Exploring Differences in Drug Response With Dr Namandjé N. Bumpus

For the same dose of the same drug, two individuals might experience very different effects. This variation in drug response can be impacted by several drug-specific, genetic, biological, and environmental factors, and the interplay between these factors.

Genetic variation in key genes implicated in the metabolism or transport of a drug can influence a patient’s personalized risk of adverse events or treatment failure. Sex-based differences can also influence drug response.

In this interview, Namandje N. Bumpus, Ph.D, Associate Dean for Basic Research and Associate Professor of Medicine from Johns Hopkins, elaborates on her work exploring the differences between people in relation to drug response. She highlights key findings from work focused on the treatment of HIV and discusses the prospect of personalized drug dosage.

Laura Lansdowne (LL): Could tell me a bit more about the specific approaches you are using to explore the differences between people and drug response, and highlight some of the benefits of using a variety of different models?

Namandjé Bumpus (NB): We use genetic approaches to try and see if there are differences in gene expression or gene regulation. We are pharmacology labs, so we're often looking at differences and drug response. We use a lot of mass spectrometry (MS) to measure drugs to see if levels might be different between males and females, for instance. We even have an MS-based imaging approach, whereby we can take a slice of tissue from an animal, image it with MS and see what drugs are present. And we've looked to see if there are sex differences, for instance, in drug distribution. We have actually had some indication that there are differences.

Sex differences are published. We know there are sex differences, especially in the case of drug metabolism for instance. I think it's just a case of ensuring people are doing the work to look at response in both sexes in any animal model they're using and as we mentioned, humans too. It is important to ensure that human studies also have representation of men and women across different regions of geographic origin.

LL: You mention that most of your work is focused on drugs used to treat HIV – I was wondering if you could elaborate on your work in this area – are there any key findings from your research that you could highlight to me?

NB: Our work with HIV looks more at differences related to ethnicity, and the genetic basis for these differences. We haven't focused so much on sex differences, even though others have published some work in that area. In one of our published studies, we investigated a HIV drug called maraviroc, that inhibits entry of HIV into the cell. This drug is used for treatment of HIV, but it is also thought to be a potential approach to HIV prevention, since it inhibits entry of the virus into the cell. We wanted to figure which enzymes within the human body are responsible for metabolizing the drug, because there were some observed inter-individual differences between people in terms of the levels of the drug.

We found that the pathway and more specifically the protein that metabolizes maraviroc to help clear it from the body, was cytochrome P450 3A5. This really excited us because cytochrome P450 3A5 is extremely polymorphic. Approximately 85–90% of people of European descent have a genetic mutation that results in them not expressing this protein, or in cases where they do express the protein, it isn’t functional. Whereas approximately 50% of people of African descent have high levels of the protein – they have two full copies of the gene.

We looked at people that had the genetic variants that lead to no expression, versus the genetic variants that result in high activity and there was a big difference in the blood levels of maraviroc. So by genotyping these people and giving them the drug, we saw that those with the genetic variant that causes high activity of the protein had reduced levels of the drug indicating a potential need to increase the dose in those individuals.

In some cases where we've been able to successfully translate findings from an in vitro to an in vivo situation, which has enabled us to demonstrate that this genetic variability has an impact. If we fail to look at diverse populations when we're doing these drug studies, we could be choosing doses that work in one population and not in others.

Whilst this was a small study showing this genetic difference, it does indicate that, for example if 90% of people of European descent don't have this protein, and clinical study participants are mostly people of European descent – as they are in the US and Europe – then we could be missing something. We could be looking at people that are going to respond one way and not capturing what's true for everyone.

I think that's probably true for other drugs – we're hoping that other scientists will start to look more broadly. We haven’t yet done a study to similarly look exclusively at male versus female, but I do think that there are differences. For me, that's another frontier, really trying to tease out sex differences in terms of drug response because whilst there are some indications, it hasn’t yet been looked at thoroughly.

Our newest genetic work has been focused on HIV prevention and nucleotide reverse transcriptase inhibitors; these must be phosphorylated to be activated. We have been genotyping people because there are some people taking these drugs for prevention, that do still become infected.

One theory for this failure is that, maybe they are just no taking the drug. But we thought, what if genetically, they just can't activate the drug, because they must be activated to become effective. We haven't yet been able to directly test a person that was taking the drug to see if they have genetic variant. But we have been able to genotype a couple of thousand people across the world and we do see that there are genetic variants in these kinases that hadn't been previously discovered. We’ve been able to predict using in silico tools that they would be loss of function. We have also tested them in the lab, by purifying the proteins to see that these variants lead to decreased activation of these drugs.

LL: Do you think we will ever be in a position where physicians have access to a patient’s genetic profile – meaning they could have the ability to assess the information and advise on an optimal personalized drug dosage?

NB: I think that would be great. At this point in time, we just don't know enough about the effect of genetics on all drugs to be able to make really strong statements for each drug. But I think that once we start doing more studies we will be in a better position.

However, if we consider drug metabolism, we already know for many drugs, especially the newer drugs, which enzymes metabolize them. That information is something that you have to provide to the regulatory agencies.

So, on that basis you could, I think, have some idea about the impact genetic variation might have. I think it would be great if we were moving towards a system where we had genetic information for everyone. However, I think people do have concerns about privacy – I think that is the big issue.

What is particularly interesting, is that a lot of the variants that we see are very different across geographic regions. The challenge is that there are some countries that won’t allow you to do this type of analysis because they have privacy concerns around genetic data.

So not only do we just not know enough about any given individual genetically, but I think there's also a barrier to understanding genetic variation across the world population, because we just can't get access to the information.

Namandjé N. Bumpus was speaking with Laura Elizabeth Lansdowne, Senior Science Writer for Technology Networks.