Here we aim to integrate PK into a generative drug design framework while considering the PD of the novel generated drugs. We simultaneously optimize target affinity and PK of small molecules in an AI-based de novo drug design framework. Subsequently, we explore the effect of the balanced optimization on predicted compound PD using simulations of a QSP model in a case study focused on the adenosine A 2A receptor (A 2A R), a drug target in immuno-oncology. More specifically we will focus on optimizing Clearance (CL), Volume of Distribution at steady state (VDSS) and the Fraction Unbound (FU), three fundamental PK properties.