Mechanistic modeling of time-dependent antibody clearance in multiple myeloma: A physiologically based pharmacokinetic model of isatuximab.

Therapeutic antibodies for treatment of multiple myeloma show considerable declines in clearance over time as the disease status evolves. Myeloma cells secrete an antibody-like protein called M-protein that binds to the neonatal Fc receptor (FcRn), competing with its ability to preserve antibodies from degradation. Successful response to therapy reduces M-protein and causes a subsequent time-varying decrease in clearance for antibody drugs. Physiologically based pharmacokinetic (PBPK) models mechanistically describe antibody catabolism and FcRn recycling but have not been previously employed to characterize time-varying clearance due to changing M-protein levels. In this work, a PBPK model of antibody clearance was fitted to longitudinal M-protein and drug concentration data from multiple myeloma patients treated with isatuximab. Parameters were fitted with high certainty and the predictions closely matched clinical data. Furthermore, the simulated change in clearance over time predicted by the PBPK model closely agreed with previously published empirical popPK analyses fitted to the clinical PK of isatuximab. The final model was utilized to simulate the time course of M-protein and drug exposure as a function of response, indicating an over three-fold difference in clearance between patients with no decrease in M-protein versus those with a complete therapeutic response.