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Drug interactions evaluation: An integrated part of risk assessment of therapeutics

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Building 51, Room 3188, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Toxicology and Applied Pharmacology (Impact Factor: 3.63). 03/2010; 243(2):134-45. DOI: 10.1016/j.taap.2009.12.016
Source: PubMed

ABSTRACT Pharmacokinetic drug interactions can lead to serious adverse events or decreased drug efficacy. The evaluation of a new molecular entity's (NME's) drug-drug interaction potential is an integral part of risk assessment during drug development and regulatory review. Alteration of activities of enzymes or transporters involved in the absorption, distribution, metabolism, or excretion of a new molecular entity by concomitant drugs may alter drug exposure, which can impact response (safety or efficacy). The recent Food and Drug Administration (FDA) draft drug interaction guidance (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072101.pdf) highlights the methodologies and criteria that may be used to guide drug interaction evaluation by industry and regulatory agencies and to construct informative labeling for health practitioner and patients. In addition, the Food and Drug Administration established a "Drug Development and Drug Interactions" website to provide up-to-date information regarding evaluation of drug interactions (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm). This review summarizes key elements in the FDA drug interaction guidance and new scientific developments that can guide the evaluation of drug-drug interactions during the drug development process.

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    • "A pharmacokinetic interaction occurs when a drug alters the pharmacokinetic processes such as absorption, distribution, metabolism (most often due to interaction with the cytochrome P450 hepatic enzymes), and/or excretion of another medication. A pharmaceutical interaction occurs when mixing chemically incompatible drugs outside the body, as for example, incompatibility of Phenobarbital with opioid analgesics when mixed in the same syringe, resulting in inactivation of one or both drugs.[8] "
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    • "We also do not know whether chimeric mice can be used to prospectively evaluate the potential for a drug-drug interaction (DDI) involving a candidate therapeutic to occur in human subjects. Because more than 30% of the US population over 57 years of age take five or more prescription drugs at a given time, DDIs have created major problems for patients and for regulatory authorities (Zhang et al., 2010). However, with use of available in vitro or in vivo animal models, it has been difficult to predict many of the clinically important DDIs, which only became apparent after drug development was completed (Bode, 2010). "
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