Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM‐406/AT‐406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer

Abstract

The inhibitors of apoptosis proteins (IAPs) are a class of key apoptosis regulators overexpressed or dysregulated in cancer. SM‐406/AT‐406 is a potent and selective small molecule mimetic of Smac that antagonizes the inhibitor of apoptosis proteins (IAPs). A physiologically based pharmacokinetic and pharmacodynamic (PBPK‐PD) model was developed to predict the tissue concentration–time profiles of SM‐406, the related onco‐protein levels in tumor, and the tumor growth inhibition in a mouse model bearing human breast cancer xenograft. In the whole body physiologically based pharmacokinetic (PBPK) model for pharmacokinetics characterization, a well stirred (perfusion rate‐limited) model was used to describe SM‐406 pharmacokinetics in the lung, heart, kidney, intestine, liver and spleen, and a diffusion rate‐limited (permeability limited) model was used for tumor. Pharmacodynamic (PD) models were developed to correlate the SM‐406 concentration in tumor to the cIAP1 degradation, pro‐caspase 8 decrease, CL‐PARP accumulation and tumor growth inhibition. The PBPK‐PD model well described the experimental pharmacokinetic data, the pharmacodynamic biomarker responses and tumor growth. This model may be helpful to predict tumor and plasma SM‐406 concentrations in the clinic. Copyright © 2013 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100147/1/bdd1850.pd