Developing reliable pre-clinical models for analyzing drug metabolism remains a challenge for the pharmaceutical industry, but is critical for streamlining drug development. Abhinav Bhushan, Ph.D., an Assistant Professor in the Department of Biomedical Engineering at the Illinois Institute of Technology, is currently developing in vitro models that more accurately mimic in vivo drug metabolism. Specifically, he is studying the role that human gut bacteria play in modulating drug metabolism.
Abhinav will be discussing his lab’s research at the Bio-Processing Symposium on Wednesday, May 1 at 2:15 p.m. Below, he answers a few questions about the barriers to studying pre-clinical drug metabolism and how his group’s experimental organ-on-chip platform may help improve the design of clinical trials.
Abhinav: Curiosity! We noticed a while ago that for many of the diseases, specifically inflammatory bowel diseases (IBD), for even the best therapies, only a very small subset of patients respond. The clinical presentation of these patients is similar, but they don't respond. We wondered why that is and hypothesized that the changes in gut bacteria are causing this variable response. We already know that the composition of the gut bacteria in patients with IBD is altered compared to normal subjects, but we have almost no information about how bacteria can change the efficacy or the working of these drugs.
Abhinav: We know that drug development is a long process. The further on in the development process a molecule is, the more expensive it is to withdraw. For any drug you see that has been recalled or has been shown to have drug-drug interactions, those are drugs for which we failed to identify these very problems at the pre-clinical stage.
Also, we currently don’t have any experimental models that can help us figure out if a specific subset of patients respond to that molecule or not. All that is done much, much later, and I think there's a lot of opportunity for rethinking ways to make these models more robust.
Abhinav: We've taken a very agnostic approach to this. So right now, since we are developing the platform, the platform is agnostic to a specific disorder. The platform is really just quantifying how any given bacteria would affect drug metabolism. And then, in the future, we could go to a patient with IBD and look to see if some bacteria are overrepresented or some are not present. Then we can start to make conclusions about how this might affect drug metabolism.
Abhinav: We use technology called organ-on-chips. This gives human cells an environment, which includes a three-dimensional environment, and dynamic fluid flows and forces, where they can grow. It also allows us to work with mammalian cells outside the body by making the cells function like they do in vivo. It provides a really good mimic of the gut environment.
We can also engineer the environment to have additional input. In our case, it’s bacteria, but we could also put in immune cells or some other cell types. The organ-on-chip helps us reliably study the interaction between bacteria and the mammalian cells long enough to extract the information that we need.
Abhinav: I'm going to give a brief overview of organ-on-chip technology, how it relates to drug development, how simple they are, and what some of the challenges are in using them. But I really want to also talk about the main topic, which is how bacteria regulate drug metabolism. I'm going to talk about some of the recent studies that has been conducted in the field, and then I'm going to share some of our findings, which are really what I'm excited about.
One of the things that we have found is that – we've tested multiple bacteria – and each of the bacteria has its own unique influence on drug metabolism parameters. We also know that the communication between the bacteria and the human intestinal cells we tested is super important for this. It doesn’t work if you only have one or the other. This validates why we need a platform like this.
Abhinav: I think for the pharma industry there are three main takeaways. One is that we can leverage these interactions with the bacteria to design better drugs. Two, they can probably find respondents in the population who could actually benefit from their drug. The third is, eventually this could help us stratify clinical trials. Instead of relying on genetics alone, this technology could tell us, in real life, how bacteria are changing drug metabolism. I think it could help us design better clinical trials.
Abhinav: In addition to testing more bacteria, we have three important tasks. The first is for us to do in vivo validation that the changes we see really are significant and specific to our findings. The next, is to partner with industry. I think we could help them and really work together. The last thing, which we're actively pursuing, is to participate in ongoing studies for clinical trials that have to do with gut disorders.