Learn how advances in biomedicine hold the potential to revolutionize drug development, drug treatments, and disease prevention: where are we now, and what does the future hold? This course will present short primers in genetics and mechanisms underlying variability in drug responses. A series of case studies will be used to illustrate principles of how genetics are being brought to bear on refining diagnoses and on personalizing treatment in rare and common diseases. The ethical and operational issues around how to implement large scale genomic sequencing in clinical practice will be addressed. After completing this course, learners will understand 1. The ways in which genetic variants can contribute to human disease susceptibility 2. How to choose among drug therapies based on genetic factors 3. That the functional consequences of the vast majority of genetic variants discovered by modern sequencing are unknown. This course is targeted primarily at physicians 5+ years out of training. Other healthcare providers, medical/health sciences students, and members of the public may also be interested. Course launches January 15, 2016. * The information presented in “Case Studies in Personalized Medicine” is offered for educational and informational purposes only, and should not be construed as personal medical advice. If you have questions or concerns about a medical matter, please consult your doctor or other professional healthcare provider.
Respiratory Arrest After Tonsillectomy
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来自 Vanderbilt University 的课程
Case Studies in Personalized Medicine
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从本节课中
UNIT 3: CASE STUDIES IN PERSONALIZED MEDICINE, PART 1
In Module 5 we will begin to discuss specific cases as these apply to personalized medicine. We will first look very closely at a case of familial hypercholesterolemia as we investigate how we use genomic medicine to move from a rare disease to a common medication, using genomics to find new drug targets, and a discussion of the side effects of statin therapy. In Module 6 we will look at a collection of "high risk pharmacogenetics"cases that illustrate adverse reactions due to drug metabolism and variable drug responses.
与讲师见面
Dan Roden, M.D.Professor of Medicine and Pharmacology
Assistant Vice Chancellor for Personalized Medicine
[MUSIC]
This module continues theme of high risk pharmacogenetics and
focuses on a case of an unexpected adverse event after tonsillectomy.
A 12-year-old undergoes uneventful tonsillectomy and is given codeine for
pain control.
They're found unresponsive at home and brought to the emergency room where
they're given naloxone, the opioid antagonist and the sensorium clears.
So what are the possible explanations?
Well again, this is not a problem of non-compliance.
This could be a problem of too much drug, clearly.
It could also be a problem of a drug interaction and
it may be a problem that has a genetic story.
So let me tell you a little bit about coding and why it is that the FDA no
longer recommends that we use coding in patients who are getting tonsillectomy and
other kinds of simple kind of pain control situations.
Codeine is a pro drug, just like clopidogrel.
It undergoes bioactivation and its bioactivation is accomplished by CYP2D6.
And the active metabolize is a compound that many of us
are familiar with, morphine.
So when you give codeine,
you expect the patients will generate morphine and receive pain relief.
Poor metabolizers predictably have less morphine generation and,
in fact, less pain relief.
And we know that.
But that's not the problem here, is it?
The problem seems to be too much of a drug effect
rather than too little of a drug effect.
So let's come back to this graph for a second and
notice that the distribution among extensive metabolizers Is pretty broad.
There's some extensive metabolizers who have some activity.
And there are other extensive metabolizers who have a ton of activity,
that little tail over on the left.
So, what is the explanation?
Well some of it is just variability across individual patients for
reasons that we don't understand, but there are patients who are known to have
more than one copy of the CYP2D6 gene, and in fact when you have more than one copy,
your liver processes the gene in the way its used to but
generates twice as much or three times as much or
13 times as much protein depending on how many copies of the gene you have.
So our ultra rapid metabolizers are individuals who are at that tail of
the distribution, often they're ultra-rapid metabolizers, because they
have more than one copy, more than one functional copy, of the CYP2D6 gene.
And that's a genetic variant that's particularly common in certain
parts of East Africa and The Arabian Peninsula but occurs world wide.
So the problem in this child was that they got coding,
they're an ultra-rapid metabolizer that generate huge amounts of morphine
from the coding and required rescue with the opioid antagonist.
This story goes back a long long long way.
This is a study long before anybody had heard of CYP2D6, or even deprizine for
hydroxylase, done by an investigator in Sweden, and
he looked at plasma concentrations of what was then one
of the most widely used antidepressants in the world, nortriptyline.
And what he noticed was that there was tremendous variability
in plasma concentrations of nortriptyline.
There were some individuals on the right who had very very high concentrations,
that one bar on the right.
Each bar is a patient, that one bar on the right is probably a poor metabolizer.
Their concentration is very very high nortriptyline is a CYP2D6 substrate.
There is also a couple of patients on the left who have no side effects.
The side effects are patients who have asterisks over their little bars,
who have no side effects but also have very, very, low drug concentrations.
So time passes, 25 years later we start to understand the mechanism underlying
variability in CYP2D6 substrate plasma conentrations.
And here's what happens with you give nortriptyline to patients as a function of
how many copies of the CYP2D6 gene they have.
Notice that if you have 13 copies,
that must be some kind of world record of the CYP2D6 gene.
Your concentrations of drug are very, very, very low compared to
the concentrations in somebody who has one copy or no copies, the poor metabolizer.
And the concentrations of the metabolite that's generated by
CYP2D6 are shown on the right, and those, of course, mirror those.
They're upside down.
The highest concentrations are patients who have 13 copies, and
the lowest concentrations are patients who have 0 copies, the poor metabolizers.
So, that's an explanation for variability in drug response.
It's been around for a long time.
But now we understand the mechanisms.
And just like we could with CYP2C19 in one of the previous modules, we can now make
a little cascade of what the dose adjustments should be for a patient
who is a poor metabolizer, an intermediate metabolizer, an extensive metabolizer,
for CYP2D6 we often don't make the distinction between intermediate and
extensive because there's a lot of overlap, and an ultra-rapid metabolizer
with respect to drug doses of CYP2D6 substrates that are antidepressants and
many of these the same drugs that are also CYP2C19 substrates so
when a drug is a substrate for both the dose adjustment becomes a little bit
riskier to make, or a little bit more uncertain, because you don't know
exactly what the contribution of each individual pathway is.
But, you're reassured, because there are two pathways.
Another example that is taken on some currency, and
some controversy is the the breast cancer drug tamoxifen.
So tamoxifen turns out to be like codeine and clopidogrel a prodrug.
Requires bioactivation,
one of the major active metabolites is the compound called endoxifen.
There are other active metabolites in.
One of the major pathways probably the major pathway for
tamoxifen bioactivation is CYP2D6.
This is a study from Germany that looked at over a thousand patients with
breast cancer treated with tomaxifen and followed the risk of recurrence over time.
Now, what these investigators were able to do was take the entire population that was
studied and genotype them and predict whether they would be extensive or
poor metabolizers, and it turned out that the extensive metabolizers had a much
better outcome then the poor metabolizers.
That makes sense because the poor metabolizers
fail to generate the active metabolite.
The extensive metabolizers do.
We don't expect absolutely everybody
who is a poor metabolizer to have a breast cancer recurrence.
Nor do we expect absolutely everyone who receives tamoxifen to be
protected against breast cancer recurrence but there are these differences.
These have become quite controversial.
People have tried to replicate these data and
sometimes they use breast cancer tissue as a source of genotyping material.
And as we'll talk about in subsequent modules,
cancers tend to have their own genomes.
And so whether you can predict if somebody is going to be the extensive report
metabolizer from a tumor block is somewhat controversial.
And the difference here, it's not huge, it's not black and white answer.
It's a bit of a shade of gray answer and so you have to ask yourself, is it worth
the trouble of genotyping everybody just to see this relatively small difference.
And again, it comes back to how complicated it is to get the information,
how hard it is to interpret, what the cost of getting the information is,
storing information, delivering the information and acting on the information.
We'll cover all those topics in later modules.
So as with CYP2C19, there is CYP2D6 inhibitors.
The main ones in clinical use are some of the SSRIs,
as I talked about in the previous module.
And these are data, again, from a pharmaceutical benefits provider,
Medco, in this case.
And they asked the question, after somebody started tamoxifen,
what is the risk of breast cancer recurrence in their data set, and
clearly patients who are getting a CYP2D6 inhibitor along with the tamoxifen had
a worse outcome than patients who were getting no CYP2D6 inhibitor and tamoxifen.
You can, this is not a randomized trial, so
you can ask all kinds of questions about whether this is a a real difference or
a difference somehow because some patients maybe depressed patients or
maybe patients who are taking SSRIs take them for different reasons.
There's also a mythology that some of the SSRIs may
actually help get rid of some of the side effects of tamoxifen,
notably the hot flashes that women often complain about.
Of course, getting rid of the hot flashes by using an SSRI may mean you're getting
rid of the therapeutic efficacy as well.
Those are all relatively controversial points.
The hazard ration here is almost two, so that's a pretty large hazard ratio as
you've seen in previous slides or previous examples, but again,
retrospective data, quite controversy in the oncology world, but there it is.
And it looks like tamoxifen metabolism is clearly CYP2D6 dependent and
that must have functional consequences.
In at least some patients.
So we have again the situation of high-risk pharmacokinetics
with a pro drug that requires a single pathway to activation and
we now have three examples of pro drugs, clopidogrel, codeine, and
tamoxifen where either the genetics or the presence of an inhibitor drug
can result in failure of bioactivation and less therapeutic efficacy.
You also have this situation of the ultra-rapid metabolizer
with clopidogrel possibly, I said that was controversial.
With codeine, there's absolutely no question.
In fact, there's such a large effect of the ultra-rapid metabolizer
that the FDA as I said before, has now recommended that codeine not be used for
routine pain control in situations like tonsillectomy,
where there is a risk of respiratory arrest.
So again, the take home messages are there are multiple sources for
variability in drug action, pro drugs and other situations of high risk
pharmacokinetics are a special problem that.
That were conditions me to look out for both in terms of
the genetics as well as in terms of the potential for drug interactions.
[MUSIC]
[SOUND] >> [APPLAUSE]
