Dataset Information

Belimumab and Rituximab in Systemic Lupus Erythematosus: A Tale of Two B Cell-Targeting Agents.

ABSTRACT: Given the centrality of B cells to systemic lupus erythematosus (SLE), it stands to reason that a candidate therapeutic agent that targets B cells could be efficacious. Both rituximab, a monoclonal antibody (mAb) that binds to CD20 on the surface of B cells, and belimumab, a mAb that binds and neutralizes the B cell survival factor BAFF, have been extensively studied for the treatment of SLE. Despite the greater ability of rituximab to deplete B cells than that of belimumab, randomized controlled trials of rituximab in SLE failed to reach their primary clinical endpoints, whereas the primary clinical endpoints were reached in four independent phase-III clinical trials of belimumab in SLE. Accordingly, belimumab has been approved for treatment of SLE, whereas use of rituximab in SLE remains off-label. Nevertheless, several case series of rituximab have pointed to some utility for rituximab in treating SLE. In this review, we provide a concise summary of the factors that led to belimumab's success in SLE as well an analysis of the elements that may have contributed to the lack of success seen in the rituximab randomized controlled trials in SLE.

SUBMITTER: Wise LM

PROVIDER: S-EPMC7338653 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Belimumab and Rituximab in Systemic Lupus Erythematosus: A Tale of Two B Cell-Targeting Agents.

Wise Leanna M LM Stohl William W

Frontiers in medicine 20200630

Given the centrality of B cells to systemic lupus erythematosus (SLE), it stands to reason that a candidate therapeutic agent that targets B cells could be efficacious. Both rituximab, a monoclonal antibody (mAb) that binds to CD20 on the surface of B cells, and belimumab, a mAb that binds and neutralizes the B cell survival factor BAFF, have been extensively studied for the treatment of SLE. Despite the greater ability of rituximab to deplete B cells than that of belimumab, randomized controlle ...[more]

PMID: 32695790

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Project description:Background and objectiveIntravenous (IV) belimumab is the first treatment approved for children ≥5 years of age with active autoantibody-positive systemic lupus erythematosus (SLE) in the USA, Europe, and Japan. Pharmacokinetic data for belimumab were collected from several clinical trials in Chinese and non-Chinese adults and non-Chinese pediatric patients with SLE. This study aimed to predict the belimumab dose-exposure relationship to Chinese pediatric patients with SLE, as part of the belimumab registration process for this population in China, using a population PK modeling approach.MethodsAn initial linear two-compartment population pharmacokinetic model was built using data from adults only, and considering and adjusting for the covariates age, body weight, body mass index, fat-free mass, race, baseline albumin and immunoglobulin G levels. The model was used to study possible ethnic differences between Chinese and non-Chinese adults and to predict pediatric pharmacokinetic data in a study of non-Chinese pediatric patients (PLUTO study; NCT01649765). The predicted data were compared with the observed data from PLUTO. The model was then updated with pediatric data from PLUTO to predict steady-state belimumab exposure in Chinese pediatric patients with SLE receiving belimumab 10 mg/kg IV every 4 weeks.ResultsThe dataset comprised 9650 sampled concentration values from 1783 patients. The pharmacokinetics of belimumab were adequately described by the final model using all adult and pediatric data with the estimated typical clearance of 238 ml/day in adult and pediatric patients and steady-state volume of distribution of 4915 ml in adults. Between-patient variability was modest (coefficients of variation: 26.1% for clearance; 8.9% and 28.5%, respectively, for volumes of distribution of the central and peripheral compartments). Six covariates were identified that influenced pharmacokinetics: age, fat-free mass, an indicator of North East Asian race, baseline albumin, immunoglobulin G, and an early study indicator (two early phase I and phase II belimumab studies: LBSL01 and LBSL02). The analysis showed no apparent difference in steady-state exposure between Chinese and non-Chinese populations and between pediatric and adult populations receiving belimumab 10 mg/kg IV.ConclusionsIn Chinese pediatric patients with SLE, belimumab 10 mg/kg IV every 4 weeks is expected to have exposure similar to that in Chinese adults and non-Chinese pediatric patients with SLE, supporting the use of this regimen in Chinese pediatric patients with SLE.Clinical trial registration numbersNCT01649765, NCT00657007, NCT00071487, NCT01345253, NCT01516450, NCT00410384, NCT00424476, NCT02880852, NCT01583530.

Dataset Information

Belimumab and Rituximab in Systemic Lupus Erythematosus: A Tale of Two B Cell-Targeting Agents.

Publications

Belimumab and Rituximab in Systemic Lupus Erythematosus: A Tale of Two B Cell-Targeting Agents.

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