Using Endogenous Biomarkers to Derisk Assessment of Transporter-Mediated Drug-Drug Interactions: A Scientific Perspective.

Comprehensive characterization of transporter mediated drug-drug interactions (DDIs) is important to formulate clinical management strategies and ensure the safe and effective use of concomitantly administered drugs. The potential of a drug to inhibit transporters is predicted by comparing the ratio of the relevant concentration (depending on the transporter) and the half maximum inhibitory concentration to a predefined "cutoff" value. If the ratio is greater than the cutoff value, modeling approaches such as physiologically based pharmacokinetic modeling or a clinical DDI trial may be recommended. Because false-positive (in vitro data suggest the potential for a DDI, whereas no significant DDI is observed in vivo) and false-negative (in vitro data does not suggest the potential for a DDI, whereas significant DDI is observed in vivo) outcomes have been observed, there is interest in exploring additional approaches to facilitate prediction of transporter-mediated DDIs. The idea of assessing changes in the concentration of endogenous biomarkers (which are substrates of clinically relevant transporters) to gain insight on the potential for a drug to inhibit transporter activity has received widespread attention. This brief report describes how endogenous biomarkers may help to expand the DDI assessment toolkit, highlights some current knowledge gaps, and outlines a conceptual framework that may complement the current paradigm of predicting the potential for transporter-mediated DDIs.

Drug interactions evaluation: an integrated part of risk assessment of therapeutics.

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.