Transporter Mediated Drug-Drug Interactions: A Case Study


Hi, my name is Jomy George. I am the director of the Clinical Pharmacokinetics
Research Lab here at the NIH Clinical Center Pharmacy Department. Today, I’ll actually be going through a case
study focused on Transporter Mediated Drug-Drug Interactions, and this will actually be an
application of the presentation that was provided to you by Dr. Ware on drug transporters and
ad me and drug absorption. So, let’s get started with the patient case. This is a 45-year old male with a medical
history significant for HIV, hypertension, and left lower leg deep vein thrombosis, or
DVT, who presents the clinic today with a five-day history of recurrent nosebleeds and
feeling fatigued. His current medications include the following:
the anti-retroviral elvitegravir, cobicistat, tenofovir alafenamide, and emtricitabine given
as one tablet by mouth daily. The anti-hypertensive a amlodipine, 10 milligrams
by mouth daily, and the oral anti-coagulant used to treat his DVT provided at 150 milligrams
by mouth twice daily, and this started about a week ago. So, when we take a look at this particular
case, we need to take a couple of steps at least to identify the problem, and identifying
the problem is important because we can come up with logical solutions on how to actually
best manage these challenges and provide optimal care for this particular patient. So, in looking at what’s highlighted in red,
the statement that’s provided there pretty much provides a lot of information that’s
extremely important for management of this patient. So, this individual has a medical history
that has a number of comorbidities that require multiple modalities of drug therapy, which
are implicated in a number of drug-drug interactions. Also of note, what’s significant is that this
individual presents in side effects presumably from his oral anti-coagulant that started
about a week ago, and when we take a look at his regimen, his medication list, we really
need to think about are any of these particular drugs have clinically relevant drug-drug interactions? And this is important because this individual’s
actually presenting with side effects, again, presumably from his oral anti-coagulant. When we take a closer look, in fact, there
is actually an interaction between cobicistat, which is a PK booster, or a pharmacokinetic
booster or enhancer, that’s provided as part of his anti-retroviral regimen and his anti-oral
coagulant dabigatran. So, our next step is understanding how to
go about figuring out what resources we need to use to provide and help support — is there
data to support this drug interaction, and is this drug interaction clinically relevant,
and could it possibly explain why this individual has developed this side effect from dabigatran? And what I’ve pulled for you here are two
resources that are reputable resources, one being from the University of Liverpool and
the second being from Lexicomp, and these are simple searches that were provided using
their drug interaction checker online. So, if you take a look at these recommendations,
they’re actually a little bit different. However, the data that is used to support
these recommendations are similar. By the recommendations provided by the University
of Liverpool, as you can see here, their recommendation is actually “do not co-administer these particular
medications”, and the data here is to support it is based on a theoretical interaction that
cobicistat can actually increase the exposure of dabigatran, and we’ll go through the mechanism
of the interaction in a few slides. If we look towards the other side of the slide
where Lexicomp provides also a drug interaction checker, the actual risk here is not to actually
do not co-administer, it’s actually to monitor therapy and really look at the patient and
understand the benefit versus risk ratio, and if there needs to be any dosage modifications
or avoidance of co-administration. So, having said that, let’s take a look specifically
at the drugs that are implicated in this particular drug interaction. So, cobicistat, as I’ve mentioned is a pharmacokinetic
booster or enhancer, it doesn’t have anti-retroviral properties per se, but its’ really main focus,
or function if you will, is to enhance the exposure of co-competent medications, namely
the anti-retrovirals that are combined within the tablet, and Dabigatran as I’ve mentioned
is the oral anti-coagulant. When you pull data on how these drugs are
metabolized or transported, you will note that cobicistat actually goes through CYP3A4-mediated
metabolism. Specifically, as highlighted here, it’s a
strong inhibitor for CYP3A4 as well as a sub-strait for it, it also inhibits CYP2D6 to some extent,
but when we take a look at transporters and the transporters that are implicated for this
particular drug, we actually see a number of transporters that are involved for this
particular medication, including P-glycoprotein, BCRP, MATE1, and OATPI/1B3, and these are
all different functions and these transporters are located all throughout the body in different-in
different areas, but what’s important to understand and appreciate is that Dabigatran happens
to be a pretty sensitive sub-strait for P-glycoprotein. The FDA defines a sensitive sub-strait as
one that in the presence of other P-glycoproteins, it’s exposure will increase more than twofold. So, in its drug development program, there
is data for Dabigatran in combination of other PGP inhibitors, however, it is not been studied
with cobicistat. So, the natural question again is, is this
a clinically relevant interaction and could this interaction be explaining the side effect
profile for this particular medication in this patient? So, let’s take a closer look at the actual
mechanism and really breaking down what actually is happening. What the picture here is depicting for you
is the intestinal membranes, specifically in the enterocytes where P-glycoprotein is
located, and P-glycoprotein, as you’ve learned from the lecture, is located all throughout
the body. P-glycoprotein is indeed an efflux transporter
and it has its specific function and role in mitigating or facilitating a transporter
diffusion across different membranes. So, looking at the intestinal membrane, there
is a apical side, which faces the intestinal tract, or the lumen, the basolateral side,
which faces the blood. Now, when an individual ingests Dabigatran
in the absence of any transporter inhibition or induction, Dabigatran sits as a P-glycoprotein
sub-strait, but in the presence of cobicistat, cobicistat actually inhibits this efflux of
dabigatran. So, essentially, what’s happening here is
that you’ve got almost a stoppage if you will of this carrier-mediated efflux, and keep
in mind that there’s always constant concentration gradient that can go from the apical to the
basolateral side, which really determines the absorption of a medication, or the intestinal
absorption of the medication, or it can go from the basolateral to the apical side, which
really determines its exertive gradient. What happens when you inhibit this particular
transport? You increase the concentrations, or you actually
increase the intestinal absorption or bio-ability of oral dabigatran, and what happens, you
have an accumulation of the drug within the blood, which then really translates to higher
concentrations, higher exposure of the blood. But again, the question is, is this relevant? Is this exposure high enough such that this
requires a dosage modification or recommendation in avoiding these medications all together? So, I’ve pulled for you here the FDA-approved
label for dabigatran, and I’ve specifically highlighted for you the section on drug interactions. If you take a look, these labels are actually
quite complicated to go through and as clinicians, we’d have to make sure that we’re looking
at these medications for the right indication, and we understand what data is available and
if that data can be extrapolated to other drugs of interest in other target populations. It should be noted that most of the drug interaction
studies that are included within a drug label are conducted in a healthy volunteer population
and not within the target population. So, things to consider are other patient co-variants
that are not actually accounted for in the actual clinical trials. So, what this section actually outlines for
you are particular recommendations based on the absence or presence of the concomitant
medication that could be interacting or interfering with drug transport. It also highlights for you in the presence
of kidney disfunction or renal impairment, if those recommendations change, and specifically
for dabigatran, Dabigatran is actually eliminated via glomerular filtration by 80 percent of
it. So, from a clinical standpoint this is actually
very, very important to appreciate and to incorporate into our final recommendation
to this particular patient. So, I’d like to focus right here where it
says, “The use of PGP inhibitors specifically when it’s called out are verapamil, amiodarone,
quinidine, clarithromycin, and ticagrelor.” All of these particular medications were studied
with Dabigatran and the exposure, although there were increased in the presence of these
PGP inhibitors, they were deemed to have — there was a margin if you will that of efficacy
and safety for that particular exposure that was deemed to be clinically irrelevant. Or really what that means is it did not require
a dosage adjustment, but what’s important is the next statement also. These results should not be extrapolated to
PGP inhibitors. So, then the question comes up in this particular
case, cobicistat, which happens to be a PGP inhibitor, what do you do? How do you manage this patient appropriately? Is it appropriate to continue to dose this
individual in the presence of this side effect, or do we need to dose suggest perhaps the
medication? And this leads essentially a research gap
in data and in response if you will to help fill this research gap, there was a publication
that was put out by Gordon et al in circulation in about 2016, which really sought out to
help fill this gap and to study the drug interaction impact of cobicistat on dabigatran. I should note here that the study actually
looks at this particular interaction in healthy volunteers, but this is a comparison between
the impact of ritonavir, which is also a PK booster, but this is an older PK booster that
has fallen out of favor, namely because of side effects and because of the fact that
cobicistat is now available and is better tolerated. So, this particular study actually looks at
both ritonavir and cobicistat. As you can see here, panel A focuses on ritonavir
and panel B, or arm B, focuses on cobicistat. These are very simple concentration versus
time curves where Dabigatran plasma concentration is plotted for you on the Y-axis, the time
of administration posted — Dabigatran administration posted is plotted for you on the X-axis. Both of these arms had three different phases. The first phase in both arms was to provide
healthy volunteers Dabigatran alone. The second phase included providing or giving
Dabigatran two hours before either ritonavir or cobicistat, and the thought here is that
because this drug interaction is mediated or modulated by P-glycoprotein, perhaps separating
their administration to mitigate this interaction would help in perhaps being able to provide
these medications together. So, that was actually studied, if two hours
was actually enough and if that separation actually did mitigate that interaction. And that third phase was simultaneous administration
of Dabigatran with ritonavir or cobicistat. And as you can see here, you can visually
appreciate that there are significant differences between both of these arms. Particularly, in the setting of simultaneous
administration of Dabigatran and cobicistat versus Dabigatran and ritonavir, you can see
a significantly increased C-max and overall exposure of Dabigatran in the presence of
cobicistat. What’s interesting here is that actually ritonavir
and cobicistat are both PGP inhibitors, so this actually speaks to what the label actually
indicates as well, that the ability to extrapolate data to PGP inhibitors may not be appropriate
in all patient populations. And this really focuses and calls out that
in the absence of data, extrapolation may not be entirely appropriate, and you need
to take a case by case benefit versus risk ratio for each of your patients. So, again, even though this PK study provided
quantitative data, it provides you a percentage increase. It provides you metrics as far as how much
the drug is increased in the setting of cobicistat and ritonavir, but again the question is,
is that exposure increase clinically relevant? Would this exposure put individuals at risk
for bleeds namely? So, in this healthy volunteer study, it’s
apparent that Co-B did have much more profound effect as a PGP inhibitor, but extrapolation
of this data may not be entirely appropriate to all target populations. Staggering the dose actually did not have
an expected pronounced effect and it actually did not mitigate the interaction, and likely
the mechanism is that Co-B is indeed a potent intestinal PGP inhibitor, whereas ritonavir
may be acting as an inducer — a mixed inducer and inhibitor or P-glycoprotein. The clinical relevance right now at this moment
is really unknown, however because our particular patient is experiencing side effects, this
really cannot be ruled out that possibly the cobicistat is propagating or perpetuating
the drug interaction with dabigatran. The therapeutic options for this individual
and really any individual based on this PK data is either to avoid its’ concomitant use
altogether, provided that there is an appropriate alternate option for the patients. Second would be to space apart perhaps the
medications for more than two hours. In the case of dabigatran, it should be noted
that Dabigatran is already being given twice a day in this particular patient and really
all patients for Dabigatran is typically dosed twice a day, so really spacing these drugs
apart for more than two hours really doesn’t provide a chance for patients to be actually
adherent to their medications and could actually negatively impact adherence, so it may not
be the best optimal choice. And then lastly, does it make sense to reduce
the Dabigatran dose? But the question then is, how much do you
reduce the dose, and would that actually have negative impact, namely on efficacy? And remember that there’s a delicate balance
between efficacy and safety. This is a drug that’s being given to an individual
to essentially anti-coagulate them after having identified thrombosis, so we do need to carefully
figure out the balance between efficacy and safety and if that reduction of dose is truly
therapeutically appropriate. And for all of those reasons, this really
provides or introduces many different management challenges. I’ve pulled for you here a number of FDA U.S.
product labels for other direct oral anti-coagulants. Select ones that are listed here for you,
Rivaroxaban, Apixaban, Dabigatran, and Edoxaban. If you look across the drug interaction potential,
actually both rivaroxaban and Edoxaban plausibly actually pose a higher drug interaction potential
because they’re sub-straits for both CYP3A4 as well as P-glycoprotein. The label recommendations essentially provide
guidance saying that rivaroxaban drugs like cobicistat should be avoided altogether. Apixaban, you could use it, but you may need
a dosage reduction depending upon the indication for the drug and the patient population and
the co-variants. Dabigatran, we already went through the label
recommendation for that and Edoxaban, which is a fairly newer direct anti-oral coagulant
for that that’s available. The data that’s actually with Edoxaban if
you actually don’t hear for in the product label is that with specific PGP inhibitors,
you actually might be able to use it without any dosage suggestions, but I would caution
or advise that we have a patient here that’s developed a side effect plausibly because
of the anti-oral coagulant, so the question of being able to safely administer in the
presence of his anti-retroviral regimen really should be questioned, and I’m not entirely
sure if switching him to Edoxaban would be the most appropriate option. But having said that, we have to do something
for our patient. We have to make a decision. So, we did identify the relevant drug interaction. We’re essentially deeming this to essentially
be clinically relevant for this particular patient case, as he’s developed side effects
presumably from his dabigatran, and because he’s feeling fatigued, remember he could have
lost actually quite a bit of blood, but we don’t have other laboratory markers to really
support that, but really it should cause concern given that he’s had recurrent nosebleeds really
temporally associated with the time of initiation of his dabigatran. And really what we need to do is think about
and ask advice from specialists and really take a multi-disciplinary approach in really
managing this particular patient. So, really it would be great to work with
his HIV provider to discontinue his cobicistat-based anti-retroviral therapy and really construct
an alternative regimen, which poses a much lesser drug interaction risk. And in this situation, you could actually
continue his Dabigatran and treat him for his DVT, or other options could potentially
be for whatever reason he cannot tolerate or cannot be switched to an alternative anti-retroviral
regimen. We do need to think about switching him to
another oral anti-coagulant but would need very frequent monitoring to ensure that he
doesn’t continue to have side effects from his oral anti-coagulant. So, in summary, drug transporters are implicated
in many clinically relevant drug interactions. It may not be important to extrapolate drug
interaction data generated from healthy volunteers to a target population or rather for drug
of interest — other drugs of interest. It is important to practice a multi-disciplinary
approach in the management of these patients who do present with rather complex comorbidities,
which end up having very complex drug-drug interactions. Thank you, and I hope this presentation was
helpful.

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