CERSI Collaborators: University of California San Francisco: Kathy Giacomini, PhD; Deanna Kroetz, PhD; Sook Wah Yee, PhD; Kelsey Trumbach, MPH; Xujia Zhou, PhD

FDA Collaborators: Center for Drug Evaluation and Research: Liang Zhao, PhD; Lei Zhang, PhD; Khondoker Alam, PhD; Andre Raw, PhD; Bhagwant Rege, PhD; Dongmei Lu, PhD

Project Start Date: 05/2022

Regulatory Science Challenge

The U.S. Food and Drug Administration issued the guidance for industry: Controls of Nitrosamine Impurities in Human Drugs in September 2020 (revised February 2021) to inform drug substance and drug product manufacturers about the risk of nitrosamine impurities in drug products. Nitrosamines, which are probable or possible human carcinogens, can be formed by nitrosating reactions during synthesis of drug substances, drug product manufacturing processes, and during product storage. Several products have been recalled because of unacceptable levels of nitrosamine impurities. One potential mitigation strategy to reduce or prevent nitrosamines in drug products is to include certain antioxidants in drug product formulations. However, it is unclear whether antioxidants may have an effect on drug transporters in the intestine, which play an important role in drug absorption, and thereby may affect drug levels in the blood.

Project Description and Goals

This project will screen 31 antioxidants to determine whether they are potential inhibitors of three important drug transporters found in the intestine: P-gp, BCRP, and OATP2B1. The results of this study will identify antioxidants that may inhibit intestinal transporters and those antioxidants that do not inhibit intestinal transporters. These data will provide fundamental information to inform the need for in vivo bioavailability or bioequivalence studies for drug products that are reformulated to add antioxidants to mitigate formation of nitrosamine impurities.