In October 2017, the FDA published revised draft guidance on DDI studies, entitled In Vitro Metabolism and Transporter-Mediated Drug-Drug Interaction Studies. The guidance is the 4th Drug-Drug Interaction (DDI) Guidance document released by the agency and replaces the previous Guidances published in 1997, 2006, and 2012.
Dr. Ron Laethem, Lead In Vitro Services, at BioIVT said, “The new Guidance represents a paradigm shift because now the agency would like in vitro DDI studies to be conducted before first-in-human studies are initiated.” This change will require a new strategy in the design of in vitro studies. The FDA is advocating testing compounds at the highest possible concentrations. Previously, researchers may have used Cmax values from early clinical studies to design in vitro DDI studies; but Cmax values will not be available if DDI studies must be conducted prior to an IND filing.
At BioIVT we recommend the following strategies to ensure DDI studies will provide predictive data that will be acceptable to regulatory agencies:
- Use Physiologically-Relevant Models: For CYP Induction studies we recommend TRANSPORTER CERTIFIED™ hepatocytes in sandwich culture. We have demonstrated that this model can show better IVIVE correlations Vs. conventional, transporter-deficient models. Maintaining physiologically-relevant intracellular concentrations of drug candidates will be even more critical for preventing cytotoxicity at higher concentrations suggested by the FDA.
- Wholistic Approach to Preclinical Studies: Incorporate reaction phenotyping (CYP identification), and transporter identification and inhibition studies into the compound screening process.
- Consistent Approach: Conduct all DDI-relevant studies using the same lots of hepatocytes and with the same research lab so data can be compared and contrasted across the studies.
View a recording of our webinar on the new DDI Guidance. Drs. Andrew Parkinson, XPD Consulting, and Ron Laethem, Ph.D., BioIVT, Technical Lead, In Vitro Services, share their perspectives on the Guidance and how it will impact drug development strategies.