Quantitative Pharmacology and Individualized Therapy Strategies in Development of Therapeutic Proteins for Immune-Mediated Inflammatory Diseases
by Honghui Zhou, Diane R. Mould
17Case Examples of Using Quantitative Pharmacology in Developing Therapeutic Proteins in Systemic Lupus Erythematosus – Belimumab
Herbert Struemper
Clinical Pharmacology Modeling & Simulation (CPMS), GSK, 5 Moore Drive, Research Triangle Park, NC, 27709, USA
17.1 Introduction
B‐lymphocyte stimulator (BLyS), also known as B‐cell activating factor, is a cytokine that promotes B‐cell selection, survival, maturation, and differentiation [1]. Elevated levels of BLyS have been observed in patients with systemic lupus erythematosus (SLE) [2] a systemic autoimmune disease that is characterized by autoantibody production, and in other autoimmune diseases. Belimumab is a recombinant, human IgG1λ monoclonal antibody (mAb) that targets and neutralizes soluble BLyS, and thereby inhibits B‐cell survival and differentiation without directly causing B‐cell death [ 1 ,3].
Pharmacometrics played a key role in the clinical development and subsequent approvals of the Benlysta intravenous (IV) and subcutaneous (SC) formulations in SLE. At the core of these modeling and simulation efforts were two population pharmacokinetic (popPK) analyses that combined serially sampled early phase studies with pivotal Phase 3 studies for the IV [4,5] and SC [6] formulations. These popPK analyses, an exposure–response analysis for the SC formulation [6] , and subsequent simulations supported protocol development, bridging from weight‐based IV dosing to fixed dose SC administration, pediatric development, a customized ...