Nitrosamine Impurities in Rifampin

N-Nitrosamine impurity findings in marketed formulations of rifampin have disrupted drug development. Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis, Mycobacterium avium complex, leprosy, and Legionnaires’ disease. As a strong cytochrome P450 3A4 (CYP3A4) inducer, rifampin was regularly co-administered with investigational products during pharmacokinetic drug-drug interaction studies. However, due to recent impurity issues, its application in these studies has been suspended in both the US and EU.

This webinar will examine the root cause of rifampin impurity and describe the industry and regulatory response to this issue. In addition, the featured speakers will address alternative approaches and CYP3A inducers to encourage the continuation of drug-drug interaction studies and drug development.

N-Nitrosamines are a class of chemicals recognized as a “cohort of concern” due to their mutagenic and carcinogenic potential. Typically, levels above an acceptable intake may lead to a probable or possible risk of cancer in humans.

Rifampin capsules were found to contain 1-methyl-4-nitrosopiperazine (MNP) above the acceptable limit of 0.16 ppm. However, it’s important to note that nitrosamines are not limited to drug products, and low levels can be found in drinking water, processed meats, and tobacco exposure. Therefore, in theory, a diet low in nitrosamines could offset any potential exposure during rifampin drug-drug interaction studies.

Alternatively, other CYP3A inducers could be applied in these studies. While the US Food and Drug Administration (FDA) does provide a list of several candidates, in practice, many of these substitutes are not ideal for healthy volunteer studies due to black-box warnings (e.g., carbamazepine), risk of serious adverse events (e.g., apalutamide, enzalutamide, mitotane), or variation in response (St John’s wort).

The speakers propose overcoming rifampin impurity challenges with the use of phenytoin for healthy volunteer pharmacokinetic drug-drug interaction studies. They will present case studies applying phenytoin as a CYP3A inducer.

Topics of the webinar include how to optimize study design, anticipated effect size and common adverse events healthy volunteers may experience with phenytoin administration during drug-drug interaction studies.


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Andrew Juurinen