Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Concepts and Lessons for Drug Development

• Published in: BioDrugs : clinical immunotherapeutics, biopharmaceuticals, and gene therapy Vol. 24; no. 1; pp. 23 - 39
• Main Authors: Mould, Diane R., Green, Bruce
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2010; Springer Nature B.V
• Subjects: Absorption; Animals; Antibodies; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - pharmacology; Biomedical and Life Sciences; Biomedicine; Cancer Research; Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Medicine; Pharmacotherapy; Receptors, Immunologic - chemistry; Receptors, Immunologic - drug effects; Review Article; Tissue Distribution; Daclizumab; Graft Versus Host Disease; Cetuximab; Progressive Multifocal Leukoencephalopathy; Trastuzumab
• ISSN: 1173-8804; 1179-190X
• DOI: 10.2165/11530560-000000000-00000

Monoclonal antibodies (mAbs) have complex pharmacology; pharmacokinetics and pharmacodynamics depend on mAb structure and target antigen. mAbs targeting soluble antigens often exhibit linear phar-macokinetic behavior, whereas mAbs targeting cell surface antigens frequently exhibit nonlinear behavior due to receptor-mediated clearance. Where nonlinear kinetics exist, clearance can change due to receptor loss following repeated dosing and/or disease severity. mAb pharmacodynamics are often indirect, with delayed clinically relevant outcomes. This behavior provides challenges during clinical development; studies must be carefully planned to account for complexities specific to each agent. Selection of a starting dose for human studies can be difficult. Species differences in pharmacology need to be considered. Various metrics are available for scaling from animals to humans. Optimal dose selection should ensure uniform mAb exposure across all individuals. Traditional approaches such as flat dosing and variable dosing based upon body surface area or weight should be supported by pharmacokinetic and pharmacodynamic behavior, including target antigen and concurrent disease states. The use of loading doses or dose adjustments to improve clinical response is also a consideration. The evaluation of drug interactions requires innovative designs. Due to the pharmacokinetic properties of mAbs, interacting drugs may need to be administered for protracted periods. Consequently, population pharmacokinetic and pharmacodynamic model-based approaches are often implemented to evaluate mAb drug interactions.