Physiologically based pharmacokinetic model for T84.66: A monoclonal anti-CEA antibody

• Published in: Journal of pharmaceutical sciences Vol. 99; no. 3; pp. 1582 - 1600
• Main Authors: Urva, Shweta R., Yang, Victor C., Balthasar, Joseph P.
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.03.2010; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: Animals; Antibodies, Monoclonal - pharmacokinetics; Biological and medical sciences; carcinoembryonic antigen (CEA); Carcinoembryonic Antigen - immunology; Cell Line, Tumor; General pharmacology; Histocompatibility Antigens Class I - metabolism; Male; mathematical model; Medical sciences; Mice; Mice, Nude; Models, Statistical; Neoplasms - metabolism; PBPK; Pharmaceutical technology. Pharmaceutical industry; pharmacokinetics; Pharmacology. Drug treatments; physiological model; preclinical pharmacokinetics; Receptors, Fc - metabolism; T84.66 anti-CEA antibody; target mediated disposition; Transplantation, Heterologous; tumor associated antigen; target mediated disposition; tumor associated antigen; pharmacokinetics; PBPK; T84.66 anti-CEA antibody; mathematical model; physiological model; carcinoembryonic antigen (CEA); preclinical pharmacokinetics; Pharmaceutical technology; Tumor associated antigen; Targeting; Preclinical trial; Monoclonal antibody; Carcinoembryonic antigen; Target; Physiologically based pharmacokinetic model; Mathematical model; Pharmacokinetics
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1002/jps.21918

Antibodies directed against tumor associated antigens are being increasingly used for detection and treatment of cancers; however, there is an incomplete understanding of the physiological determinants of antibody pharmacokinetics and tumor distribution. The purpose of this study is to (a) compare the plasma pharmacokinetics of T84.66, a monoclonal anti-CEA antibody directed against tumor associated carcinoembryonic antigen (CEA), in control and CEA expressing LS174T xenograft bearing mice, and (b) to develop a physiologically based pharmacokinetic (PBPK) model capable of integrating the influence of CEA and the IgG salvage receptor, FcRn, on T84.66 disposition. T84.66 pharmacokinetics were studied following i.v. administration (1, 10, 25 mg/kg) in control and xenograft bearing mice. In control mice, no significant differences in clearance were observed across the dose range studied. In mice bearing xenograft tumors, clearance was increased by four- to sevenfold, suggesting the presence of a “target mediated” elimination pathway. T84.66 plasma disposition was characterized with a PBPK model, and the model was applied to successfully predict antibody concentrations in tumor tissue. The PBPK model will be used to assist in the development of antibody-based targeting strategies for CEA-positive tumors. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1582–1600, 2010