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

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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.

Section snippets

Overview of drug–drug interactions involving metabolizing enzymes and transporters

The desirable and undesirable effects of a drug are generally related to its concentration at the sites of action, which in turn is related to the amount administered (dose) and to the drug's absorption, distribution, metabolism, and/or excretion (ADME). These processes are influenced by intrinsic factors such as age, race, gender, disease states, and extrinsic factors such as drug interactions and food effects. Observed changes arising from pharmacokinetic drug–drug interactions can be as

Regulatory requirements of drug–drug interaction studies

Drug interaction potential is recognized as an important consideration in the evaluation of a new molecular entity (NME) (Huang et al., 2007, Huang et al., 2008) and is an integral part of drug development and regulatory review prior to its market approval. Metabolism, transport, and drug interaction information play a key role in benefit/risk assessment. Several FDA guidance documents developed since the mid-1990s reflect the agency's view that the metabolism of an NME should be defined.

Highlights of the draft drug interaction guidance and its revision

This guidance document (Draft Guidance for Industry: Drug Interaction Studies—Study Design, Data Analysis, and Implications for Dosing and Labeling, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072101.pdf) provides recommendations for industry regarding the evaluation of drug metabolism and transporter interactions during the drug development process. It recommends that in vitro drug interaction studies be conducted early in the drug development

Summary

The understanding of drug interactions based on alterations in drug metabolism has matured to the point that the FDA includes considerable detail on the evaluation of metabolic drug interactions in vitro and in vivo in the recently published guidance (Draft Guidance for Industry: Drug Interaction Studies—Study Design, Data Analysis, and Implications for Dosing and Labeling, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072101.pdf). Emerging clinical

Conflict of interest statement

All authors declare no conflict of interest.

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