S. W.S. Yapa, H. Struemper; GlaxoSmithKline, Research Triangle Park, NC
BACKGROUND: Belimumab is a recombinant, human immunoglobulin (Ig)-G1λ monoclonal antibody that targets B-lymphocyte stimulator (BLyS). Intravenous (IV) belimumab is indicated for the treatment of active, autoantibody-positive systemic lupus erythematosus (SLE). Subcutaneous (SC) administration of belimumab in SLE patients has shown biological activity and comparable safety profiles to IV administration. This posthoc analysis characterizes the population pharmacokinetics (PK) of SC belimumab in two different healthy populations.
METHODS: Data from two Phase I studies (BEL114448 - 118 US subjects, BEL116119 - 16 Japanese male subjects; IV and single/multiple SC doses) were analyzed with non-linear mixed effects modeling approach using NONMEM. A structural model was developed by exploring compartmental behavior, inter-individual and residual variability, and other model features.
RESULTS: The PK of belimumab was best described by a linear two-compartment model. The population estimates for CL and Vss were 208 mL/day and 5250 mL, respectively. An absorption lag time was included for SC administration in addition to a first order absorption. The bioavailability of belimumab was estimated to be 76%. Of the significant covariates from the IV population PK model only baseline body weight, BMI, albumin and IGG had 95% confidence interval not including zero. The terminal half-lives for IV and SC administration were 19.5 and 19.8 days, respectively.
CONCLUSION: The PK of SC belimumab in healthy subjects is consistent in terms of distribution and elimination with the IV PK in SLE patients. The bioavailability of 76% supports the choice of weekly 200 mg belimumab for the SC SLE program to achieve similar AUC-based exposure as for the monthly 10 mg/kg IV dose approved for SLE.