The Pharmaceutical and BioScience Society (PBSS) hosted the workshop “Drug-Drug Interactions: Update on Risk Assessment, Clinical Evaluation and Regulatory Requirements” on October 16 at the Crowne Plaza Hotel in Foster City, CA.
The workshop was well attended and provided a great update on DDI potential. There were eight presentations, which were primarily focused on interpretation and application of the drug-drug interaction (DDI) guidance documents issued by the FDA in 2017, the EMA in 2013 and PMDA in 2017. Although SEKISUI XenoTech was unable to present because of prior presentation commitments, we sent company representatives and provided financial assistance for the event.
The initial topic focused on the conduct of in vitro drug-drug interaction assays and how to use the data to predict a possible clinical DDI. The presentation featured time-dependent inhibition of CYP enzymes, including mechanism-based CYP inactivation, and CYP enzyme induction in plated human hepatocytes, referencing the white paper issued by the Innovation and Quality Induction Working Group, and reaction phenotyping to determine victim potential. The presentation also discussed the application of calculations to determine the extent of a possible clinical DDI and referenced a paper published by SEKISUI XenoTech on calculating a Ki value from the experimentally determined IC50 value for CYP inhibition, thereby eliminating the need to experimentally determine a Ki value.
The second presentation topic covered possible interactions between therapeutic proteins and small molecules. Therapeutic proteins have the potential to change the level of cytokines, such as interleukin 6. Cytokines in turn can affect the expression of CYP enzymes. Several clinical examples were discussed, including the potential to de-suppress CYP enzymes thereby increasing CYP capacity clinically. The 2017 guidance on DDI from the FDA did not include interactions between therapeutic proteins and small molecules, but the FDA is seeking input to update or create a new guidance. Several in vitro methods to investigate the interaction between therapeutic proteins and small molecules were discussed, including SEKISUI XenoTech’s patented approach. In that method, whole blood is treated with the therapeutic protein and then plated hepatocytes are treated with the plasma containing cytokines and the effect on CYP enzymes.
The third presentation delved into Physiologically Based Pharmacokinetic (PBPK) modeling to determine DDI risk. Guidelines were issued by the EMA in 2016 and by the FDA in August, 2018. Eight case examples were discussed. It was noted that the regulatory agencies currently suggest at least one clinical DDI and predict other scenarios with PBPK.
The fourth presentation discussed clinical DDI studies, including timing, design and incorporation of results into the drug label. The fifth presentation reviewed pharmacokinetic-based DDI in drugs approved in 2017. For approved drugs, the number of DDI studies both in vitro and in the clinic referenced in the label has increased in recent years. The largest increase has been in the transporter field. It was noted that CYP3A is the predominant enzyme responsible for clinically significant DDIs, and also that OATP1B1 and OATP1B3 are being recognized for having a large role in changes in exposure of victim drugs.
A member of the FDA then presented on the updates in the 2017 guidance on DDI from the FDA as compared to the 2012 guidance. SEKISUI XenoTech has presented two webinars and issued a poster on this topic, which can be requested through our website.
The last two presentations focused on transporter-mediated DDI. In the 7th presentation, changes to the FDA guidance from 2012 to 2017 were discussed, including the list of included transporters, preliminary assays to determine solubility, toxicity and non-specific binding as well as the calculations to determine the clinical significance and several case examples. SEKISUI XenoTech also presented a webinar on this topic that has been posted on our website.
The final presentation discussed the use of endogenous probes to asses transporter-mediated DDI. The suggested strategy was to first assess the potential for a DDI in vitro, and if a potential DDI is implicated, measure the effect on endogenous substrates in the clinic (e.g., phase I) before conducting clinical DDI studies.
This workshop was an outstanding addition to PBSS’s ongoing lineup of seminars, symposiums and other workshops. We would like to thank PBSS for sponsoring the event, the organizers (Simon Wong, Snow Ge and Joseph Polli) and speakers for the informative presentations, as well as the attendees for their participation. If you have any questions on the in vitro topics discussed during this workshop, please contact your local SEKISUI XenoTech representative.
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