Search

Disease trajectories following antibody therapy can have a significant impact on the pharmacokinetics of the antibody. Although this phenomenon can often be explained by reduced target-expressing cells, other mechanisms may play a role. We use a novel minimal physiologically-based pharmacokinetic model to evaluate an alternative drug-disease interaction mechanism involving competitive inhibition of neonatal Fc receptor (FcRn)-mediated Immunoglobulin G recycling by paraproteins. The model is validated with clinical data from the anti-FcRn antibody M281 and is used to conduct a scenario test to quantify the interaction among M-protein, the characteristic paraprotein of multiple myeloma (MM), and the anti-CD38 antibody daratumumab indicated for MM treatment. Simulations predict up to a 3.6-fold increase in daratumumab half-life following M-protein reduction, which lends credence to the hypothesis that FcRn competition in MM can manifest as time-dependent reduction of clearance for daratumumab. This model can inform optimal dosing strategies for antibodies in MM and other pathologies of paraprotein excess., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)