Figure 5.

Model-predicted exposure–response relationship between belinostat plasma concentrations and fold change in global protein lysine acetylation. Global protein lysine acetylation (AcK) was assessed predose and 12, 36, and 60 hours postdose, and fold changes in AcK at 12, 36, and 60 hours were incorporated into the final PPK model using an indirect response model (model II). The PK parameters were fixed during PK/PD model development and validation because of the complexity of the model. Model-predicted AcK fold changes paralleled that of predicted belinostat plasma concentrations. The reversible inhibition of histone deacetylase enzymes by belinostat is evident in the rapid decrease in fold change pf AcK upon the end of belinostat infusion.