Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast Narrator - ? 00:11 is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk. Episode 82 I'm your co host, Dr. Kane. Unknown Speaker 00:35 I'm Dr. Schuman. I'm Dr. Patel Speaker 1 00:37 and I'm Dr. Rahul Deshmukh. This is the very first time, I'm joining a wonderful group of people to discuss a little more about the topic for the day. Unknown Speaker 00:46 We're very happy to have you. Speaker 2 00:48 So I'm going to kick off today's episode. Really excited to introduce, let's get heavy deuterium substitution as a pathway for drug design. Again, what we're really going to look at here is the use of deuteration, specifically involving the medication deutetrabenazine, which is when we discussed way back in episode 76 looking at tardive dyskinesia management feature. Again, we have our guest here, Dr. Deshmukh, looking from the pharmacy sciences department at the role of this medication, not just this current medication, but really as it as the future holds for drug design and development, and some of the new concepts about essentially a new paradigm in drug molecule shifting and discovery for future targets. Speaker 1 01:31 And I hope to make some contributions to this deuterium as a molecule that is a part of this discussion today. It's not a novel molecule. And as we discuss more, you will realize that it's just a heavy isotope of hydrogen, and it has a lot of unique properties that are being currently exploited to see if we can get into some kind of drug development with it, and that's what we'll be discussing. Dr. Sean Kane 01:57 And for those listeners who are maybe a little bit far removed from the pharmacy sciences courses that they took in pharmacy school. I just want to caution you here that this is stuff that is coming out right now. We've already seen it in deutetrabenazine that we covered in Episode 76 this is a huge area of direct pipeline development. We're going to see more of this. So even if you're not as familiar with what heavy hydrogen would be, you're going to see this in clinical practice. Speaker 2 02:22 The first question is, again, you kind of already alluded to this, but what is deuterium? Speaker 1 02:27 So deuterium is basically a isotope of hydrogen. So hydrogen basically has one proton and one neutron. Deuterium is isotope which has one extra neutron in the system, and as a result, it becomes a double in weight to that of hydrogen. In addition to deuterium, there is another isotope of hydrogen, and it's called tritium, and it is slightly more heavier and it is radioactive. The unique aspect about deuterium is it is a non radioactive isotope of hydrogen, and from a pharmaceutical perspective, its physiochemical properties are very, very similar to that of hydrogen. So the hypothesis here is, if we can somehow use this particular isotope of hydrogen and use it to modify drugs, it would be a paradigm shift in how drug development happens, one unique aspect of this chemistry is whenever carbon is linked to hydrogen, it forms a bond. It's called a carbon hydrogen bond. But when we have deuterium, instead of hydrogen connected to the carbon, what we get is a carbon deuterium bond, and this bond is about six times stronger and compared to that of hydrogen. And as a result, when a chemical reaction happens, whether in a flask or inside the body, this bond is difficult to break. And it is this specific property of the breakage of carbon deuterium bond that will be exploited to see if drug properties can be altered, to come up with new drug molecules, to come up with modified drug molecules that can have more clinical benefit compared to the parent drug, right? Speaker 2 04:11 So the way I think about it again is we know all about different medications that need an extended release formulation. We've had plenty of times that either due to tolerability concerns, or due to a short half life. We say, you know, if we could encapsulate this in a slow release formulation, we could change our kinetic properties and get a better drug with better tolerability, better adherence. What if we could do that again, just with the drug molecule itself? Now, you know, maybe the crushing issues and some of these other formulation issues we don't have to worry about. We just change the drug itself just a little bit. Again, you said we're not producing anything radioactive here. Nobody's glowing from the use of it, but we can create a new drug, a slower release drug, again, with one step, instead of through the formulation process. Dr. Khyati Patel 04:56 And that was a wonderful explanation about how the mouse. Molecule in itself is heavy, and that makes sense. Why the title is, let's get heavy. Speaker 2 05:05 So I guess my question is, is, is there, are there any negatives? Is it possible that by deuterating a drug could be changed again, as you said, it's very similar, but since hydrogen bonds are important, is there any negative could some drugs become less effect it could there be problems. Let's say we were to expand this to every drug on the market and say, let's come up with do again, do duloxetine, or something like that, for example. Speaker 1 05:29 So I think what we should do here first is basically see how this carbon deuterium bond can be exploited with a couple of examples. And the way we can go about it is first understanding some pharmacokinetic principles that are associated with drug metabolism. So whenever a drug, a normal drug, goes into the body, there are primarily these cytochrome P450 class of enzymes that are responsible for breaking down this drug. They generally do it through what is referred to as phase one metabolism, where there is some kind of oxidation or a dehydrogenation process. And I'm re emphasizing the word dehydrogenation process, that is part of breaking down the molecule so that either it is made inactive or more water soluble and can be eliminated into the body. So for drugs where this carbon hydrogen bond is susceptible to be broken down by these CYP enzymes, cytochrome P450 enzymes, if we exploit this feature of the carbon deuterium bond, which is six times stronger, we could basically prevent that particular molecule from breaking down that easily in the body, and as a result, we can increase the half life of the drug, prolong the drugs residents in the body for a longer period of time. And basically, in turn, this could lead to a smaller amount of drug that will need to be administered. The drug load in the body can be reduced, or we may have to give the drug at a much lower frequency. So this is the basic principle that most of the companies that are trying to use this approach of deuterium exchange are trying to exploit to see if they can alter the pharmacokinetic properties of the drug. Dr. Sean Kane 07:15 So then, if I understand correctly, we're basically targeting the site of metabolism for that drug. So in thinking about which hydrogen do we want to have heavy we probably want to target the aspect of the drug molecule that is metabolized or is chemically altered. Then it doesn't have to be every single hydrogen on it. It's just the one that is the most common site of metabolism, absolutely. Speaker 1 07:38 And this is the primary reason why this deuterium approach is more feasible with molecules that are already on the market, because the drugs that are on the market, we have a good understanding of their pharmacokinetic profile. We know the kind of metabolites they produce and how cytochrome P450 enzymes are involved in their breakdown. So it is this this approach cannot be applied to all molecules. It's only certain molecules that are susceptible to that carbon hydrogen breakdown are the ones that would benefit from this particular approach. And now, with that background talking about, does this have any negative effects, from a body perspective, pharmacology perspective, we have to understand that these molecules basically are targeting the same receptor. We are not changing the molecules in any significant way. The drug receptor interactions are going to be similar. And as I had stated earlier, the physiochemical properties associated with deuterium are not very different, the pKa, the lipophilicity, the hydrophobicity and all these different aspects are not very different compared to that of hydrogen, also in terms of size, even though this is two times heavier in terms of its physical bulk size, deuterium is not very different from hydrogen as well, and these together basically make the molecule look exactly similar to the receptor to the receptor as the non deuterated version of it, and as a result, we can expect that the molecule will not have any different interaction with the receptor. Having said that, since we are basically altering the pharmacokinetic profile of the molecule through this deuterium exchange, the nature of the metabolites that will be formed in the body can alter significantly in this process, sometimes we may have a completely different metabolic profile because of this deuterium exchange. There will be shift of metabolism. Some different enzymes may get involved, and as a result, what is more important is to understand how the metabolic profile of this molecule has changed because of deuterium Exchange, which, in turn, can have some effects. With regards to efficacy, we may have an active metabolite that may stay longer in the body, or we may have some new metabolite that could be generated because of metabolic shift that can have side effects. So those are the things that we don't understand. And until clinical studies are carried out to characterize this, it's difficult to predict that outcome, Dr. Khyati Patel 10:06 so obviously, efficacy and and perhaps the tolerability of the drug would change based on the metabolites. But the bottom line over here is that is this process toxic? Can they can an outright cause systemic toxicity, Speaker 2 10:21 and it does seem that, from the studies with this drug with deutetrabenazine, it has not shown systemic toxicity with it again, which is good, because in this case, it's not theoretical. The drug is, is already on the market. And then, just to reiterate, Dr. deshmukhs mentioning about the metabolic shift is it can be variable. The one thing to be clear is it doesn't lead to the production of a new metabolite. But if, for example, a drug, usually 70% of it becomes metabolite a, through that phase I metabolism, 30% becomes metabolite B, that reversal may be shifted, because energetically, one may be preferred. So you have to be aware that shifting could occur. And I believe in some cases that could be a good thing is there's, a number of drugs we do have on the market that there's concern for, maybe a toxic metabolite. And so maybe another way to look at it is, what if, in some ways, not only can we just make it, you know, from too neutral to too neutral, but what if they're, what if we're shuttling it away from a toxic metabolite and towards a either beneficial or a neutral one? So maybe we can actually make a drug more safe this way, again, if we choose the right hydrogen bonds to adjust. Speaker 1 11:27 And I completely agree with that. And that's basically the primary idea of how, of seeing how we can modify these molecules to achieve these exact same outcomes. The only downside here is it's the human body. Human body is one of the most fascinating creations, and our bodies can always behave very, very differently to chemical structure, and as a result, as much as we understand the science behind it, it is really difficult to predict whether these shifts will happen and whether we can get a more safe molecule if we can reduce the toxic metabolites associated with it, but that's the primary goal. Let me get back to that example that you mentioned about tetrabenazine and talk a little bit about more. So this particular drug, from a chemistry perspective, it has an aromatic ring, which is a benzene ring, and it has two methoxy groups that are attached to that particular aromatic ring. And the deuterated version of this is where the methyl CH three group is being replaced by C, d3 where deuterium is replacing the methyl group, and it is the deuterated version of that methyl group. So from a metabolism perspective, this particular drug undergoes phase one metabolism, and the primary approach by which this undergoes metabolism is through a process called as demethylation, where the methyl group is removed from that benzene ring. And this process is primarily driven by the enzyme called as cytochrome, CYP2D6 enzyme. This is a polymorphic form of an enzyme. So CYP2D6 enzyme, as we understand, it, has a lot of variants in bodies. And based on that, people are classified as poor metabolizers, ultra rapid metabolizers and so on. And as a result, the pharmacokinetic properties of this particular molecule depend significantly on the person, himself or herself. And by adding this deuterium, what the company has tried to do is basically somehow reduce the rate of elimination of this drug by the CYP2D6 enzyme, and in turn, this has provided a better control of the pharmacokinetic profile of the drug, resulting in smaller dose that is required to achieve the therapeutic concentration and also the lower frequency of dosing. Right? Speaker 2 13:56 We can go from taking tetrabenazine, which was administered three times a day, and now deutetrabenazine can be given twice a day. And that I know in our population, of my population with there's a lot of cognitive impairment, and, you know, again, we're thinking schizophrenia, bipolar disorder, even different kinds, or, you know, even Huntington's with these is that's a big deal. Is the less you know the pillbox difference in terms of how many times you have somebody coming in and getting you to take the medication, that's a big deal. Speaker 1 14:22 So that's where exactly we are trying to reduce the toxicity of that. To your point, Dr. Patel, you had asked, Are these molecules toxic? So we haven't necessarily altered too many things, but by reducing the drug load associated with this particular molecule, we are being able to reduce the toxic effects of this, which may happen at much higher concentrations. Dr. Khyati Patel 14:44 So one established example is deutetrabenazine. Are there any other examples that uses this technology or drug development process? Well, I Speaker 2 14:53 think first I want to kind of give one example is nevirapine. So kind of an older medication, NNRTI or. Non nucleoside reverse transcriptase inhibitor used in HIV treatment. You know, it's a nasty rash. I remember learning in school the rash and hepatotoxicity can occur as side effects. What they found in, again, this is an animal models the deuterated form cleared faster by kind of showing around this one toxic metabolite and going toward a different, more Preferred Pathway. And so in that case, it seems that you can avoid metabolites that cause rash and Another similar example of efavirenz, another NNRTI, which causes nephrotoxicity in rats, and you shuttle it past that toxic metabolite, you get a more pleasing or less negative effect on the kidneys. And so if you treat HIV positive rats, that's a great way to improve treatments. However, in humans, it's not really something that we've been shown and doesn't really necessary at this point, so it's not really gone further. And I Dr. Sean Kane 15:52 think that probably highlights some of the trepidation and using animal studies, knowing that we may have a different metabolic profile for these drugs that you'd see in a rat versus in a human. As we start playing around with how the drug is actually metabolized, there may be a big difference in an animal model versus in a human Speaker 1 16:10 model, and if I may add on that same point and talk a little bit about pipeline, but that's again true that whenever pharmaceutical companies do drug studies in animal models, they may get a very different profile when they go into the human studies, the phase one, phase two, phase three studies, and that's, again, always an unknown. More often than not, we have some good idea, but that is always an unknown that can trip a program or cause things that are completely unexpected. Having said that since Dr. Schuman mentioned about a lot of the drugs in the pipeline, what I would like to state here is why there is a desire to follow this particular approach of deuterating the current existing molecules. And is again peaking some interest. We already have one approved drug, but there are more drugs in the pipeline. One primary reason for that to happen is by having this deuterated version. Many of these companies are trying to reduce their cost of pre clinical drug development. Drug development is a very expensive effort. It can cost up to a billion dollars, and as a result, if we have some information about existing drugs on market, we can really significantly cut down on pre clinical studies with this new molecules. With regards to FDA, FDA does consider the deuterated version as a novel chemical entity, and as a result, clinical studies are needed, but the burden of those studies is significantly lower. Another second reason for many companies who are attempting this route of making drugs is to see if they can extend their patent protections. That's one of an important things for many companies that drugs that are on market and who are losing their patent is there any way for these companies to extend their patent protection. And finally, one of the most important reasons, at the end of the day is all the drugs are intended for patients, and one of the goals of this strategy is to see if we can improve patient compliance, improve safety and toxicity of current drugs that are on market. And that's one of the primary drivers of pushing this approach. Dr. Sean Kane 18:22 It's not like this patent extending approach or trying to target, let's say, a more safe chemical entity. This isn't something new, right? We've seen a similar concept in a variety of different ways in the past, right? Speaker 2 18:34 So I think again, in just just in that same realm of Neuropsychiatry, it's been done with taking racemic mixtures like citalopram, and moving it to the purified isomer or S form, s citalopram, which they literally made s citalopram, brilliant, or omeprazole, racenic mixture cleaned up to s, omeprazole. Again, these, these names are brilliant, the way they come up with them. Or you had a Modafinil. And what if we had a mixture in our version? What do you think the name would be? Our Modafinil? Well, if you're a pirate or so our Modafinil, yes, exactly, right. So that's been this. The concepts not new. And I think to go back to your first point, something that's really important is the idea. So they let them, in some of these early studies, is actually, as you said, bypass them to say we're gonna we know that the general material in humans of that initial drug, and so we can bypass some of those initial phases of the studies and move on further into human studies, saving again, millions and millions and millions of dollars that way, almost a sense, sort of fast tracked approach by using A deuterated molecule. So there's some incentive for the companies to then take these molecules and move them through and repurpose them using some of the new information we know about deuteration. Speaker 1 19:50 And actually, thanks for bringing that word about those chiral drugs, the S and the arm form R, form of the drug, if I may add. And made a note of this up. This process is referred to as chiral switching, whereas the drugs are on market, and you learn more about the drugs at some point during the process. It's always a learning phase for drugs that are even on the market. You learn that one form is more superior, it is more potent. One form may lead to toxic effects and so on. And then the idea is that you separate out the more potent form and give that particular form to the patient. And that's what has happened with a lot of different drugs. And the classic example that many of the students that would encounter in their PharmD program is the PPIs proton pump inhibitors. That's the first class of drugs that were really subjected to this test where the S form of the drug or the R form, depending on the specific drug, one was found to be better. And the best example that we have, which has been a spectacular success over the decades, is Nexium, the purple pill, Nexium, the S omeprazole form of this drug. It's the active form of the drug, and it is superior, far more superior compared to the racemic mixture and it's being used. So that same concept, if we can extend it to the deuterium, is being tried out. But there are some major downsides. We said earlier on that pharmaceutical companies definitely have an interest. And Dr. Schuman also mentioned that we can really bring down the costs of drug development. And so on the downside of this process is FDA, the regulatory agency that is monitoring drug development process across the board. They are concerned that many of these companies are taking this approach primarily to extend their patent life, and as a result, one of the arguments that FDA makes when companies are attempting this approach is, was this effort that you're trying to put in obvious? Is it prior art? Is there an evidence that anybody who has very minimal knowledge of drug development or very basic knowledge? Could they have anticipated that changing the hydrogen to the deuterium will lead to less metabolic breakdown of a molecule. And in that instance, if that has is the case, FDA is very reluctant to allow such companies to pursue this strategy, and for good reason, because once you have a patent protected drug, you have exclusivity on it, and as a result, pharmaceutical companies have to be very careful and vary that you do not want to do. Take this approach only to show extend your patent life, but the aim of this approach should be really to improve the existing class of drug in a meaningful way that is clinically beneficial to the patients. And I'm Speaker 2 22:38 sure you all can think about in your respective fields about the idea we have that negative connotation of the ME TOO drug, as you can think, of different drugs that just come out on the market somewhat arbitrarily, because you want a piece of that that pie for that disease. And I think wanting to avoid going for further with that connotation. Dr. Sean Kane 22:54 So with that in mind, it seems like deutetrabenazine has really set the stage for deuteration and whether it will be a marketing success, knowing that it's on in a very niche market, right? So this kind of Huntington's chorea type indication, right? So are there other drugs that are perhaps further along in the pipeline, that are taking advantage of deterioration for safety, efficacy, or some other reason that we can talk about, Speaker 2 23:18 I think one interesting one that, the one, the first ones I can that came across in reviewing the literature is a deuterated form of Paroxetine. So paroxetine, brand name Paxil, is commonly used for PTSD, depression, anxiety disorders. But there's also some effect that's been used for for management of hot flashes. Well, one of the things they've noted is, by deuterating it, it takes away the drugs ability to inactivate 2D6. One of the big issues we talk about kinetics is those drug drug interactions as well. And so again, in this case, they discover that if you deuterate it, it can't cause those interactions with other medications. And so maybe, you know, interactions with opioids or a lot of these other really important medications we use, if you could take away those drug drug interactions in the human body, you know, maybe it makes these drugs a little bit safer for use. And that was one that was in phase one studies in 2014 Unfortunately, nothing on clinical trials.gov. It seems to have somewhat disappeared in the literature. So I'm not quite sure where that one's at in the status, but that's one example. So another example, and one that's newer, is called Nuedexta. This is a combination of dextromethorphan and quinidine, which is used the only thing it's approved for pseudobulbar affect so you know some individual who has inappropriate laughter or crying in a situation where that's not the appropriate response, somewhat of a niche market, but it's being used in other indications. And what's interesting is, in that case, they use quinidine, again, to inhibit 2D6. And so the goal there was, by using quinidine, they can prolong the amount of dextromethorphan that's available fewer times, giving it more consistent profile. What they found there is, by deuterating the dextromethorphan, it allows for lower doses of the quinidine. Because. They can stabilize the dextromethorphan so it has a longer half life on its own. And so again, since quinidine, by using it deliberately to inhibit 2D6, you're opening yourself up to a whole host of drug, drug interactions, and you know, increasing levels of any other drug metabolized by 2D6. So in this case, by extending the half life of it a totally different way, fewer other drug interactions. And so that's a medication right now. They call it AVP, 786, in Nuedexta, the quinidine dose was 10 milligrams. It's kind of considered exclusive information, so I can't find the dose, but I would imagine it's going to be much, much smaller. And what's interesting too, is they've got this drug in the pipeline, not just for that pseudo bulb or affect, which is a somewhat narrow diagnosis. I've seen very infrequent use of this drug, but they've got it in phase three. And so again, they were able to completely skip phase two studies by the by this fast tracking process, they went from phase one and healthy subjects all the way to phase three using the existing, Nuedexta phase two studies, and now they're studying it for Alzheimer's dementia and again. So if, if that becomes this, if that's the second drug that's deuterated and approved, that's a major, major market share right there for the company, as well as, again, another win in avoiding some of these drug interactions. Speaker 1 26:19 So Dr. Schuman talked about some successes and drugs that are in the pipeline. But at this point, I would also like to add that this is not a slam dunk approach. This approach of deuterating drugs may not be a win win in all respects. And there's a company, actually. It's called concert pharmaceuticals. And this company is primarily come into existence, basically to make deuterated molecules, repurpose the existing molecules, make it into a deuterated form, and then try to gain some markets or some benefits associated with it. But they had a major failure in the recent past. They're one of their drugs that was intended for diabetic neuropathy. It's called CTP 499, and this drug had a significant clinical trial failure. It just did not make it so. Again, as much as there is a committed effort on part of these companies to come up with novel ideas, it's not guaranteed, and that the drug will always make it through and get through the clinical trials. And this also brings us to another important point, that FDA as a regulatory authority, it is important that as much as these drugs are supposed to be very, very similar to the original drugs, it is important that these clinical studies be truly carried out, so we have evidence based medicine as the way to go forward and ensure that these are just not novel drugs, but drugs that are truly clinically beneficial for the patients. Dr. Sean Kane 27:46 And I think again, in terms of a take home point, as you mentioned in the beginning, when a drug molecule is deuterated, like you said, they're actually submitting an NDA, a new drug application. It's not as if they're coming up with something that they can use the original NDA for, right? Speaker 1 28:03 So it's not basically a reformulation. Reformulations are generally ANDAs, where you have an abbreviated NDA is what it is referred to. But this is definitely from FDA perspective. It's considered as a novel chemical entity, even though it's exactly similar to the original drug, but just deuteration, and as a result, the whole process of FDA approval has to be followed. The only advantage here is you can eliminate some of the earlier studies, and depending on the evidence that you generate in your Phase One studies, you may be able to have a shorter version of a phase two and a phase three clinical trial, Dr. Khyati Patel 28:42 but nonetheless, they still have to improve the efficacy and patient safety in these trials, absolutely. Speaker 1 28:48 And another thing as we talk about some point, Dr. Kane mentioned about market share and success of the drugs, one thing that we have to be aware of is in this era of evidence based medicine, where the payers are equally important part and in the healthcare system that even though a company may have a drug and there might be enough evidence to say that this drug is patentable and has been approved by FDA, the payers and the healthcare system truly needs to see the evidence, not just from A clinical benefit, but a pharmaco economic benefit that are you charging a price for the drug, and does it give that overall benefit of the drug that is going to be significant above and beyond the current drugs and medications that are on market? So the pharmaco economic evaluation becomes another integral part of this new approach to drug development, and it is important that all parties involved right from patients who eventually have to pay for those medications, the insurance companies, the payers, all of them, are on board in terms of the benefit of this drug. Dr. Sean Kane 29:55 So Dr. Deshmukh, that's a lot of really interesting points. Maybe. Dr. Schuman, you could just throw one. More example at us in terms of where we may be seeing deuteration in the future as well. Speaker 2 30:04 So another one is a medication that, in the realm of mental health is been thrown around and around for a number of years. Is venlafaxine. So we think, Oh no, that one again. But do if there's a deuterated form right now, I think it's only known as SD 254, that's currently being studied. And the rationale here is to avoid all the complex metabolic pathways, and something I didn't realize until preparing for this, but venlafaxine has over 48 different metabolites it forms. And so the goal would be is, again, if you could refine some of those bonds and kind of filter it so you've got all these pathways, but what if we could kind of close off a number of those pathways and create just one desired pathway and create a drug with a longer half life and maybe a more established as far as the active metabolite, I Speaker 3 30:46 think we have an answer over here. They already have desvenlafaxine right now, that one Speaker 2 30:49 that's and that's a great point. We already have desvenlafaxine, and we even have extended release venlafaxine. So we have active metabolites. You know, O-desmethyl venlafaxine is the metabolite, and they just cleaned up the name and made it desvenlafaxine. And then we've got extended release Effexor XR, so we've already got them. Do we need another form of it? I think that goes back, Dr. Deshmukh, what you're saying about, again, not getting in this, me too, but establishing Is there really a need for and so I think that's going to be the question here. Is, if we do change the relative amounts of these different metabolites. Will that change safety? Will that change efficacy? What change any clinically meaningful outcomes again? Or is this just another money grab? And I think that's something, as you said, from a payer perspective, you need to be intimately aware of. Dr. Sean Kane 31:34 So I think that nicely summarizes the topic of deuteration and kind of where the market is going from this fairly niche drug of deutetrabenazine, all the way to potentially some of these more blockbuster Nexium esque drugs that we may see in the future. Then. So what are some key concepts that you got out of today's discussion? Dr. Khyati Patel 31:54 Well, I definitely learned that, you know, the deuteration is not a new concept in medicine. You know, has been tried and discussed for decades, and the very first approved medication was deutetrabenazine that became available in 2017 after the FDA approval. Speaker 1 32:10 So from a chemistry perspective, I would say again, as this is not a new concept, but the primary goal of this approach is basically to exploit the carbon deuterium strength for a chemical bond, and see if that can be used to alter the metabolic profile, and in turn, impact the pharmacokinetic and eventually the pharmacodynamic outcome of these drugs. Dr. Sean Kane 32:33 And again, with respect to that, we have to be cognizant that changing how it gets metabolized can change the percent of a given metabolite, it can completely shut off a metabolite. It can change how it maybe has a drug, drug or an action. And unfortunately, animal models may not give us a full picture. We have to have those human studies to have a good concept of what the implications of that change will be. Speaker 2 32:56 And lastly, what we did is we looked forward into the pipeline. And so there's a number of these medications, which drugs that also undergo deuteration in some form, a deuterated form of dextromethorphan in combination with quinidine for Alzheimer's dementia, a deuterated form of paroxetine for hot flashes, as well as venlafaxine in a deuterated form. And then two we didn't discuss in detail, but audience can look out for pioglitazone, a deuterated form for diabetes, and then also a deuterated form of polyunsaturated fatty acids to extend the half life there, and looking again for Parkinson's and dementia seems to be a common target for a lot of these medications. Dr. Sean Kane 33:34 So with that, if you want to read some of the key concepts or references, check us out at HelixTalk.com this is episode 82 we love the five star reviews in iTunes. We love the comments that you provide to help us understand what kinds of episodes you'd like to hear. So with that, I'm Dr Speaker 1 33:50 Kane, I'm Dr. Schuman, I'm Dr. aldeshmukh, Dr. Khyati Patel 33:53 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 33:57 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store, search for HelixTalk and place your review there Narrator - ? 34:08 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.