After a few months on the topic of funding, we’ll move back into the pharmaceutical space with a discussion of drug-drug interactions. The study of this important class of potential toxicities has developed alongside our understanding of general and specific pharmacology. Today, significant pre-clinical and clinical efforts are made to detect, document, and understand their potential risks before a new drug or therapeutic protein is approved. In this series, we’ll take a closer look at drug-drug interactions (abbreviated as DDI) and their importance in clinical pharmacology.

Pharma companies and researchers spend a significant amount of time evaluating the DDI potential of their new drug candidates with multiple studies during discovery, pre-clinical development, and clinical development. A DDI is a change in drug effect when the affected person takes another substance alongside the drug. That simple definition is easier to understand if we take a closer look at what happens when a person takes a drug, how DDI might change the drug’s effect, and what researchers do to evaluate DDI potential before a new drug is approved.

To understand how a DDI occurs, let’s look at what happens when someone takes a drug in oral form (via pill, capsule, or liquid). The dose goes into the stomach, dissolved if necessary, and absorbed through the stomach lining into the bloodstream. This blood goes immediately to the liver via the portal vein. One of the liver’s many functions is cleaning the blood of potentially toxic substances, including our drug. In many cases, the drug molecules are removed from the blood by enzymes in the liver, which breaks them down into other molecules. The amount of drug not cleared by the liver enzymes goes on to circulate through the rest of the body and reach the site of action. Any part of the dose not taken up in the stomach has a chance to be absorbed in the intestines. Some drugs are pulled into and out of the bloodstream by transporter proteins in the intestines. The entire picture of drug absorption, circulation, metabolism, and elimination is known as its pharmacokinetics. A DDI occurs when another molecule changes a drug’s pharmacokinetics. The drug might also alter the pharmacokinetics of the other molecules. It’s not hard to see that, with a complex metabolic system, there are many places to affect the pharmacokinetics of any molecule.

A DDI causes unexpected effects, which may be desirable, unwanted, or toxic. All drugs have a therapeutic index or a range of concentrations that are both safe and effective. The most common way for a DDI to occur is via changes to the circulating concentration of the affected drug, often because the drug metabolism pathways change. When the concentration decreases, the drug is less effective. For example, an increase in metabolism for contraceptives from increased metabolizing enzyme activity reduces their ability to prevent pregnancy. Conversely, when drug concentrations rise, toxic side effects can appear and grow. The most common example is increased bleeding risk due to decreased metabolism of warfarin, an anti-clotting drug with a narrow therapeutic index. It’s also possible to have DDI from pharmacodynamic interactions, with two molecules producing additive or canceling drug effects. An example of this type is the dual action of nitrates and phosphodiesterase-5 inhibitors (think Viagra) in triggering an excess decrease in blood pressure.

The potential risks have triggered increasing levels of research and regulatory guidance. A simple search of PubMed.gov, the National Library of Medicine’s biomedical literature database, for drug-drug interactions returns over 315,000 results. These articles describe multidisciplinary research of all types. Some examples include reviews of drug interactions with commonly consumed herbs, updates on the role of specific metabolizing enzymes or transporter proteins in DDI, and discussions of DDI for particular classes of drugs. Research has informed multiple FDA guidance documents available for small molecule in vitro and clinical DDI evaluations caused by CYP450 enzymes and drug transporter proteins, changes in gastric pH, or oral contraceptives. Separate guidance covers assessing DDI for therapeutic proteins and biological drugs, for which fewer interaction mechanisms are known. The European and Japanese regulatory agencies have issued a similar direction. All three agencies expect data from DDI evaluations in both IND and NDA applications. In addition, sponsoring companies evaluate DDI potential before promoting a new drug candidate molecule into development.

A DDI, whether between drugs or drugs and foods/herbs/supplements, presents a significant risk of adverse events for persons in treatment. A DDI occurs when a body systems change occurs that changes the concentration of the drug, triggering unwanted effects. Therefore, DDI is the subject of considerable ongoing research and guidance. Developers of new drugs should expect to expend substantial resources to evaluate DDI potential for their development candidates. 

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Text Copyright © 2021 Katrina Rogers

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