This year, a publication authored by Lois Haupt was cited in the FDA’s Final Guidance for Industry setting expectations for metabolism- and drug transporter-mediated drug interaction studies as part of a risk-based approach.
As part of our Meet the Scientist series, we introduce you to one of our most notable Enzyme Inhibition experts and explore how her team’s research impacts both regulatory expectations for drug developers and internal processes for helping clients produce sound, reliable data.
Lois Haupt has been a scientist with SEKISUI XenoTech since 2000. Prior to joining SEKISUI XenoTech, she obtained her B.S. in Chemistry from Creighton University in Omaha, Nebraska. Lois has extensive experience in in vitro CYP inhibition studies, regulatory compliance, and project management. As a Principal Scientist in Scientific Operations, she is responsible for the conduct and oversight of the nonclinical, drug interaction-related contract studies in the Program Oversight Department of SEKISUI XenoTech’s Scientific Division. Lois is also a featured internal expert on our Scientific Consulting team, providing insight and guidance for challenges relating to CYP and UGT inhibition.
You are one of our leading scientists in Enzyme Inhibition studies. Can you describe your experience in this area and how CYP inhibition data, coupled with the right interpretation, helps sponsors push their molecule through the pipeline?
CYP inhibition studies are much different now than when I first started at SEKISUI XenoTech 20 years ago. When I first started out in the lab, we only focused on direct inhibition of CYP enzymes, and study design was very basic.
Over the years, the science has evolved, and we’ve learned that predicting CYP inhibition is much more complicated. Time-dependent inhibition was a foreign concept at one point, but it’s not a standard part of study design. We’ve learned that we may need to tailor CYP inhibition studies for the compound being tested, whether it’s recommending a test system other than human liver microsomes (HLM) or suggesting a longer preincubation time.
We’ve also come to understand that CYP inhibition may not be the only type of enzyme inhibition of concern, so it may be important to test inhibition of other enzymes such as UGT or MAO. A complete understanding about what assays and designs are needed can remove regulatory hurdles later on during the submission process.
Your research was cited in the most recent FDA finalized guidance for industry on drug interactions. How did the conclusions in that paper affect regulatory expectations for drug developers?
For years, regulatory agencies emphasized the importance of Ki values in determining clinical relevance of in vitro inhibition studies.
However, for many years, it was understood that a conservative estimation ofKi value could be predicted as IC50/2. This paper provided data showing that this prediction was valid regardless of which type of direct inhibition was observed. This allowed for submission of IC50 data to regulatory agencies in lieu of determining a Ki value.
Your team has produced important data affecting the regulatory landscape, what other resources would you recommend for someone to learn something interesting about our internal research/drug metabolism?
I would definitely recommend our publication about system-dependent inhibition.
It’s probably the publication about CYP inhibition that I most frequently forward to our sponsors. Regulatory guidance does not specify a single test system for use in all CYP inhibition studies. Rather, it leaves discretion as to the choice of test system to the scientists conducting those studies. This paper helps show why defaulting to only one test system for CYP inhibition studies may not provide the most relevant data for in vivo predictions.
What’s something that the service clients working with you on contracted studies should expect?
We tend to ask a lot of questions up front during the design phase of studies. The reason we do this is so that we can better understand the compounds we are working with and so that we can recommend the best design for each molecule based upon the available guidance.
Our hope is that these questions early in the design phase help improve your successes with submissions to regulatory agencies.
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Access the Haupt 2015 paper
Find a full PDF download of the 2015 publication cited by the FDA in their January 2020 Final Guidance for Industry, “The reliability of estimating Ki values for direct, reversible inhibition of cytochrome P450 enzymes from corresponding IC50 values: A retrospective analysis of 343 experiments”