부산대학교 도서관

It is well-recognized that therapeutic proteins (TPs) with pro-inflammatory activities elevate the pro-inflammatory cytokines and result in cytokine-drug interactions. In the current review, several pro-inflammatory cytokines, including IL-2, IL-6, IFN-γ, and TNF-α, as well as an anti-inflammatory cytokine IL-10, were summarized for their respective effect on major cytochrome P450 enzymes and efflux transporter PgP. Pro-inflammatory cytokines are generally associated with suppression of CYP enzymes across assay systems but have varied effect on Pgp expression levels and activities depending on the individual cytokines and assay systems, whereas IL-10 had no significant impact on CYP enzymes and P-gp. A cocktail drug-drug interaction (DDI) study design could be an ideal approach for simultaneously assess the impact of TPs with pro-inflammatory activities on multiple CYP enzymes. Clinical DDI studies using the cocktail approach have been conducted for several TPs with pro-inflammatory activities and for those TPs with pro-inflammatory activities which had no clinical DDI study conducted, languages for potential DDI risk due to cytokine-drug interaction were included in the label. Up to date drug cocktails, including clinically validated and unvalidated for DDI assessment, were summarized in this review. Most clinically validated cocktails focused either on CYP enzymes or transporters. Additional effort was needed to validate a cocktail to include both the major CYP enzymes and key transporters. In silico methods for assessment of the DDI for TPs with pro-inflammatory activities were also discussed.
(© 2023 Pfizer Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)