117: Analyzing Drug-Drug Interaction Risk Assessment Strategies for Protein Therapeutics in Inflammatory Bowel Disease: A Literature-Based Evidence Review

Statement of Purpose, Innovation or Hypothesis: Drug-drug interactions (DDIs) may impact efficacy and/or safety of medications. Cytochrome P450 (CYP) enzymes are primary metabolizers of most drugs on the market, and expression of CYPs may be affected by changes in cytokine concentrations.1–3 Therapeutic proteins (TPs) are mainstay therapies in the treatment of inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn’s disease (CD).4–6 Administration of TPs in UC and CD patients are anticipated to decrease cytokine concentrations which may normalize CYP expression and lead to changes in exposure of drugs that are metabolized by CYPs. It is not clear how well in vitro assessments translate to in vivo DDI risk, nor is it understood to what degree drug clearance through CYPs may change after introduction of cytokine modulators. Although the U.S. Food and Drug Administration (FDA) provides a guidance for industry on TP DDIs,7 there is no consensus among sponsors on risk assessment of TP DDI potential. Therefore, this work aims to identify the literature-based evidence of potential in vivo DDIs in IBD patients that may be due to disease symptoms and physiological changes and how this can inform on DDI risk assessment for TP drugs in the future.

Description of Methods & Materials: An extensive literature search was conducted to identify studies that addressed the following research objectives: determine what evidence exists regarding the potential of in vivo DDIs in UC and CD, how sponsors conducted DDI risk assessments for pro-inflammatory modulator TPs, and to investigate potential mechanisms that explain exposure differences in observed in vivo DDIs in UC and CD patients due to physiological changes caused by disease. Key words used to identify studies included “drug-drug interaction study”, “inflammatory bowel disease”, “Crohn’s disease”, and “ulcerative colitis”. Studies were included in the analysis if they administered a small-molecule drug in IBD patients to identify exposure changes. Additional review of the FDA-approved labeling of existing immunotherapy was conducted to determine if DDI warnings were included.

Data & Results: Multiple examples were identified that addressed the above objectives. One sponsor took a biomarker approach to demonstrate a lack of change in CYP3A expression before and after introduction of vedolizumab, which resulted in no FDA-approved labeling implicating the DDI potential of vedolizumab on CYP3A substrates. Additional studies compared sensitive CYP3A substrates, including midazolam and alfentanil, in CD patients, which is a more severe inflammatory state than UC, versus healthy volunteers. Mixed results were reported in substrate exposure changes which suggests that the mechanism of change in drug exposure is more complex than differences in CYP3A expression alone.

Interpretation, Conclusion or Significance: This analysis demonstrates the need for more work to understand DDIs following cytokine-modulating TP administration given that UC and CD are two complex disease states with pathological changes that potentially could alter drug pharmacokinetics. More research should be conducted to understand the mechanisms that contribute to DDIs to work toward a consensus on the risk assessment strategy to systematically assess compounds in development for DDI potential to further promote safe and efficacious use in complex disease states.

Disclosures: All authors are employed by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co Inc, Rahway, NJ, USA and may own stock in Merck & Co Inc, Rahway, NJ, USA.

Citations/References: 1. Aitken AE, Morgan ET. Gene-Specific Effects of Inflammatory Cytokines on Cytochrome P450 2C, 2B6 and 3A4 mRNA Levels in Human Hepatocytes. Drug Metab Dispos. 2007;35(9):1687-1693. doi:10.1124/dmd.107.015511 2. Aitken AE, Richardson TA, Morgan ET. REGULATION OF DRUG-METABOLIZING ENZYMES AND TRANSPORTERS IN INFLAMMATION. Annu Rev Pharmacol Toxicol. 2006;46(1):123-149. doi:10.1146/annurev.pharmtox.46.120604.141059 3. Morgan ET, Goralski KB, Piquette-Miller M, et al. Regulation of Drug-Metabolizing Enzymes and Transporters in Infection, Inflammation, and Cancer. Drug Metab Dispos. 2008;36(2):205-216. doi:10.1124/dmd.107.018747 4. Strober W, Fuss IJ. Proinflammatory Cytokines in the Pathogenesis of Inflammatory Bowel Diseases. Gastroenterology. 2011;140(6):1756-1767.e1. doi:10.1053/j.gastro.2011.02.016 5. Abu-Sbeih H, Faleck DM, Ricciuti B, et al. Immune Checkpoint Inhibitor Therapy in Patients With Preexisting Inflammatory Bowel Disease. J Clin Oncol. 2020;38(6):576-583. doi:10.1200/JCO.19.01674 6. Catalan-Serra I, Brenna Ø. Immunotherapy in inflammatory bowel disease: Novel and emerging treatments. Hum Vaccin Immunother. Published online April 6, 2018:1-15. doi:10.1080/21645515.2018.1461297 7. U.S. Food and Drug Administration Center for Drugs Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). Drug-Drug Interaction Assessment for Therapeutic Proteins. Guidance for Industry. FDA Guid. 2020;(August):1-11.

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