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  1. Drug Interactions & Labeling

Drug Development and Drug Interactions

This web site focuses on drug development issues.

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Drug-drug interactions can lead to changed systemic exposure, resulting in variations in drug response of the co-administered drugs. In addition to co-administration of other drugs, concomitant ingestion of dietary supplements or citrus fruit or fruit juice could also alter systemic exposure of drugs, thus leading to adverse drug reactions or loss of efficacy. Therefore, it is important to evaluate potential drug interactions prior to market approval as well as during the postmarketing period.

This Web site provides drug developers with FDA's current understanding of how to conduct drug-interaction studies and resulting labeling. The FDA has published several documents that provide guidance to industry and Agency reviewers regarding the use of various methodologies to address metabolic (especially CYP based) drug-drug interaction issues. Recent data are increasing our understanding of transporters’ roles in drug interactions. In 2004, FDA published a concept paper,  to facilitate the discussion of study design, data analysis, and implication of drug interactions for dosing and labeling. a new draft guidance including additional discussions on emerging areas, such as drug transporters, has been published in September of 2006. it is available in [PDF] format, and is open for public comment.

In addition, FDA organizes and participates in various conferences and workshops and regularly publishes new considerations and findings in the scientific literature. FDA also engages in various clinical research projects to evaluate and understand drug interactions. We will regularly update this Web site with the results of these efforts.

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Background Information

The effects (desirable as well as undesirable) of a drug result from its concentrations at the site or sites of action. Once a drug has been administered (dosed), absorption, distribution, metabolism, and/or excretion will influence the concentration of the drug and its elimination from the body. Elimination of a drug or its metabolites occurs either by metabolism, usually by the liver or gut mucosa, or by excretion, usually by the kidneys and liver. Protein therapeutics may be eliminated through a specific interaction with cell surface receptors, followed by internalization and lysosomal degradation within the target cell. Hepatic elimination occurs primarily by the cytochrome P450 family (CYP) of enzymes located in the hepatic endoplasmic reticulum, but may also occur by non-P450 enzyme systems, such as N-acetyl and glucuronosyl transferases. Many factors can alter hepatic and intestinal drug metabolism, including the presence or absence of disease and/or concomitant medications. Although most of these factors are usually relatively stable over time, the presence of concomitant medications can alter metabolism abruptly and is of particular concern. The influence of concomitant medications on hepatic and intestinal metabolism becomes more complicated when a drug, including a prodrug, is metabolized to one or more active metabolites. In this case, the safety and efficacy of the drug/prodrug are determined by exposure to the parent drug, as well as by exposure to the active metabolites.

Transporter-based interactions have been increasingly documented. Various reported interactions attributed earlier to other mechanisms of interaction, such as protein-displacement or enzyme inhibition/induction, may be due in part to the inhibition or induction of transport proteins, such as

  • P-glycoprotein (P-gp)
  • organic anion transporter (OAT)
  • organic anion transporting polypeptide (OATP)
  • organic cation transporter (OCT)
  • multidrug resistance-associated proteins (MRP)
  • breast cancer resistant protein (BCRP)

Examples of transporter-based interactions include the interactions between

  • digoxin and quinidine
  • fexofenadine and ketoconazole (or erythromycin)
  • penicillin and probenecid
  • dofetilide and cimetidine

Of the various transporters, P-gp is the most well understood and may be appropriate to evaluate during drug development.

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Contact Information

To provide comments on this website, please contact us at:

Email: ocp@fda.hhs.gov 

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