Xuan Zhou, Tsung-I Lee, Peiming Ma
Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Shanghai, China
Introduction: Belimumab is a human IgG1λ monoclonal antibody that binds to and antagonises the biological activity of soluble B-cell activating factor. Intravenous (IV) belimumab is approved in patients ≥5 years of age with autoantibody-positive systemic lupus erythematosus (SLE); the approved dosing regimen is 10 mg/kg IV infusion at 2-week intervals for the first 3 doses and at 4-week intervals thereafter (Q4W). Recently, a multicentre, Phase 2 efficacy and safety study (GSK Study BEL114055; NCT01649765; PLUTO) was conducted in North, Central and South America, Europe and Japan to support the extension of the original adult indication to children (5–17 years of age) with SLE. For paediatric patients in China, we proposed a similar indication extension based on extrapolation. Key questions in paediatric extrapolation included: for the same belimumab dosing regimen, how do the exposures compare between Chinese paediatric and adult patients, and between Chinese and non-Chinese paediatric patients. To answer these questions, a population pharmacokinetic (PK) analysis integrating all relevant PK data was performed to compare the predicted/simulated exposure distributions among these populations.
Objectives: (1) To develop a population PK model from data sets from key belimumab studies to extrapolate dose–exposure relationship to Chinese paediatric patients with SLE. (2) To predict and compare PK parameters and exposure in Chinese paediatric patients with SLE with 1) non-Chinese paediatric patients with SLE, and 2) Chinese adult patients with SLE.
Methods: The initial model was built using data from adult patients only (GSK Studies 200909, LBSL01, LBSL02, 110751, 110752, 114448, 113750, 116119) . Covariates of body weight, body mass index, fat-free mass (FFM), race, baseline albumin and IgG levels were evaluated for their influence on the main PK parameters [2, 3]. Model selection was based on evaluation of minimum objective function values, goodness-of-fit, and precision of parameter estimates. The model built with only adult data was used to predict paediatric PK data from the PLUTO study. The predicted data were then compared with observed data and the model was updated with paediatric PK data from PLUTO. This final model was used to predict steady-state belimumab exposure in Chinese paediatric patients with SLE under the dosing regimen of 10 mg/kg Q4W. The predicted exposures were compared with those of non-Chinese paediatric and Chinese adult patients with SLE. The population PK analyses were performed using nonlinear mixed-effect modelling with NONMEM software version 7.3. The NONMEM estimation used ADVAN3 TRANS4 subroutine and the first-order conditional estimation method with interaction term. R version 3.6.0 was used for generating model diagnostic plots.
Results: The PK of belimumab in adult and paediatric patients was adequately described by a linear two-compartment model. The estimated typical clearance of 238 ml/day and the steady-state volume of distribution of 4915 ml. Between-patient variability was modest with coefficients of variation: 26.1% for clearance, 8.9% for central volume of distribution and 27.9% for peripheral volume of distribution. Six covariates that influence PK were identified: age, FFM, Northeast Asian race, baseline albumin and IgG, and an early study indicator. Predicted distribution of steady-state average concentration (Cavg_ss) for paediatric patients following belimumab 10 mg/kg IV administration is similar to the distribution of adult Cavg_ss, both in the overall population and in the Northeast Asian (including Chinese) population.
Conclusions: The modelling analysis revealed no substantial differences in steady-state belimumab exposure between Chinese and non-Chinese patients or between Northeast Asian and other patients under the belimumab 10 mg/kg IV Q4W dosing regimen. Furthermore, steady-state belimumab exposure in paediatric patients was similar to that of the adult population (including Northeast Asian race) receiving belimumab 10 mg/kg IV Q4W dosing regimen, which suggests no great difference in exposure between paediatric and Chinese adult populations. The proposed belimumab 10 mg/kg IV Q4W dosing regimen for Chinese paediatric patients with SLE appears to have a similar dose–exposure relationship to that of Chinese adult and non-Chinese paediatric patients.
Study funding: GSK. Editorial support (GSK-funded): Olga Conn, PhD, Fishawack Indicia Ltd, UK.
References:
[1] Chaudhury C et al. J Exp Med 2003;197(3):315–22.
[2] Janmahasatian S et al. Clin Pharmacokinet 2005;44(10):1051–65.
Reference: PAGE () Abstr 9362 [www.page-meeting.org/?abstract=9362]
Poster: Drug/Disease Modelling - Paediatrics