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Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Final Guidance

Thank you for joining us for another episode of the Guidance Recap Podcast. The Guidance Recap Podcast provides highlights for FDA guidance documents straight from the authors. My name is Kylie Haskins, and I am the host for today’s podcast. I am a member of the Guidance, Policy, and Communications Team in the Office of Translational Sciences here at the FDA. In today’s episode, I am excited to be talking with Dr. Kellie Reynolds, who is the Deputy Director of the Division of Infectious Disease Pharmacology in the Office of Clinical Pharmacology. Dr. Reynolds will be sharing some thoughts with us on the recently published, drug interaction final guidance titled, “Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions.” Welcome, Dr. Reynolds! Thank you for speaking with us today.

Can you explain to the audience why clinical drug interaction studies are important and provide some of the reasons that FDA issued this guidance?

Yes, clinical drug interaction studies are important because many people take multiple drugs. Unanticipated, unrecognized, or mismanaged drug-drug interactions, also known as DDIs, can change the systemic exposure of a drug when taken in combination with specific other drugs. The change in exposure may alter the drug’s effectiveness or cause unexpected side effects. A patient who takes multiple drugs needs to understand the potential for drug interactions. For example, systemic exposure of the drug rosuvastatin, a cholesterol-reducing drug, is increased, when taken in combination with cyclosporin, an immunosuppressant medication. The increased exposure of rosuvastatin may cause serious side effects, including kidney and liver problems, in some patients. DDIs are a significant but avoidable cause of morbidity and mortality associated with prescription drugs. The rate of adverse drug reactions increases significantly for patients who take four or more medications. Currently, close to 40 percent of the U.S. population receive prescriptions for four or more medications. FDA issued this guidance to provide best practices for clinical studies evaluating DDIs and to provide recommendations for determining essential information to communicate in labeling to health care providers.

For listeners less familiar with this area, can you provide a little background about Cytochrome P450 enzyme and transporter-mediated drug interactions?

Cytochrome P450 enzymes, also called CYP enzymes, and membrane transporters are the most common mechanisms for affecting drug absorption, distribution, metabolism, and excretion (also known as ADME). Drug metabolism primarily occurs in the liver and intestine, mainly through the CYP family of enzymes. Membrane transporters can have clinically relevant effects on the pharmacokinetics and pharmacodynamics of a drug in various organs and tissues by controlling its absorption, distribution, and elimination. Because of their roles in ADME, changes in baseline CYP enzyme and membrane transporter activities or levels due to taking multiple drugs can lead to a DDI. For example, elvitegravir, an HIV-1 treatment, is metabolized by CYP3A. Thus, coadministration of elvitegravir with drugs that induce CYP3A enzymes may decrease elvitegravir plasma concentration and potentially reduce its therapeutic effect.

Can you give us a brief overview of the evolution of this guidance?

A 2012 draft guidance contained both clinical and in vitro DDI content. FDA received feedback that the guidance was difficult to navigate. Thus, in the 2017, we split the 2012 guidance into 2 draft guidances – covering in vitro and clinical DDIs separately. Then in 2020, we published the final version of both DDI guidances. For the clinical DDI guidance, there are no major changes in recommendations from the 2017 draft version. However, there are some clarifications and format changes. Based on comments received, the final version includes wording that clarifies the scope of the guidance - PK interactions mediated by CYP enzymes or drug transporters. We added a few details about the design of prospective interaction studies. Additionally, we removed the lists of CYP index inhibitors, inducers and substrates and the examples of transporter substrates and inhibitors. Instead, we will provide the lists on the FDA ‘s drug development and drug interaction web site for ease of update.

How do you anticipate this guidance will affect external and internal stakeholders?

The goal of any drug interaction program is to understand the potential for clinically significant DDIs and inform strategies to manage them. With the wide range of possible clinical DDI evaluations, it can be overwhelming for industry and reviewers to determine the most informative and efficient practices for conducting the studies. We anticipate the guidance will be welcomed by both industry and FDA staff because it provides specific recommendations for conducting clinical drug interaction studies and interpreting the results.

This guidance contains an incredible amount of useful and important information. What are a couple of key items that you especially want listeners to remember?

I want listeners to remember that at the beginning of a drug development program, it is important to determine how the potential for drug interactions will be evaluated. Unanticipated or mismanaged DDIs can impede the development of drugs that may otherwise be safe. Although a full drug interaction program that includes evaluation of metabolic and transporter mediated interactions can appear overwhelming, following the advice in the FDA guidances can simplify the process. The interpretation and management of DDIs is specific to each drug and intended population. However, the overarching process for DDI evaluation adheres to the same concepts for all drugs.

Dr. Reynolds, thank you for taking the time to share your thoughts on the clinical drug interaction studies final guidance. We have learned so much from your experience and insights in this area, and we appreciate all the hard work that you do to ensure the safe and effective use of the drugs and biologics we regulate. We would also like to thank the guidance working group for writing and publishing this final guidance.

To the listeners, we hope you found this podcast useful. We encourage you to take a look at the snapshot and to read the final guidance.