PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
PAGE 22 (2013) Abstr 2792 [www.page-meeting.org/?abstract=2792]
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Poster: Covariate/Variability Model Building
Herbert Struemper (1), Wendy Cai (2)
(1) Clinical Pharmacology Modeling & Simulation, GlaxoSmithKline, RTP, NC, USA; (2) Human Genome Sciences, Inc., Rockville, MD, USA
Objectives: Belimumab is a recombinant, human immunoglobulin (Ig)-G1λ monoclonal antibody (mAb) that targets B-lymphocyte stimulator (BLyS), a cytokine that promotes B-cell selection, survival, and differentiation. Belimumab currently is indicated for the treatment of adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) who are receiving standard therapy. The objective of this analysis was to characterize the population pharmacokinetics of belimumab following intravenous infusion in patients with SLE.
Methods: Data from 1 Phase I, 1 Phase II and 2 Phase III studies (1603 subjects total, doses ranging from 1-20 mg/kg) were analyzed with a non-linear mixed effects modeling approach using NONMEM. A structural model was developed by exploring compartmental behavior, interindividual and residual variability, and other model features. Available covariates included standard demographics and laboratory values, markers of SLE disease activity, and a wide range of SLE-specific and more general classes of comedications. For stepwise covariate model building a 0.001 α-level was chosen as the significance threshold for forward addition and backward elimination.
Results: The final population PK model described belimumab PK in the form of a linear 2-compartment model with clearance from the central compartment (CL). The population estimates were 0.22 L/day for CL and 5.3 L for Vss with a corresponding terminal half life of 19 days. The model included a total of 16 covariate effects of which 9 were related to patient characteristics. The effect of proteinuria on CL was best represented by a linear relationship with a slope of 18.7 mL/g.
Conclusion: The PK parameters were consistent with results for other IgG1 mAbs without marked target-mediated disposition. The large number of SLE subjects allowed to characterize covariate effects typically not identified in mAb PK analyses. Interestingly, proteinuria and estimated creatine clearance were identified as effects on CL, although renal clearance of mAb is typically deemed negligible. Based on the slope of the proteinuria effect a marked decrease in exposure would be predicted in populations with higher proteinuria levels. Other covariates supported by physiological mechanisms incuded effects of IgG on CL and haemoglobin on central volume. However, none of the covariate effects on belimumab PK were found to alter exposure in a manner requiring dose adjustment in the SLE population.