Translational Pharmacokinetic/Pharmacodynamic Modeling of Tumor Growth Inhibition Supports Dose-Range Selection of the Anti-PD-1 Antibody Pembrolizumab.

ABSTRACT: Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has a manageable safety profile and robust clinical activity against advanced malignancies. The lowest effective dose for evaluation in further dose-ranging studies was identified by developing a translational model from preclinical mouse experiments. A compartmental pharmacokinetic model was combined with a published physiologically based tissue compartment, linked to receptor occupancy as the driver of observed tumor growth inhibition. Human simulations were performed using clinical pharmacokinetic data, literature values, and in vitro parameters for drug distribution and binding. Biological and mathematical uncertainties were included in simulations to generate expectations for dose response. The results d

SUBMITTER: Lindauer A 

PROVIDER: S-EPMC5270293 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature