Preclinical and Translational Sciences
Manthena Varma, PhD
Research Fellow
Pfizer Inc
Groton, Connecticut
Fei Hua, PhD
VP of Modeling and Simulation Services
Applied BioMath
Concord
Endogenous biomarkers are increasingly applied and showing promise in enabling the drug development process on several fronts. As molecular indicators of drug effect on target to quantitate pharmacodynamics or off-target effects to understand adverse events, biomarkers have played a significant role in the discovery and development of many successful drugs. On the other hand, the ability to predict pharmacokinetic changes due to drug-drug interactions (DDIs) and disease state is essential to minimize unexpected clinical study readouts and manage the associated adverse risks in drug development. The last decade has witnessed considerable efforts towards the identification, characterization, and validation of endogenous biomarkers to monitor transporter activity in human. In this session, speaker will focus discussion on the strategies of leveraging transporter activity biomarkers along with the physiologically-based pharmacokinetic (PBPK) modeling to assess in vivo DDI risk in clinical development. Comprehensive studies illustrating the adequacy and utility of endogenous biomarker-informed PBPK modeling in mechanistic understanding and quantitative predictions of organic anion transporting polypeptide (OATP)1B1/1B3-mediated and renal OCT2/MATE DDIs will be discussed along with selective examples. Current understanding on the biomarkers for other hepatic and renal transporters and CYP-based metabolism will also be presented.