Why Primary Cells Are Important for In Vitro ADME-Tox Studies

An interview with Dr Maureen Bunger, Senior Product Manager ADME Tox Solutions at Lonza, conducted by Adam King

Can you give a brief overview of Lonza, the markets you serve and the types of products that you produce?

Lonza is a large, multinational corporation serving the entire pharmaceutical product development and manufacturing pipeline, from non-clinical research products to final dosage and delivery solutions. Our Bioscience Business Unit, in particular, primarily serves the non-clinical and preclinical phases of drug development. Within this unit we have a state-of-the-art Center for Cell Excellence, where we manufacture a breadth of primary cells including liver, skin, renal, intestinal and lung cells derived from multiple donors. Additionally, our custom services group can respond to specific cell type requests. We further support the use of primary cells for drug discovery applications with complementary products such as cell culture media, transfection technologies and assay kits.

Could you please explain what primary cells are and how they are useful in ADME and toxicology studies?

Primary cells are isolated directly from healthy human or animal tissues. They are different from tumor cell lines in that they have normal diploid chromosomes and maintain much of the physiological properties of the tissue from which they are derived.

During drug development, and before ever administering a new drug to a human patient, it’s necessary to predict how the drug might be metabolized in a healthy individual, and how that individual might adversely respond to the drug. Our experience shows that tumor cell lines make for poor predictors of how a healthy person may respond to a drug due to typically being diseased and aneuploidy (the condition of having an abnormal number of chromosomes in a haploid set). On the contrary, we find that testing primary human cells derived from different donors allows us to assess the effects of biological variation of drug metabolism.

In the not so distant past, the field mainly relied on animal studies to determine these predictions. Now, primary cells derived from human tissue are increasingly accepted as alternatives to animal models due to our increased understanding of the physiological inner workings of cells.

As the FDA increases scrutiny on the selection of animal models, there is greater utilization of in vitro assays using normal human cells to enable developing the right markers and models for downstream studies. Primary human hepatocytes isolated from the liver, for example, are now widely accepted as a predictive in vitro model for drug metabolism.  Other primary cells derived from normal healthy skin, kidney, intestine, heart, muscle, and lung are being increasingly used as models for either drug metabolism or toxicity predictions.

How can a researcher use primary cells in drug-drug interaction studies?

It is widely recognized that drug-drug interaction (DDI) studies are a crucial part of the pre-clinical stage in any small molecule drug development program. Drug-drug interactions arise when the metabolism of a drug influences the effects of another drug either positively or negatively. Since many people are taking multiple medicines daily, these kinds of interactions need to be included in the specific use indications provided to doctors and pharmacists. The updated FDA Guidance on in vitro studies during pre-clinical development recommends using primary human hepatocytes from at least three different donors to predict the potential of DDI for any new chemical prior to the start of clinical studies. Depending on the results from these primary human hepatocyte studies, the developer may need to include warnings on the packaging of the drug.

How is this different from how primary cells can be used in drug toxicity studies?  

This is one of the particularly exciting opportunities for primary cells and one where we can reduce the amount of animal testing. Until now, regulatory agencies have typically recommended animal studies for toxicity testing.  However, because animal models are not often predictive of human responses, and there is an increasing desire to minimize animal testing for ethical reasons, many researchers are now using primary human cells derived from healthy tissue to complement and even replace animal studies.

Primary cells become especially important when an incidence of toxicity in animals occurs during pre-clinical testing. By including both animal and human cells side-by-side in mechanistic toxicity studies, researchers can more definitively demonstrate to regulators how the mechanism of toxicity is different between animals and humans, and find ways to modify the drug to eliminate the toxicity potential. 3D cell models and organ-on-chip platforms that more readily mimic human physiology are also increasingly important in this phase of drug development.

Are there any organs that researchers can't derive primary cells from?

Primary cells can actually be isolated from almost any tissue. The one organ from which it’s difficult to isolate primary cells is the human brain. For this reason, most primary cells of neural origin used in mechanistic toxicity studies are animal-derived.

Can primary cells be used in research concerning neurons and ADME and toxicology studies?

Yes, in vitro assays have been developed to support in vivo testing for adult and developmental neurotoxicity. Neurite outgrowth assays can assess the toxicity of compounds on neuron growth and can be configured for high throughput analysis. Lately, multielectrode arrays (MEAs) are emerging as the tool of choice for understanding the function and mechanisms of neurotoxic responses to compounds. In a recent study, researchers used Lonza’s rat cortical neurons cultured on an MEA platform, and were able to demonstrate that network electrophysiological responses could reliably distinguish proconvulsant compounds from excitatory compounds, inhibitory compounds and anti-epileptic drugs. This ability to perform functional characterization of neural cell culture activity and connectivity opens the door for further safety and toxicology studies, disease-in-a-dish modeling, and drug discovery research.

Are there any other applications of primary cells with ADME and toxicology studies?

We currently find that primary cells derived from lung tissue are preferred by many companies in the chemical industry who need to understand the effect of volatile drugs and nanoparticles on the lungs. For example, primary human bronchial epithelial and small airway epithelial cells can form the tight barriers, and other specific features, of human airways which can be easily placed into special cultures at the interface of air and liquid.

Skin modelling is another major application of primary cells in toxicity studies.  Determining what happens to skin when it comes into contact with a new chemical is essential and the use of animal models for this purpose is often not allowed. To address this, primary human keratinocytes and dermal fibroblasts can be combined in a collagen matrix to mimic full-thickness skin for performing testing in the laboratory rather than in animals.

We should also stress the importance of the kidney as a key organ in the path of the excretion of chemicals, which results in it being a common site of toxicity. In response, primary human renal proximal tubule epithelial cells have been used in special flow-through models to mimic the passing of a chemical through the tubules and measurement of toxicity. With the advances in the development of biologic drugs, we would suggest it is becoming ever more important to test across multiple tissues for cross-reactivity and associated toxicities using primary cells derived from normal, healthy skin, kidney and intestine tissues.

What’s next for Lonza?

Based on our experience, we anticipate major growth in the acceptance of primary cells as valid predictive models for ADME and toxicology applications in drug development. Our new Center of Cell Excellence in RTP, North Carolina, USA, means that Lonza is ideally positioned to expand our R&D and manufacturing capabilities to meet the market’s growing needs for a wide range of high quality primary cells isolated directly from healthy human or animal tissues.

With our integrated solutions and expertise in cell biology, we are already supporting several major pharmaceutical companies who are working towards developing and validating new complex primary cell models in support of their pre-clinical programs. Backed by our commitment to quality and continuous improvement, Lonza strives to become the provider of choice where primary cells are concerned.

About Dr Maureen Bunger

Dr Maureen Bunger is Senior Product Manager for ADME Tox Solutions at Lonza. She has extensive knowledge in this field and its important role in drug discovery.  With over 20 years of experience in the life science domain, Maureen combines hands-on expertise in life science tools, including developing primary cell assays for ADME and toxicity assessment,  with sales and marketing experience to drive new product development and commercialization strategies. Maureen received a PhD in Molecular Toxicology from the University of Wisconsin-Madison in 2001 and completed postdoctoral training at the National Institute of Environmental Health Sciences (NIEHS), which is part of the National Institutes of Health (NIH) and has co-authored 18 peer-reviewed articles.

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