Premium
A Minimal Physiologically‐Based Pharmacokinetic Model Demonstrates Role of the Neonatal Fc Receptor (FcRn) Competition in Drug–Disease Interactions With Antibody Therapy
Author(s) -
Abdallah Hussein M.,
Zhu Andy Z.X.
Publication year - 2020
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1619
Subject(s) - daratumumab , paraproteins , neonatal fc receptor , antibody , pharmacokinetics , immunology , pharmacology , multiple myeloma , drug , dosing , medicine , bispecific antibody , monoclonal antibody , chemistry , immunoglobulin g , monoclonal
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‐ CD 38 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.