A Three-dimensional and Dynamic (3DD) Cell Culture System for Evaluation of Pharmacokinetics, Safety and Efficacy of Anti-cancer Drugs

Abstract

Purpose of ReviewIn this work, we will describe a scalable and versatile three-dimensional and dynamic (3DD) cell culture system used in our laboratory as an in vitro tool for pharmacokinetic (PK), pharmacodynamic (PD), and toxicodynamic (TD) evaluation of anti-cancer agents in mono and combination therapy.Recent FindingsCertain attributes of the 3DD cell culture system such as its ability to sustain high-density cell growth, simulation of clinically relevant PK profiles, and sampling of PK, PD, and TD endpoints make it suitable for long-term in vitro studies. Here, we highlight two case examples from our laboratory using this system. First, we have successfully evaluated the PK and PD of a novel combination regimen against human epidermal growth factor receptor type 2 (HER2)–positive breast cancer refractory to HER2 therapy. The resulting PK/PD relationships allowed optimization of drug dosing of the agents in the combination. Second, our laboratory is currently examining the clinical PK determinants controlling doxorubicin (DOX)–induced cardiotoxicity, linking them with TD endpoints and evaluating optimal dosing regimens of DOX for alleviating cardiotoxicity.SummaryOur promising state-of-the-art in vitro 3DD cell culture system holds several advantages over traditional tissue culture systems. The in vitro simulation of human PK profiles in combination with serial sampling over several weeks allows to more accurately study and predict tumor killing, resistance, and toxicities of anti-cancer agents and combinations for future rationally designed studies in patients.