S12 Endogenous Probes for Transporter-mediated Drug-Drug Interaction

Yurong Lai , Gilead Sciences, Inc., Foster City, CA
Drug transporters play a pivotal role in drug absorption, disposition and elimination. Inhibition of drug transporter activities can cause clinical significant DDIs, which have become the most concerns during the drug development. Per the current regulatory decision trees, transporter interactions with a new chemical entity are assessed in vitro and the potential for transporter DDIs in the clinic is to conduct a drug-interaction study using probe substrates for each transporter. However, the potential for a high-rate of false-positive predictions has been a particular concern in the pharmaceutical industry. From the industry perspective, the potential PK interactions should be addressed as early in drug development as possible, allowing important plans and decisions to be made about compound selection for clinical development prior to significant investment of late-phase clinical trials. Therefore, seeking for specific and reliable endogenous biomarkers to assess transporter DDI has become special emphasis areas in both academic and industry. The development of a sensitive, specific endogenous biomarker to monitor transporter activity and assess DDI liability as early as in human phase I clinical trials through monitoring endogenous biomarkers in conjunction with new chemical entity pharmacokinetics analysis would be very beneficial to early drug development efforts. The presentation aims to give an overview of the role of endogenous biomarker involving transporter inhibitions using OATP1Bs as an example, to summarize the recent advance in characterizing CP-I and III as specific and reliable biomarkers to assess OATP activity during FIH for potential DDIs. Moreover, the challenges and opportunities in using endogenous biomarkers for DDI assessment are also discussed.