GVK BIO CYP enzyme induction studies also simply called as CYP induction studies can be designed to meet the needs of the client based on the criteria and recommendations of the FDA or EMA guidelines. GVK BIO maintains a minimum of three cryopreserved primary human hepatocyte lots that have been extensively characterized with a series of weak to strong CYP3A4 inducers to acquire a Relative Induction Score (RIS) for each individual lot. The use of these RIS characterized lots as the standard in our enzyme induction studies allows clients to predict the magnitude of clinical DDI by CYP3A4 induction as necessary with the proper in vitro study design. Our definitive CYP induction studies utilize either fresh or cryopreserved primary human hepatocytes.
CYP induction assays assess whether the test article can increase the production of metabolizing enzymes or transporters involved in the distribution and clearance of all administered medicines. Plateable cryopreserved hepatocytes from one or more donors are used to assess the potential of a compound to induce drug metabolizing enzymes and transporters. The receptors tested include AhR, PXR, and CAR and the endpoints include mRNA and enzyme activity.
GVK BIO offers a range of services to evaluate the potential for drug-drug interactions, including cytochrome P450 (CYP450) induction studies, CYP inhibition studies, and CYP/UGT reaction phenotyping. In vitro drug-drug interaction studies are performed in accordance with FDA Guidance on Drug-Drug Interaction Studies
We recommend the following study design to meet the EMA / FDA guidelines:
- Cryopreserved primary human hepatocytes, RIS characterized
- CYP1A2, CYP2B6, CYP3A4 mRNA expression by qRT-PCR
- 6 – 8 concentrations of test article (how to choose your concentration range)
- EC50 / Emax data
- Vehicle control (test article solvent)
- Negative control for induction (clinical and in vitro non-inducer)
- Multiple positive controls (prototypical inducers)
- Pre-study solubility testing
- Spent media analysis with multiple time point collections as recommended by the EMA and FDA
- Full submission quality report
Study options to exceed the EMA / FDA guidelines:
- CYP1A2, CYP2B6, CYP3A4 in situ based activity by a 2-step cocktail incubation
- Microsomal based activity by single substrate incubation
- Pre-induction study toxicity assessment
- Full GLP Dose Solution Analysis on-site
- CYP2C8, CYP2C9 and CYP2C19 activity and/or mRNA expression endpoints
- Additional commercially available probes for mRNA expression endpoints (e.g., MDR1)
GVK BIO Pharma Discovery Services has an industry-leading portfolio of In Vitro services, including phase I and phase II enzyme assays, designed to help you understand the metabolic profile of your compound.
The phase I (e.g. cytochrome P450’s) and phase II (e.g. GSTs and UGTs) metabolizing enzymes in the liver are responsible for the majority of drug metabolism that occurs in the body. Drugs can also interact with these enzymes, by inhibiting their enzymatic activity (CYP inhibition) or through activation of nuclear receptors leading to induction of their gene expression (CYP induction).
Metabolism-mediated drug-drug interactions (DDI) can occur when a drug affects the Absorption, Distribution, Metabolism, Excretion –ADME, and Pharmacokinetics – PK of simultaneously administered drugs by altering the activities of drug metabolizing enzymes and/or drug transporters.
Following regulatory guidelines set forth in the FDA and EMA Guidance document (2012)1, we provide CYP inhibition and induction assays for 3A4, 2B6, 2D6, 1A2, 2C8, 2C9, 2C19 and other isoforms. Our CYP induction assays can performed by measuring gene expression levels by real time qPCR (mRNA analysis) or by traditional methods of measuring enzyme activity and are available in cultured primary hepatocytes from human and animal species. All our CYP assays can be ordered individually, combined or as a selection of key stability services provided in our drug candidate assessment packages to provide cost savings.