Incorporating Target Shedding Into a Minimal PBPK-TMDD Model for Monoclonal Antibodies.

ABSTRACT: Shedding of a pharmacological target from cells, giving rise to a soluble target that can also bind therapeutic proteins, is a common phenomenon. In this study, a minimal physiologically based pharmacokinetic model was used to simulate the pharmacokinetics of trastuzumab and the simultaneous binding of the compound to soluble (in blood and tissue interstitial space) and membrane-bound (in the tissue interstitial space) forms of human epidermal growth factor receptor 2 (HER2). The parameter values describing binding of trastuzumab to HER2 were largely derived from in vitro data, and the effects of varying HER2 levels, the affinity difference between membrane-bound HER2 and shed antigen, and slow binding kinetics were investigated. The model simulates a sharp decrease in trough drug concentr

SUBMITTER: Li L 

PROVIDER: S-EPMC3910015 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature