Prediction of Belimumab Pharmacokinetics in Chinese Pediatric Patients with Systemic Lupus Erythematosus

Xuan Zhou, Tsung-I Lee, Min Zhu, Peiming Ma, Xuan Zhou, Tsung-I Lee, Min Zhu, Peiming Ma

Abstract

Background and objective: Intravenous (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.

Methods: An 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.

Results: The 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.

Conclusions: In 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 numbers: NCT01649765, NCT00657007, NCT00071487, NCT01345253, NCT01516450, NCT00410384, NCT00424476, NCT02880852, NCT01583530.

Conflict of interest statement

XZ is an employee of GSK and holds stocks and shares in the company. T-IL and PM were employees of GSK and held stocks and shares in the company at the time of the study. MZ is an intern of GSK.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Pediatric prediction scheme from Chinese adult and non-Chinese adult and pediatric patients
Fig. 2
Fig. 2
Model predictions vs. observations in pediatric patients from PLUTO. Left: run607 (adult data only); right: run613 (final model); top: normal scale; bottom: log scale. PRED predicted
Fig. 3
Fig. 3
Goodness-of-fit plots for the final population pharmacokinetic model. Run613. Blue points are pediatric data; black points are adult data; black dashed lines are the identity or zero line; red lines are Loess fit
Fig. 4
Fig. 4
Visual predictive check of observed vs. simulated data stratified by adult (upper) and pediatric (lower) patients. Left: linear scale, right: log scale. Black dots are observations; lines are the 5%, 50%, and 95% quantiles of the observations; bands are 95% confidence intervals of the corresponding quantiles of the simulated model
Fig. 5
Fig. 5
Pharmacokinetic exposure comparison of (A) North East Asian vs. non-North East Asian populations, (B) Chinese vs. non-Chinese populations, (C) simulated pediatric patients (blue) vs. all adults (red), and (D) simulated pediatric patients (blue) vs. simulated North East Asian adults (red). Cavg_ss steady-state average concentration, NE North East Asian populations

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