Using micropatterned co-cultures to model human-specific drug metabolism, disposition and drug-drug interactions

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Webinar was presented on 10 March, 2016 by Dr. Salman Khetani, Associate Professor, Department of Bioengineering, University of Illinois at Chicago, USA In this webinar, Dr Salman described how micropatterned co-cultures (MPCCs) containing cryopreserved hepatocytes in industry-standard multi-well plates have been shown to be useful for CYP450 phenotyping, drug clearance prediction, metabolite identification and to model clinically-relevant drug-drug interactions.

Summary: Since the liver metabolizes ~70% of marketed drugs, accurate prediction of liver’s role in the metabolism and disposition of drugs is a critical exercise in the drug development pipeline in order to flag compounds with poor pharmacokinetic characteristics and/or properly investigate liver-drug interactions before clinical trials. Animal models are not sufficient for such purposes given the differences between animals and humans in drug metabolism pathways. Thus, human-relevant assays are needed to supplement animal testing. Isolated primary human hepatocytes are widely considered to be the “gold standard” for creating human liver models; however, in culture formats that rely exclusively on extracellular matrix, hepatocyte functions (i.e. cytochrome P450s) display a rapid decline in key functions (i.e. drug metabolism enzymes, transporters), which prevents long-term drug dosing. In our view and others, an ideal hepatocyte culture platform should maintain high levels of drug metabolism enzymes with proper hepatocyte polarity for prolonged times in order to allow incubations with drugs that interact with multiple pathways, including transporters. Furthermore, such a culture platform should be compatible with multiple batches of cryopreserved hepatocytes for on-demand and reproducible screening, thereby avoiding inter-donor variability when necessary. Since primary human hepatocytes are a limited resource, a culture platform should also use as few hepatocytes as possible to allow screening over many more experiments than possible with fully confluent monolayers. The ability to evaluate drug disposition in MPCCs created using hepatocytes from different species (i.e. mouse, rat, dog, monkey, human) allows for selection of the most appropriate animal species for downstream in vivo investigations. Case studies from multiple pharmaceutical companies will be presented to demonstrate the “real-world” utility of the MPCC platform. More recently, we are creating versions of MPCCs that display specific pathologies (i.e. hepatitis, diabetes) towards ultimately investigating how drug disposition is affected with specific disease backgrounds. In the future, MPCCs can be used to reduce drug attrition and prevent harm to patients in the clinic.