title: Physiologically-based modeling to predict the clinical behavior of monoclonal antibodies directed against lymphocyte antigens.
abstract: Many clinically approved and investigational monoclonal antibody (mAb)-based therapeutics are directed against proteins located in the systemic circulation, including cytokines, growth factors, lymphocyte proteins, and shed antigens. Interaction between mAb and target may lead to non-linear pharmacokinetics (PK), characterized by rapid, target-mediated elimination. Several groups have reported that determinants of target-mediated elimination could include mAb-target binding, target expression, and target turnover. Recently, we scaled a physiologically-based pharmacokinetic model for mAb disposition to man and used it to predict the non-linear PK of mAbs directed against tumor epithelial proteins. In this work, we extended the previously described model to account for the influence of lymphocyte proteins on mAb PK in man. To account for the dynamic behavior of lymphocytes in the circulation, lymphocyte cycling between blood and lymphoid organs was described using first-order transfer rate constants. Use of lymphocyte cycling and reported target turnover rates in the model allowed the accurate prediction of the pharmacokinetics and pharmacodynamics (PD) of 4 mAbs (TRX1, MTRX1011a, rituximab, daclizumab) directed against 3 lymphocyte targets (CD4, CD20, CD25). The results described here suggest that the proposed model structure may be useful in the a priori prediction of the PK/PD properties of mAbs directed against antigens in the circulation.
authors.affiliation: a Department of Pharmaceutical Sciences , School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York , Buffalo , NY , USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Glassman
authors.affiliation: a Department of Pharmaceutical Sciences , School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York , Buffalo , NY , USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Balthasar
mesh_terms: D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D018951:Antigens, CD20 / Q000187:drug effects; D015704:CD4 Antigens / Q000187:drug effects; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects*; D008954:Models, Biological; D000069283:Rituximab / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D015704:CD4 Antigens; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D000069283:Rituximab
keywords: Clinical pharmacokinetics; lymphocyte; monoclonal antibodies; physiologically-based pharmacokinetics; receptor occupancy