Belimumab Pharmacokinetic Simulations to Select an Appropriate Subcutaneous Dosing Regimen to Treat Paediatric Patients with Active Lupus Nephritis
Esmée Vendel (1), Martijn van Noort (1), Peter Vis (1), Lia Liefaard (2), Richard Dimelow (2)
(1) LAP&P Consultants BV, Leiden, The Netherlands; (2) GSK, Stevenage, United Kingdom
Introduction: The cytokine B-cell lymphocyte stimulating protein (BLyS) plays an important role in the production and differentiation of B cells and circulating levels of BLyS have been shown to be elevated in systemic lupus erythematosus (SLE), which is a chronic auto-immune disease with a complex pathophysiology1. Active lupus nephritis (LN) is a severe manifestation of the disease which affects the kidneys2. Belimumab (Benlysta) is a human immunoglobulin G (IgG) monoclonal antibody that binds to and inhibits BLyS and has been approved as an intravenous (IV) and subcutaneous (SC) formulation in adults with SLE3,4 and active LN5; approval of the SC dose in adults with active LN was based on PK bridging simulations6. In the paediatric population IV belimumab has been approved for SLE based on a pharmacokinetic (PK) and efficacy study7, and for active LN based on bridging PK simulations8, both with the same dosing regimen as in adults. Belimumab SC has recently been studied in paediatric patients with SLE9 and the current work presents PK bridging simulations to identify an appropriate belimumab SC treatment regimen for paediatric patients with active LN.
Objectives:
- To construct a fit-for-purpose population PK model for paediatric LN patients receiving belimumab SC, based on available models in adult patients with SLE and LN and in paediatric SLE patients.
- To perform simulations to derive an appropriate SC dosing regimen and assess SC loading doses in paediatric LN patients to match adult exposures for which efficacy has been established.
- To explore body weight-belimumab exposure relationships to justify the SC dosing regimens.
Methods: A fit-for-purpose model was constructed to simulate belimumab concentrations following SC dosing in paediatric LN patients 5-17 years and ≥15 kg. The model was an extrapolation from an earlier model developed on adult LN IV data5, replacing baseline fat-free mass (FFMBL) with baseline weight (BWT) scaling and including SC absorption parameters estimated from paediatric SLE IV+SC data9. A clinical study in paediatric patients with active LN has not been carried out and so the PK model selected for this population was part-validated by comparing against the population PK model previously developed for paediatric patients with SLE.
PK simulations were performed to select an appropriate dosing regimen, including a 4-week loading period, which ensured that exposures were consistent across the paediatric weight range with early exposures as much within the adult LN IV target range (41-161 μg/mL)8 as possible.
Results: The final population PK model was used to perform simulations to select the appropriate SC dosing regimen, including loading dose, in paediatric LN patients. The following 2-weight band regimen was proposed as a good balance between exposure and simplicity of the regimen, after consideration of several alternatives:
- ≥15-<40 kg: 200 mg SC weekly (QW) for the first 4 doses, followed by 200 mg SC every two weeks thereafter.
- ≥40 kg: 400 mg SC QW for the first 4 doses, followed by 200 mg SC QW thereafter.
An alternative 3-weight band regimen was also considered. The 2-weight band regimen, in addition to being convenient for patients and caregivers, resulted in a belimumab exposure that was consistent across the paediatric weight range and that was approximately in the same range as in the adult LN population, receiving the approved IV dosing. Moreover, the inclusion of loading doses during the first weeks of administration was shown to be beneficial as this ensured early transition into steady state.
Conclusions: Simulations based on an extrapolated, fit-for-purpose, population PK model enabled the selection of an appropriate dosing regimen for belimumab SC administration in paediatric LN patients.
Funding: GSK; Study 217481.
References:
[1] Tsokos G. Systemic lupus erythematosus. N Engl J Med 2011; 365:2110-7
[2] Hoover P and Costenbader K. Insights into the epidemiology and management of lupus nephritis from the US rheumatologist’s perspective. Kidney Int 2016; 90:487-92
[3] Struemper H, Chen C, and Cai W. Population pharmacokinetics of belimumab following intravenous administration in patients with systemic lupus erythematosus. The J Clin Pharmacol 2013; 53:711-20
[4] Struemper H, Thapar M, and Roth D. Population Pharmacokinetic and Pharmacodynamic Analysis of Belimumab Administered Subcutaneously in Healthy Volunteers and Patients with Systemic Lupus Erythematosus. Clin Pharmacokinet 2018; 57:717-28
[5] Dimelow R. GSK Document 2020N433185_00. Population Pharmacokinetic Analysis of study BEL114054, a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Belimumab plus Standard of Care versus Placebo plus Standard of Care in Adult Subjects with Active Lupus Nephritis. Clinical Pharmacology Modelling Report. 114054
[6] Dimelow R. GSK Document 2020N437442_00. Pharmacokinetic simulations of belimumab in a lupus nephritis population: effect of baseline proteinuria and loading dose regimen. Clinical Pharmacology Modelling Report. 114054
[7] Dimelow R, Ji B, and Struemper H. Pharmacokinetics of belimumab in children with systemic lupus erythematosus. Clin Pharmacol in Drug Develop 2021; 10:622-33
[8] Dimelow R. GSK Document RPS-CLIN-061677. A study to extrapolate the pharmacokinetics of Benlysta to children with lupus nephritis - Amendment 1. Clinical Pharmacology Modelling Report. 217143
[9] Dimelow R. A Population Pharmacokinetic Analysis of Subcutaneous Administered Belimumab Plus Standard Therapy to Paediatric Patients Aged 5-17 Years with Systemic Lupus Erythematosus. Statistical Analysis Report. May 2023
