-211631.
    1. Yamada M, Akita M, Nakagawa T, Takahashi N, Endo A, Yoshida P. Safety, tolerability, pharmacokinetics and pharmacodynamics of belimumab in Japanese patients with mild-to-moderate systemic lupus erythematosus. J Drug Assess. 2013;2:40–48. doi: 10.3109/21556660.2013.792823.
    1. Furie R, Stohl W, Ginzler EM, et al. Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus. Arthritis Res Ther. 2008;10:R109. doi: 10.1186/ar2506.
    1. Gill KL, Machavaram KK, Rose RH, Chetty M. Potential sources of inter-subject variability in monoclonal antibody pharmacokinetics. Clin Pharmacokinet. 2016;55:789–805. doi: 10.1007/s40262-015-0361-4.
    1. Struemper H, Chen C, Cai W. Population pharmacokinetics of belimumab following intravenous administration in patients with systemic lupus erythematosus. J Clin Pharmacol. 2013;53:711–720. doi: 10.1002/jcph.104.
    1. Keizer RJ, Huitema AD, Schellens JH, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:493–507. doi: 10.2165/11531280-000000000-00000.
    1. Navarra SV, Guzman RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377:721–731. doi: 10.1016/S0140-6736(10)61354-2.

Source: PubMed

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