Review Article

BioDrugs

, Volume 24, Issue 1, pp 23-39

First online:

Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies

Concepts and Lessons for Drug Development
  • Diane R. MouldAffiliated withProjections Research Inc. Email author 
  • , Bruce GreenAffiliated withProjections Research Inc.Model Answers Pty Ltd

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Abstract

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.