Guest: Dr. Shivang Joshi

View the recording from our Migraine Clinician Masterclass, developed in partnership with IVPN Neuropsychiatry. In this webinar, we hear from Dr. Shivang Joshi, who talks about the Mechanism of Action in Migraine Therapeutics. Please note that this video is intended for healthcare providers.

TRANSCRIPT

Dr. Shivang Joshi: Well, thank you for inviting me. It’s a pleasure and an honor to be able to speak to such a wonderful audience of pharmacists, neurologists, residents. And we’re here today to talk about a very important topic because there’s so many advances in pharmacological therapy. I think we forget what we learned sometimes in medical school or residency, and the complexity of it is very important to understand because it does matter to clinicians and patients. And I hope by the end of this discussion that you are able to agree with me that mechanism of action in migraine therapeutics is very important.

These are my disclosures. So today the objective is to review the mechanism of action of acute and preventive medications, newer and traditional medications, and understand the clinical implications. We’re going to review the relevant pharmacokinetics of standard and newer classes of migraine preventive and acute medications. And then understand the potential for drug-drug interactions based on pharmacokinetic principles. 

So I’m going to sort of paint the picture with some epidemiology data here, okay? This data is from 2006 from the United States, but it gives you a perspective on what can happen if you have adverse drug events. And this is a big burden for patients as well as clinicians as well, and hospital systems and networks. So in inpatient setting, the ADEs account for 1 in 3 hospital adverse events, 2 million hospital stays per year, and prolong the hospital stay by 1.7 to 4.6 days. And as you know, the longer you are in the hospital setting, the more costs associated with it. If you look at the outpatient setting there are over 3.5 billion office visits, 1 billion ER visits according to this data presented, and multiple hospitalizations. So there’s huge amount of costs associated with adverse drug events. 

You know, when we talk about pharmacology, pharmacotherapeutics, there’s also pharmacogenetics. I don’t think that we are here completely advanced with pharmacogenetics yet. I think there’s a lot of potential, a lot of research that still needs to be developed, but there are a lot of things that we do know about. There are variations in enzyme inhibition and induction with individuals. There are several polymorphisms that may occur and there are some patients that are ultrasensitive. And I know you may see this in your practice whether you are a neurologist, neuropsychiatrist, or even a pharmacist. You have some patients that are very sensitive to some medications and some patients they have no adverse reactions, and you need to go to much higher doses. So I do think that pharmacogenetics does play a role, but I still think that there’s still more research that needs to be done in understanding this aspect of pharmacology.

For example, when we look at some of the metabolisms of enzymes, as we are aware, there are two different phases. The phase one is the oxidative phase, which involves cytochrome P450. For example, the CYP2C19 and 2D6 are very highly polymorphic.

As an example of a medication, amitriptyline – very commonly used TCA medication both for migraines, tension headaches, used for anxiety, mood disorder, multiple different uses for this – undergoes demethylation to nortriptyline and then hydroxylation, right? And then there’s phase two, which is a conjugative phase. And why does this matter? 

Here’s another example. Pharmacogenetics and psychiatry. If you look at clozapine, which is an atypical antipsychotic medication, there are a number of patients who experience agranulocytosis, which is one of the most severe adverse reactions of this medication. But in patients who had this marker HLA-DQB1 versus in patients who did not have the marker, you can see the dramatic difference. So I present this just to illustrate that pharmacogenetics is something real and can play a clinical impact in patients’ lives. 

Here’s another example, trazodone. We use this for sleep. And if we look at the study, we can see that it has a higher clearance in women, okay? And there are some polymorphisms in the metabolisms of this medication. In particular, the ABCB1-influenced metabolism route. And when this occurs, there’s a decrease in blood pressure and a prolongation of the QT interval, okay? Now, if you have a cytochrome P452D6 and ABCB1 mutation, there’s also dizziness and prolonged QT prolongation as well, too. I also like to make a little side note about trazodone. When trazodone is metabolized, there’s a metabolite of trazodone which actually has been known to induce more migraines or make migraines worse. So sometimes higher doses can induce this separate from the pharmacogenetic principles.

So this brings us to the question. And this is a very interesting question. And this is a great study that was used to highlight this. You have patients that have migraines. You have patients that don’t have migraines. If we give them topiramate, who is more likely to have adverse reactions? So it turns out that same doses of topiramate were associated with different adverse reactions and more so higher adverse reactions in patients with migraines versus patients who had epilepsy. The migraine patients who had more reactions tended to be older and there were more females who did a slower titration.

This is important because it goes back to the pathophysiology understanding of migraine. Migraine is a hyperexcitable complex neurological disorder, right? Patients experience hyperacusia, sensitivity to light. So the brain is just hardwired differently where you’re more likely to have more adverse reactions versus someone else who does not have a migraine.

So this is an interesting study where even if you have some benefit, patients are still less willing to take the medication due to potential for adverse reaction. This is illustrated graphically here in this chart. The proportion of patients willing to take on the left versus the percent reduction of headache frequency on the right. And you can see this is beautifully illustrated that even though you do get some benefit, 75% here, you don’t have as many patients willing to take the medication, and they may be due to adverse reactions. 

Since this is an international talk, I thought I would mention this in here. This is the report of counterfeit medications by therapeutic classes, which was reviewed by the World Health Organization. And you can see the multiple different classes here, antibiotics, other therapeutics, analgesic antipyretics, and as well as asthma and allergy medication. So there is some concern about where the patients were getting these medications as well, too, if they’re not prescribed and not obtained from a regulated pharmacy source.

Right, let’s do a quick overview. For some of the pharmacists out there, this may be something simple for you, but I think for the juniors, this might be something very helpful to gain an understanding. When we look at the cytochrome P450 system, the CYP here notes the cytochrome. The 2, which is highlighted here, notes the family, right? So there’s about less than 40% homology placed in separate families with this specific indication. The C notes the subfamily, and then the number at the end notes the individual enzymes. 

Now, this is important. If you look at the distribution of the major cytochrome P450 enzymes, majority are CYP3A4, 28%. But I want you to keep in mind this other metabolism here as well, too, because that plays, you know, somewhat of a role in just our understanding of some of the newer medications. 

What are some factors that affect cytochrome P450 metabolism? So the dose, the route, the frequency all play an important role. Obviously, if you have a higher dose, you’re going to saturate the pathways. Some orally administered medications undergo first-pass hepatic metabolization. And there are genetic polymorphisms as well too, right, including certain ethnicities, such as Asians and Caucasians, maybe higher metabolizers.

Basic pharmacokinetic metabolism definitions. So a substrate is a medication that is metabolized by an enzyme, or a medication can be a substrate for multiple enzymes. There are enzyme inducers, as well as there are enzyme inhibitors, okay? We’re going to keep it as simple as this.

So we look at other metabolism, there are three that come to mind, in particular because of recent advancements in the gepant class of medications. They list these three other metabolism pathways in their package insert. So I thought, you know, let’s familiarize ourselves with them. 

The first one is the permeability glycoprotein, PG-1. It’s a membrane transport protein. Relevant substrates include atogepant, rimegepant, ubrogepant, topiramate, and verapamil. There’s also breast cancer-resistant peptide, which is an efflux type of transport protein, similar to PG-1. Relevant substrates include atogepant, rimegepant, ubrogepant. And there’s also the organic anion transporter peptide, OATP, and substrates include atogepant. 

Now, just because they’re metabolized through this pathway, does not necessarily mean that it’s clinically significant. So I think that this is important to know only because the newer agents do have this listed in the package insert. It’s something that we’re generally not familiar with because we’re more used to the cytochrome P450 route of metabolism. 

Now let’s look at some general metabolism concerns, right? So grapefruit juice, right? So there are components within grapefruit called furanocoumarins. They inhibit cytochrome P450. They also inhibit P-glycoprotein, which can then enhance the bioavailability and reduce the P-glycoprotein substrates. Something to be aware of, there are some standard medications that are metabolized by this, including some calcium channel blockers, like amlodipine and others as well, too. 

Cigarette smoking, okay? Very important. Cigarette smoking by itself is an enzyme inducer, okay? The carbon monoxide that comes out of the smoking is an enzyme inhibitor. It’s very important to understand this. If you have some patients that are not getting some benefit and they are avid smokers, it could be that their medication is being cleared faster.

And as I mentioned earlier, there are some genetic polymorphisms as well. For example, P-glycoprotein expression is reduced in specific polymorphisms of Asians and Caucasians. Classic example of that is carbamazepine, right? So some patients who are Asians have a difference in metabolism with carbamazepine.

Now let’s review some of the mechanisms, pharmacokinetic properties, migraine preventatives, and the clinical implications. So we’re going to go a little bit more in depth. All right, so these are the general class of medications we’re going to take a look at. They happen to be more of the common classes of medications, and we’ll look at some of the newer medications as well. 

First, when we look at beta-blockers, these are very commonly used worldwide. However, there are numerous potential drug-drug interactions. You can see the enzymes that it belongs to, but I think of importance here is the one with rizatriptan. So if the patient is on a beta-blocker, the rizatriptan dose will be doubled, okay? So if you’re using the 10-mg dose, you might want to consider using a 5-mg dose to prevent adverse reactions from the triptan, such as triptan-like effects if someone is on propranolol. 

Another noteworthy adverse reaction is with metoprolol in someone who’s on paroxetine, or Paxil. Because they both are modulated by the CYP2D6 system and there’s a possibility that your patient is complaining of or will have bradycardia. So this is something important to make note of. 

Now, when we look at the beta-blockers, we also look at drug-disease interactions too. So in diabetes, as you recall, beta-blockers may mask or hide or cover the hypoglycemic effects. And so a patient could be hypoglycemic, but you might not realize this because it can be masked by the beta-blocker effects. So this is something to be aware of. We know that beta-blockers are also triggering COPD exacerbations, especially if they’re nonselective, such as propranolol, nadolol, versus the more selective beta-blockers, which include metoprolol and atenolol.

There’s also increased risk of cardiovascular events, higher incidence of severe hypoglycemia as well, too. When we look at depression and beta-blockers, there are some reports out there that suggest that beta-blockers can make depression worse. But in actuality, if you do a meta-analysis, it doesn’t appear that this is actually real. But you might have some individual cases that you may be seeing this. There have been reports of depression that’s worse in the elderly patients receiving more of the lipophilic beta-blockers. 

Now, on the opposite side, we do tend to use beta-blockers in let’s say you have a migraine patient that may have some anxiety component. So this is another area where you might want to use a beta-blocker. Or let’s say you have someone that has a tremor. And this is another place where we try to get something called the twofer, which is a dual effect, a migraine benefit and also a secondary benefit as well, too. 

Now let’s take a look at the antiepileptic medications. Divalproex or Depakote, it’s not really commonly used as a first-line preventive medication. It does have level A evidence according to the American Academy of Neurology and American Headache Society. However, we don’t use this as a first line because of multiple potential adverse reactions. One of the primarily important one is that women of childbearing age should not be placed on this due to potential for teratogenic related effects. Depakote is also used in IV formulations or in a short pulse mode to break headache cycles as well, too. But as you can see here, that if you have a patient that’s on certain enzyme inhibitors, such as aspirin or fluoxetine, or other medications, they may increase the dose of Depakote leading to more adverse reactions and including hepatic related effects. 

The more commonly used antiepileptic medication is topiramate. Topiramate is only a weak inhibitor of the CYP2C19 and only a weak inducer of the CYP3A4. It’s unlikely to interact with highly protein-bound medications. And some of these substrates for topiramate include amitriptyline as well as verapamil. Now, clinical considerations include if someone is on a highly protein-bound medication, so these include Warfarin or others which have Sulfa, this can be displaced as well, too. When you have a patient that is placed on topiramate, there is a warning in the package insert that higher doses, around 200 mg a day, will decrease the effectiveness of the birth control, in particular, birth control containing ethinyl estradiol. So obviously, we don’t want any unplanned pregnancies in patients, and you do want to make them aware that there is this potential interaction.

Now, you may have patients that are diabetics receiving metformin. You may also have patients that are receiving metformin for other related symptoms, such as sometimes other fatty liver-related or obesity-related indications. But remember, the combination of both metformin and topiramate can lead to lactic acidosis, not to mention potassium-related decreases as well, too. So something you want to monitor for. 

All right, let’s look at one of the other common medications prescribed. Amitriptyline is metabolized by 2C19. Of note, 2C19 is also very highly variable in terms of a patient’s genetics. So there are people who are rapid metabolizers and there are people who are very slow metabolizers. And obviously, if they are rapid metabolizers, you’re not going to have the benefit. And if they’re very slow, they’re going to have more of the adverse reactions.

There’s concomitant use with SSRIs, can lead to QT prolongation or anticholinergic toxicity. You want to be careful in elderly patients with using amitriptyline due to urinary retention as well, too. There may be some risk of anticoagulation or hemorrhagic risk with use in someone with Warfarin as well, too.

All right, so there’s other interactions listed here. If we look at the other TCAs and the SNRIs that are commonly used in migraines, they include nortriptyline and venlafaxine as well, which are metabolized by the 2D6 route versus 2C19. 

Let’s take a look at verapamil more closely. Verapamil is not really a first or second line medication for migraines. Nevertheless, it is used and it does have a level C indication, but we might be using this more as a first line for prevention in cluster headache patients, correct? So the verapamil is modulated by the P-glycoprotein pathway. There are some common drug interactions, but you should be careful in combining it with beta-blockers because you can get cardiovascular depression as well, too. 

In rare instances, you may also exacerbate myasthenia or induce myasthenia crises in patients that are placed on verapamil, okay? A very important clinical note is that if you do have a cluster headache patient and you are increasing the dose on verapamil, very important to, let’s say after 120 mg of verapamil, to obtain a baseline EKG before you advance to higher doses to make sure there are no issues. Again, for the patient, verapamil at higher doses can also cause more constipation as well, too, and sometimes peripheral edema. I have rarely seen verapamil also cause elevated prolactin levels as well, too, which is more on the rare side.

Now, before we talk about some of the newer agents, let’s do a flashback. So one of the first gepant class of medication was telcagepant. It was developed by Merck. It was a very effective medication, very good efficacy data, but it resulted in some hepatic side effects, okay? And part of the reason why it developed the hepatic side effect was that the molecule was not only targeting CGRP specific for migraine, but it was also targeting extrahepatic or other receptors as well, leading to adverse reactions. And the theory behind it is that it has to do with this phenyl glycosyl precursor, which was found in the original molecule versus the newer molecules do not contain this phenyl glycosyl precursor as noted here in ubrogepant as well as the atogepant. 

Now, this information here is basically taken out of the package insert of these medications. Now, I bring this up because this is a newer sort of area of metabolism that we’re not familiar with. And so I want to emphasize that these are the statements made in the package insert and the FDA, there are recommendations. Now, the clinical significance of this still has to be determined, but I’ll show you some more updated slides that may address some of the clinical concerns or lack of concern with some of the data mentioned here.

For example, when we look at ubrogepant, the metabolism pathway is CYP3A4 P-glycoprotein inhibitors. You know, if you have someone that’s on a strong inhibitor, such as ketoconazole, itraconazole, or clarithromycin, you may not want to use this according to the product label. Moderate inhibitors, the recommendation is dose adjustments. And then weak inhibitors, no dose adjustment is needed. Now, if you have a strong inducer, you want to avoid taking this medication. Some of the strong inducers include penicillin, barbiturates, and St. John’s wort.

So St. John’s wort is marketed in the United States. It’s an over-the-counter medication. It’s an herbal medication primarily used to treat depression, but it actually has a lot of P450 enzyme-induction abnormalities. So it’s something to be aware of. So if someone has a moderate or weak inducer, dose adjustment is recommended. 

Now, when we look at rimegepant, which is indicated both for acute and prevention, it’s metabolized to a lesser extent, 2C9, primarily 3A4. The recommendations include with strong inhibitors to avoid and avoid a second dose until 48 hours for moderate inhibitors and avoid use in strong or moderate inducers. Both of these medications are substrates of P-glycoprotein and BCRP, and increased exposure to gepants with PG and BCRP inhibitors recommendation is to avoid, but I’m going to show you some data in subsequent slides that has been done post-marketing. Some of these substrates for PG and BCRP include verapamil, itraconazole, and some of the other medications listed here, including carvedilol as well, too, and curcumin.

This is, again, taken from the package insert. Atogepant, the recommendations are to adjust the dosing based on the inhibitors, so 10 mg for strong CYP3A4 inhibitors, 30 or 60 for strong or moderate, and if you have an OATP inhibitor, 10 mg or 30 mg, once a day. 

Now, let’s take a look at some of this data that’s presented here. This is presented at the American Headache Society in 2021 as a virtual poster in their annual meeting. The effect of strong PGP and BCRP inhibition using cyclosporine and quinidine on the pharmacokinetics of oral rimegepant in healthy subjects. So the data is shown here, but in terms of the interpretation of this data and conclusion, so the authors felt that the strong PG inhibitors, such as cyclosporine and quinidine, moderately increased rimegepant exposure, less than twofold. Rimegepant was safe and well tolerated. The moderate effects of rimegepant exposure may be generalized to other strong P-glycoprotein inhibitors. The similar effect of cyclosporine and quinidine on rimegepant exposure suggests that BCRP inhibition has minimal influence on rimegepant exposure, okay? So important to know. 

Now let’s take a look at another recent study that was published in Breastfeed Medical Journal in March of 2022, and basically they wanted to investigate whether rimegepant, an oral small molecule calcitonin G-related peptide, which you’ll learn about in more detail in the next lecture to come, if it’s excreted in human milk after a single dose of 75 mg. And then they wanted to characterize the concentration. So when they did this analysis, they found that on a weight-adjusted basis, the relative infant dose of rimegepant was less than 1% of the maternal dose. So here’s the data showing you breast milk versus the plasma concentration of the infant, and it was found to be less than 1%. 

Now let’s take a look at the evaluation and pharmacokinetic interactions, where we look at atogepant co-administered with topiramate. So on the left, we look at the concentrations of atogepant. On the right, we look at the concentrations of topiramate. And the purpose of this is to see if there was a change in the concentration when both of these medications were taken together. So atogepant plasma concentrations were marginally lower upon concomitant use of topiramate, which is a mild inducer of CYP3A4. And the topiramate concentrations were only marginally lower when used concomitant with atogepant. 

Here’s another more recent study published very recently, actually. It was a Phase 1b open-label study looking at a drug-drug interaction potential and safety between atogepant and ubrogepant. This was a study done by Dr. Blumenfeld and other authors as well. So a single dose of ubrogepant had no statistical significant effect on atogepant pharmacokinetics. In fact, administering both of them together resulted in 19% increase in the ubrogepant area under the concentration curve and 26% increase in the ubrogepant maximum plasma concentration. So the statistical significant changes in the ubrogepant exposure were not clinically meaningful, okay? So there was no new safety concerns that were identified for this combination. 

Now, let’s take a look at the other class of medications, monoclonal antibodies. And as you recall, the monoclonal antibodies are not metabolized by your cytochrome P450 system. Instead, they are metabolized by your reticuloendothelial, which is also known as the mononuclear phagocytic system. Their specific target-mediated clearance and also nonspecific elimination mechanisms that occur parallel, right? So basically, it’s broken down into individual amino acids, and it just goes away.

So here’s another specific study that looked at erenumab, which is a monoclonal antibody. They looked at combined oral contraceptives, ethinyl estradiol, and showed no clinically relevant drug-drug interaction. In addition, at standard doses, antibody-antibody interactions is also unlikely since IgG clearance is dependent on the FCRN saturation, which is unlikely to occur at typical therapeutic doses of the monoclonal antibodies.

Now, acute medications, which you’re familiar with, come in multiple different forms. They come in tablets, nasal spray, injections. In some parts of the world, they also come in suppositories as well. So here are the classical oral triptans. These have all been marketed throughout the years. The sumatriptan was the first one. We do like to exploit some of the differences between these medications and take advantage of them. For example, frovatriptan has a long half-life, so we sometimes use that for menstrual-associated migraine as a premenstrual preventive indication. 

Naratriptan itself also has the second-longest half-life, and we may use this as a menstrual migraine prevention as well. Sometimes we like to use this twice a day, two days before the actual start of the menstruation, and you continue into the menstrual cycle. Sumatriptan has been around the longest. It has a very poor oral bioavailability, and it also has a short half-life, and sometimes this is leading to rebound headache.

There are also certain anti-inflammatory medications. The diclofenac oral solution has been approved for FDA. They have two randomized, double-blind, placebo-controlled trials. It is not marketed by the company in a brand form, but it is something that is available still. There’s also ibuprofen and naproxen, and there’s also celecoxib, which is a COX-2-specific inhibitor, was also marketed in the US as a solution. This is no longer actively marketed, as far as I know, but this was a recent change.

Important things to know that are important to patients and clinicians is that the triptan package insert still carries a warning for hemiplegic migraine. Now, there’s some debate about that because we have a better understanding of migraines now, that migraines are not as much of a vascular condition, more of a neuroinflammatory condition that involves CGRP, and more of a neurovascular component, where vasodilation is not a main mechanism of action. So, again, the product label still indicates migraine with brain stem aura, which is the old terminology. The newer terminology is basilar migraines, where there still is a contraindications.

Obviously, we don’t like to use triptans in someone who has uncontrolled hypertension. Concomitant use with MAO inhibitors has been not recommended. Also, you should not use within 24 hours of ergotamine because the ergotamine also potentiates multiple different serotonin receptors. You don’t want to trigger a serotonin syndrome. It is pregnancy category C, but that’s the old sort of nomenclature. The newer nomenclature, in the United States, we don’t use pregnancy categories anymore, but the package insert presents data and leaves it up to the clinician to determine if this is safe.

Now, there are several articles that have been published which look at the use of sumatriptan throughout and during pregnancy without having any significant difference between any adverse reactions if they didn’t use sumatriptan or with other agents. So there are some pregnancy registry data that has been published where it suggests that this can be used in your pregnant patients.

Again, contraindications, ischemic heart disease. But not only that, if you have multiple risk factors, let’s say you do have controlled hypertension, controlled diabetes, controlled hyperlipidemia, and you have maybe sleep apnea, you’re morbidly obese, I would still use caution to those patients who have multiple risk factors for coronary artery disease. 

Now, let’s take a look at the new generation of medications. Rimegepant, ubrogepant, we’ve discussed already. I’m going to take a brief moment, only a few more slides left, to talk about lasmiditan, dihydroergotamine nasal spray, and sumatriptan nasal as well. And in the future, there is in development zavegepant, which is an intranasal gepant, which is the first and only intranasal gepant in development. But I do not have any detailed data to share with you at this time. But this is in development. 

So let’s take a look at lasmiditan. So lasmiditan is a new class of medications that belong to medications called the ditans. It has a very high affinity, highly selective to bind to the 5-HT1F receptor, and it acts on the trigeminal system without causing any vasoconstriction because it does not bind to the 5-HT1B receptor. As you recall, the triptans typically bind to the 5-HT1B and D receptor, which are also found in cardiac tissue and cardiac blood vessels as well. So lasmiditan does not do this. It’s indicated for the acute treatment of migraines with or without aura. It has good data showing efficacy versus placebo. There is a warning in the package insert recommending not driving for 8 hours after use because there may be a potential for dizziness as well. 

So let’s take a look at why this is unique, okay? So we look at the pathophysiology of migraines. We know that it involves the trigeminal vascular system, and there’s also these trigeminal cervical complex. So what happens is you have afferent impulses that release CGRP. Those impulses then go to the trigeminal ganglion. And from the trigeminal ganglion, remember, the trigeminal ganglion is outside the blood-brain barrier. The trigeminal ganglion has pseudounipolar neurons that connect into the brainstem here.

And the brainstem, they connect with a trigeminal nucleus caudalis, which not only receives input from the peripheral nervous system, it also receives input from the C1 and C2. The combination of the trigeminal ganglion, the trigeminal nucleus caudalis, and the C1/C2 nerve input forms something called the trigeminal cervical complex.  At this point, signals go to higher parts of the brain. They go to the hypothalamus, thalamus, cortex, and also there’s a descending pathway as well, too. 

Now, what’s important to note here is that the 1F receptor is found both in the peripheral nervous system as well as the central nervous system. So in this section over here on the bottom where I indicate E, the 1F receptor is found in the cortex, in the brainstem, the trigeminal ganglion, the cerebellum, higher parts of the hypothalamus as well. And this is the target where the 1F receptor is targeted by lasmiditan. So lasmiditan works by theoretically inhibiting the 1F receptor both peripherally and centrally. And as you’re aware, the migraine pathophysiology involves both peripheral and central sensitization. The peripheral sensitization leads to the throbbing pain component, whereas the central sensitization is the part where patients complain about allodynia. 

Okay, all right, dihydroergotamine nasal spray. Now we are familiar with DHE as an IV formulation. However, this is not practical and is associated with many different adverse reactions in patients. So there has been a different formulation available on the market, but there have been issues with effectiveness as well as availability of getting the medication to the right site. So what happened here was that this company developed this precision olfactory delivery device, which allows it to be absorbed with one-tenth of the Cmax of IV DHE, but yet IV-like plasma concentrations from 20 minutes on. So you’re getting good efficacy with a lower dose. Important things to know. As you know, DHE targets agonistically multiple different receptors, including multiple different serotonin receptors, as well as antagonist activity and multiple different other receptors, including dopamine receptors as well, too. 

So there is a cardiovascular warning. The package insert does suggest that before starting a patient to consider EKG as a baseline in patients. The other important thing to know is that you should space this medication 24 hours apart from any triptans if your patients are using both this medication and a triptan. 

Now, here is the difference between a typical nasal spray, which delivers the medication primarily to the lower part of the nasal mucosa here, but you have three different sections, lower, middle, and upper section here. The upper section is very rich in the vasculature. So you have the posterior ethmoidal artery, the sphenopalatine artery, and this is where the medication is absorbed. So using this technology, this POD technology, it delivers the medication in a plume, which reaches the upper nasal passageway, preventing more nonspecific absorption as well, too. So that is the technology of this medication delivering DHE. 

Now, there is also another nasal spray. Now, this is the DFN-02. It’s a sumatriptan nasal spray. What’s unique about this nasal spray is that it delivers sumatriptan, but it’s combined with a permeation enhancer, okay? So this permeation enhancer, when it opens the gap junctions in the membranes in the nasal mucosa, when these gap junctions are open, the medication is better absorbed. So you’re getting less amount of sumatriptan, but you’re getting absorbed effectively. So you don’t get the adverse reactions of higher doses of sumatriptan when they’re used. So this is used for acute treatment of migraines. And you can see the data here showing you 2-hour pain freedom to be 43% versus 20% placebo.

Now, here’s some pharmacokinetic data showing you the curves here regarding absorption. Your standard Imitrex nasal spray, you can see the absorption is very poor, not to mention that it has a very burning-like sensation. Most patients won’t like you if you give this to them because of the burning sensation versus the sumatriptan nasal medication spray. You can see it reaches peak plasma in a short period of time, and this is where the effectiveness of the medication takes place. The goal is to get the medication absorbed effectively, and a lower dose allows you to do that without having side effects from higher doses. 

All right, so in conclusion, here are some important takeaway points.

The mechanism of action does matter for both clinicians and patients. Drug-drug interactions are important to consider in patients who use migraine-preventive polytherapy. I mean, you know it, we have patients that are on topiramate, a TCA, a beta-blocker. And sometimes you have to think about the combination of all this and streamline, right? So polypharmacy is something that we always strive to reduce in all of our patients. So some consideration should be taken when you think about metabolisms through the CYP450 system, of which the CYP3A4 is the most common one. And when you tailor your clinical management, you can reduce drug-drug interactions, hospitalizations, adverse events in patients with comorbid conditions.

So the newer generations of therapy, which I pointed out, may certainly be a safer choice and a better-tolerated option for some patients. You know, something to consider as a whole when you think about your migraine patients. 

So thank you so much for your attention. I appreciate being able to convey this information to this audience. And I believe we’re going to be moving on to the next presentation. I’ll be happy to field any questions in the general question and answer session. Thank you.

*The contents of this video are intended for general informational purposes only and does not constitute professional medical advice, diagnosis, or treatment. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition. AMD and the speaker do not recommend or endorse any specific course of treatment, products, procedures, opinions, or other information that may be mentioned. Reliance on any information provided by this content is solely at your own risk.