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Emergency Medicine Takes a Crash Course in Pharmacogenomics

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At A Glance

Name: Bradley Freeman

Title: Assistant professor of medicine, department of general surgery, Washington University

Education: BS, chemistry, University of Central Florida; MD, Duke University

Age: 43

 

Slowly but surely, pharmacogenomics is entering the frenetic world of critical-care medicine. Though largely on the fringes of this discipline, pharmacogenomics technologies and methodologies are gradually taking root in emergency rooms and intensive-care units at an increasing number of hospitals across the United States, according to anecdotal reports, peer-reviewed journal abstracts, and interviews.

Though it is difficult to discern how many ERs or ICUs currently use or study pharmacogenomics technologies, it’s easy to see how the discipline can fit into the critical-care setting. For example, an article in the April 1 Nature shows that carbamazepine, a drug used to treat seizures that is often prescribed in ERs and ICUs, can cause Stevens-Johnson syndroe, a skin disorder, in certain populations with a particular gene mutation.

“It should be possible to exploit this association in a highly reliable test to predict severe adverse reaction, as well as for investigation of the pathogenesis of Stevens-Johnson syndrome,” the authors write in the study.

To learn more about the association between critical-care medicine and pharmacogenomics, SNPtech Pharmacogenomics Reporter caught up with Bradley Freeman, assistant professor of surgery at Washington University. Freeman next summer will wrap up a 5-year study looking at the use of pharmacogenomics in the surgical critical-care setting.

The long-term goal of your study is to apply the use of pharmacogenomics technologies and methodologies to the critical-care setting. Most people view pharmacogenomics research and practice as this staid, thoughtful exercise that takes a great deal of time — something that is always in demand in the critical-care setting.

First of all, in terms of framing the problem, it’s qualitatively different than critical care versus, say, drug use in an ambulatory population. And one of the things I think is different is, typically, in the critical-care environment, people use a lot more drugs. It’s not uncommon to walk into an ICU and see a patient on 10 or 15 drugs. And even while polypharmacy … is prevalent in the ambulatory population, typically it’s not to the same extent.

One of the reasons there is so much polypharmacy and redundancy is that medicines are not used optimally. In other words, we don’t understand the extent to which genetics underlie differences in metabolism and efficacy in drugs. In a nutshell, this is one of the reasons why we wanted to apply pharmacogenomics to that environment.

This brings up a lot of interesting questions. One is that you have to develop a technology that can rapidly genotype a person — say, one who has become critically ill — and you can use that information to prescribe drugs. Stepping back a moment, I’m not sure we have the technical platform in place yet to allow us to do that. However, I think that’s certainly on the horizon. I think these techniques, for rapid genotyping, are going to be used in this environment.

The second aspect is that, when you talk about pharmacogenomics, and people talk about using it to identify non-responders or responders or those who will have an adverse event. [For example,] if you look at the earliest examples of pharmacogenomics, patients in the 1950s would have a very prolonged effect to succinolcholine, which is an anti-polarizing paralytic agent. There’s a very small fraction of Caucasians, particularly those that lack the pseudocholinesterase to metabolize the drug [that] would have, literally, hours of paralysis.

Succinolcholine is still used, and I think it is a very good example of potential use of genetic screening to find adverse effects. I think that for the foreseeable future — five to 10 years — I think that those kind of applications are probably what we’re going to see with respect to pharmacogenomics.

I think less clear to me is how we are going to use pharmacogenomics to actually guide dosing, such antibiotics or antiarrhythmics, or antihypertensives, or vasopressors. Because, my sense is, that contribution of genetic variation to differences in metabolism and disposition and efficacy of those drugs is probably going to be less consequential than a lot of other effects, where it is organ dysfunction or resuscitation or medication interactions.

Critical-care medicine has sometimes been referred to as the poor relation in medicine. Do you think that the application of pharmacogenomics will follow suit?

The jury is still out. But let’s take one example: One of the reasons that people have a long stay in the ICU is because we have an imprecise way to predict how patients will respond to sedation. Say that I’m taking care of a patient who has had a multiple trauma, and he is receiving sedation — mechanical ventilation, and various other interventions. Something that happens with great frequency is that, once we stop the sedation with the intent of allowing him to become more arousable … there is a fraction of patient[s] who are very slow to metabolize or clear those agents.

And to the extent that pharmacogenomics might be a useful tool for identifying slow metabolizers that would have, say, liver or kidney dysfunction [that would have an effect on drug metabolism], that would be a powerful tool. This goes for cardiovascular drugs more strongly.

Many of these kinds of drugs are used very liberally in the ICU or in the post-operative patient, and to the extent that you can refine either drug selection or dosing using genetics, I think that that will have direct application [in the critical-care setting].

Beside the research you’re doing, do you think there is a good amount of pharmacogenomics-related research going on with an eye toward the critical-care setting?

I think most of the interest in genetics and critical care right now is probably … predominantly focused on patients with sepsis and septic shock, both to identify the genetic areas that predispose the development of that disease, and which might stratify patients with respect to outcome.

Where do you now see the cutting edge in terms of pharmacogenomics and the critical-care setting?

I definitely think that the greatest amount of interest, and the greatest potential for a breakthrough truly in critical care, will be in the realm of sepsis — both for identifying genotypes which are susceptible to sepsis, and as a tool for developing stratification. I think the second-most prominent role will be translating what people are doing in other domains in the critical-care environment.

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