Modelling of the Time-Varying Pharmacokinetics of Therapeutic Monoclonal Antibodies: A Literature Review.

Therapeutic monoclonal antibodies (mAbs) are increasingly used to treat a variety of conditions. The sources of their interindividual pharmacokinetic (PK) variability have been extensively studied, but few data on their intraindividual PK variability are available. In this article, we reviewed the published population compartmental models used to describe the time-varying PK of mAbs in clinical settings. Of 189 publications, 13 report the use of time-varying parameters and 30 describe the effects of antidrug antibody (ADA) development. Currently published time-varying models mainly describe fast decreases in clearance due to target-mediated elimination or slow decreases in clearance owing to cachexia reduction. Immunogenicity models mostly describe 'on-off' increases of clearance due to a rapid elimination of mAbs-ADA complexes. Some more sophisticated models attempted to decipher the time course of immunogenic response, notably by accounting for the time of onset and progressive increase in ADA production. Currently available time-varying and immunogenicity models are empirical approximations of the complex mAb disposition, but they emphasize the necessity to account for the temporal variations of mAb PK in model building. The clinical implications of the time-varying PK of mAbs are not fully understood, but some publications reported a link between clearance decrease and disease improvement. The future perspectives offered by this knowledge include the possibility to adapt the regimen to the disease and the patients' state, and also to immune status, and to monitor their evolution by monitoring PK variations.