Abstract

The induction of relevant drug metabolizing enzymes such as e.g., cytochrome P450 (CYP) isoforms can either result in a decreased systemic exposure of the inducing drug itself and/or of concomitant medications (when those are metabolized by the induced enzyme) or can lead to an increased exposure towards active or toxic metabolites. CYP1A2, 2B6, and 3A4 are the key enzymes to detect induction effects on the three drug-drug interaction (DDI) relevant nuclear receptors AhR, CAR, and PXR.

The enzyme induction potential of a drug candidate and its metabolites is typically evaluated first in vitro by measuring mRNA expression as primary endpoint in cultured human hepatocytes. Nuvisan has implemented a bDNA-based multiplexing technology for mRNA quantification allowing the measurement of all genes of interest from a single 96-well. On top of providing economic benefits compared to conventional qPCR, this methodology also offers the opportunity to gain a deeper understanding of the mechanism of action of the drug candidate. Moreover, various options for customizing the CYP induction experiments driven by the drug’s characteristics can generate added value.

Depending on the intended drug market, the study design and subsequent data evaluation should follow the guidelines for the conduct of such DDI studies issued by the three regulatory agencies EMA, FDA, and PMDA. Pre-characterization of hepatocytes e.g., concerning general inducibility and relative induction score (RIS), can support predicting the occurrence as well as estimating the potential extent of induction in humans.

In this 45-minute presentation, Dr. Kathleen Boehme, project manager at Nuvisan will present some approaches on how to boost your regulatory in vitro CYP induction studies:

• CYP induction and DDIs
• Standard regulatory assay set-up
• bDNA-based multiplexing technology
• Options for optimized study design
• Data analysis & risk assessment strategies

In a Q&A session following this case study presentation, it will be possible to discuss further on these or any other topics of interest.

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