Abstract
Induction of cytochrome P450 (CYP) can impact the efficacy and safety of a drug molecule upon multiple dosing of co-administered drugs. This strategy is focused on CYP3A since the majority of clinically relevant cases of CYP induction are related to this enzyme. However, the in vitro evaluation of induction is applicable to other CYP enzymes but the in vivo relevance cannot be assessed because the scarcity of relevant clinical data. In the pre-clinical phase, compounds are screened using PXR reporter gene assay and, if necessary, structure-activity relationships (SAR) are developed. When projects progress towards the clinical phase, induction studies in a hepatocyte derived model using HepaRG cells will generate enough robust data to assess the compounds induction liability in vivo. The sensitive CYP3A biomarker 4β-hydroxycholesterol is built into the early clinical Phase I studies for all candidates since rare cases of in vivo induction have been found without any induction alerts at all from the currently used in vitro methods. Using this model, the AZ induction strategy integrates in vitro assays and in vivo studies to make a comprehensive assessment of the induction potential of new chemical entities. Convincing data can be found in the scientific literature that supports the validity of both the in vitro models and the use of the biomarker. However, regulatory authorities recommend the use of primary human hepatocytes and do not advise the use of sensitive biomarkers. Therefore, primary human hepatocytes and midazolam studies will be conducted during the clinical program as required for regulatory submission.
- cell models
- cytochrome P450
- drug development/discovery
- drug-drug interactions
- enzyme induction
- hepatocytes
- nuclear receptors
- The American Society for Pharmacology and Experimental Therapeutics