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AFIR: A dimensionless potency metric for characterizing the activity of monoclonal antibodies

Stein, Andrew and Ramakrishna, Ramprasad (2017) AFIR: A dimensionless potency metric for characterizing the activity of monoclonal antibodies. CPT: pharmacometrics & systems pharmacology.. ISSN 21638306


For monoclonal antibody (mAb) drugs with soluble targets (e.g. cytokines and growth factors), target may accumulate several thousand fold after binding to the drug. To understand this process and its potential impact on efficacy, time course data for both the mAb and the total target is often collected. The free target concentration, which is more directly related to the clinical effect, can be difficult to measure directly, and thus mathematical models of the drug and total target data are often used to predict the free target concentration over time. These models can then used to make predictions for how changes in the dosing regimen or binding affinity will affect target inhibition. In this article, a ``potency factor'' is introduced as an approximation for the model-predicted target inhibition. This potency factor is defined to be the the time-\uline{A}veraged \uline{F}ree target concentration to \uline{I}nitial target concentration \uline{R}atio (AFIR), and it is shown that AFIR depends on three key quantities: the average drug concentration at steady state, the binding affinity, and the degree of target accumulation. Applications of AFIR to three marketed mAbs with soluble targets (omalizumab, bevacizumab, and siltuximab) are presented. It is shown that AFIR provides intuition for how changes in dosing regimen and binding affinity affect target capture. AFIR can be used to guide drug development by providing predictions for both the druggability of new targets, and the dosing regimen needed for second generation mAbs to have comparable or superior efficacy to mAbs already on the market.

Item Type: Article
Keywords: pharmacokinetics and pharmacodynamics, pharmacometrics
Date Deposited: 12 Apr 2017 00:45
Last Modified: 12 Apr 2017 00:45


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