Over the past few years, an increasing number of commercially available drugs have been reported to contain N-nitrosamine impurities above acceptable intake limits, which has compromised the availability of various drugs for the treatment of patients. In addition, since several of these marketed drugs are regularly co-administered as perpetrator or substrate drug together with investigational products in drug-drug interaction (DDI) studies, the N-nitrosamine issue has also disrupted clinical drug development. Rifampin, a strong cytochrome P450 3A4 (CYP3A4) inducer, is one of the principle perpetrators employed in DDI studies and, due to N-nitrosamine impurities across all commercial batches, its application in DDI studies has been suspended in both the US and EU. This has forced drug developers to consider alternative CYP3A4 inducers, yet many of the substitutes recommended by the FDA are not ideal for healthy volunteer studies due to unfavorable safety profiles. This presentation will review the N-nitrosamine issue, DDI drugs at risk of containing N-nitrosamines, and consider suitable alternatives to continue DDI studies and drug development.
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