Mechanism‐Based Modeling Approaches to Quantify the Effect of Immunogenicity on the Pharmacokinetics of Therapeutic Proteins in Drug Development

ABSTRACT Therapeutic protein administration in both preclinical and clinical studies can result in the formation of anti‐drug antibodies against the therapeutic protein. Anti‐drug antibody formation may alter the pharmacokinetics of the therapeutic protein, reduce its plasma concentrations, increase exposure variability, and may lead to a loss of efficacy and adverse events. In an effort to quantitatively understand the effect of anti‐drug antibodies on the concentration‐time profile of a therapeutic protein, as well as develop effective strategies to mitigate its impact in the preclinical and clinical development of therapeutic proteins, mathematical models have been developed to characterize the therapeutic protein pharmacokinetics and its modulation by anti‐drug antibodies in vivo. Here, we review several different mechanism‐based modeling frameworks, summarize their approaches to predict immunogenicity effects, and explore the merits and limitations of each model.