Herbert Struemper (1), Richard Dimelow (2)
(1) Clinical Pharmacology Modeling & Simulation, GlaxoSmithKline, RTP, NC, USA; (2) Clinical Pharmacology Modeling & Simulation, GlaxoSmithKline, Stevenage, Hertfordshire, UK.
Introduction
Belimumab (BENLYSTA) is a human IgG1λ monoclonal antibody that neutralizes B-lymphocyte stimulator protein (BLyS; also known as B-cell activating factor, BAFF) and is currently approved for the treatment of active systemic lupus erythematosus (SLE) in adults. To address the needs of pediatric patients with childhood-onset SLE (cSLE), the Phase 2, multicenter, randomized, double-blind trial BEL114055 (NCT01649765) evaluated the efficacy, safety, and pharmacokinetics (PK) of intravenous (IV) belimumab vs placebo, plus standard therapy, in pediatric patients 5-17 years of age with cSLE.
Objectives
- To characterize the population PK (popPK) of belimumab following IV administration in pediatric patients with cSLE and evaluate the potential effect of selected covariates on PK parameters.
- To compare belimumab exposure in pediatric patients with cSLE to exposure in adult SLE Phase 3 patients with IV administration.
Methods
Patients with cSLE were randomized to the weight-normalized belimumab dose of 10 mg/kg approved for adults or placebo, administered on Days 0, 14 and 28, and every 28 days thereafter for 52 weeks. PK data were provided by the 53 patients on active treatment, of which 20 patients were included in PK lead-in cohorts with more intense PK sampling (median 16.5 samples). Ten of the 53 subjects were in the younger age group (5-11 years of age). PK data were analyzed with a non-linear mixed effects modeling approach using NONMEM. Model development was guided by the previously developed popPK model for IV belimumab in adults [1]. Results using a MAXEVAL=0 approach on the adult model were compared with a revised popPK model with covariate effects updated for pediatrics, re-estimating all model parameters, then reducing the models with a variation of the full model approach [2]. Individual post-hoc parameters were used to derive steady-state PK profiles and exposure parameters (e.g. Cavg, average serum concentration over dosing interval), which were compared to the corresponding adult Phase 3 results.
Results
The resulting popPK model described pediatric belimumab PK in the form of a linear 2-compartment model with clearance from the central compartment (CL). The population estimates for central clearance, steady-state volume of distribution and terminal half-life were 158 mL/day, 3.5 L, and 16.3 days, respectively, in the overall pediatric population.
Fat-free mass (FFM) [3] best described the effects of body size on the PK.; estimates for allometric exponents were 0.691 for central/intercompartmental clearance and 0.944 for central/peripheral volumes of distribution (V1/V2). Age did not have a statistically significant effect on clearance after accounting for body size effects. Additional covariate effects retained in the final model were baseline IgG, proteinuria, and estimated glomerular filtration rate on CL baseline white blood cell count on V1.
Belimumab Cavg exposures for the overall pediatric study and both pediatric age groups were similar to adult exposure at the 10 mg/kg dose level in Phase 3 trials; younger subjects had slightly lower exposures than the older subjects.
Conclusions
- The structure and parameters of the belimumab IV pediatric popPK model are consistent with those of the corresponding adult popPK model [1] after accounting for differences in body size and subject numbers.
- Enriched sampling in PK lead-in cohorts (n=20) together with sparse sampling in other subjects (n=33) supported estimation of popPK parameters with sufficient precision based on pediatric data only.
- The estimated allometric exponents on clearance and volume were consistent with values expected from allometric theory (0.75 and 1, respectively) when FFM was used, but lower when total body weight was used to characterize body size.
- Individual pediatric PK parameters predicted by the adult popPK model using the MAXEVAL=0 approach were appropriate, but the pediatric popPK model had superior simulation performance.
- Belimumab exposures were similar between pediatric and adults SLE subjects.
- These PK results support the approved adult IV dose of 10 mg/kg as an appropriate dose for pediatric patients with cSLE and that, other than weight-proportional dosing, no dose adjustments are required in the studied pediatric population.
References:
[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(7):711–20.
[2] Gastonguay M. Full covariate models as an alternative to methods relying on statistical significance for inferences about covariate effects: a review of methodology and 42 case studies. Population Approach Group in Europe (PAGE) 20 (2011) Abstr. 2229.
[3] Janmahasatian S, et al. Quantification of Lean Bodyweight. Clin Pharmacokinet 2005; 44 (10): 1051-1065.
Reference: PAGE 28 (2019) Abstr 8985 [www.page-meeting.org/?abstract=8985]
Poster: Drug/Disease Modelling - Infection