Drug Development and Drug Interactions
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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
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draft guidance including additional discussions on emerging areas,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 both[HTML] and [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.
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.
Shiew-Mei Huang, PhD, FCP
Deputy Office Director for Science
Office of Clinical Pharmacology
Center for Drug Evaluation and Research
Food and Drug Administration
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Date created: May 1, 2006
Date updated: October 11, 2006