Veterinary Vertex
Veterinary Vertex is a weekly podcast that takes you behind the scenes of the clinical and research discoveries published in the Journal of the American Veterinary Medical Association (JAVMA) and the American Journal of Veterinary Research (AJVR). Tune in to learn about cutting-edge veterinary research and gain in-depth insights you won’t find anywhere else. Come away with knowledge you can put to use in your own practice – along with a healthy dose of inspiration to remind you what you love about veterinary medicine.
Veterinary Vertex
Navigating Bioequivalence: Why Formulation Matters for Emodepside Treatment
When traditional dewormers fail against resistant hookworms, veterinarians may turn to emodepside as a last resort. But are all formulations created equal? Not according to recently published research.
Join us as Theresa Quintana and Drs. Jeba Jesudoss Chelladurai and Stephanie Martinez reveal critical findings about bioequivalence between different emodepside formulations. Their research demonstrates that the feline topical formulation, when given orally to dogs at 3 mg/kg, produces approximately three times higher peak concentrations and 2.4-2.8 times greater systemic exposure compared to the EU canine modified-release tablet at the same dose.
These findings carry significant clinical implications, particularly for dogs with MDR1 mutations lacking P-glycoprotein transport mechanisms. Without this protective system, emodepside can accumulate in the brain and cause neurotoxicity. The research team guides us through proper diagnostic confirmation of resistant hookworms, recommended treatment approaches, and crucial safety considerations before turning to this last-line therapy.
The conversation expands into formulation differences, bioavailability challenges, and practical clinical protocols. Teresa, Jeba, and Stephanie emphasize that clients must follow strict fasting guidelines before and after administration, as food dramatically enhances emodepside absorption and could potentially lead to toxicity with the already higher-concentration feline product.
Whether you're dealing with suspected resistant hookworms in your practice or simply want to understand the science behind bioequivalence and drug safety, this episode provides essential knowledge for evidence-based clinical decision-making. This episode centers around the intersection of parasitology, pharmacology, and clinical medicine and highlights why the details matter when it comes to drug formulations and routes of administration.
AJVR article: https://doi.org/10.2460/ajvr.25.01.0027
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Speaker 2:This is Veterinary Vertex, a podcast of the AVMA Journals. In this episode, we chat about how topical and oral emodefside formulations for last-line treatment of multi and homotic drug-resistant hookworms, when given orally to dogs, are not bioequivalent with our guests Teresa Quintana, Jeeva Jaecidos, Chela Dore and Stephanie Martinez.
Speaker 3:Welcome listeners. I'm Editor-in-Chief Lisa Fourier, and I'm joined by Associate Editor Sarah Wright, teresa, jeba and Stephanie. Thank you so much for taking time out to be with us here today. Thank you for having us Thanks for inviting us.
Speaker 2:Yes, all right, let's dive right in. So, jeba, your AJVR article provides critical pharmacokinetic data on amodepside in dogs, highlighting significant differences in systemic exposure between formulations and routes of administration. Please share with our listeners the background on this article.
Speaker 4:Emodepside is this new drug class of antiparasitics that is called the octadepsypeptide. It was first patented in 2001 for nematodes of animals. It is a wholly different mechanism of action compared to the other drug class that we have on the market, so currently it is available as a broad-spectrum antihelminthic and it is used for the treatment of parasitic nematodes in dogs and cats, especially in Europe, where there are two products that are available. It has also recently been used to treat Onchocerca in humans, although in the US we only have a cat product that is applied topically. So there is a European formulation for dogs, which we do not have in the US, and that is where our story begins.
Speaker 2:Yeah, I learned a lot through reading your manuscripts. So, Teresa, what are the important take-home messages from this HABR article?
Speaker 6:Yeah. So I think formulation and route of administration really matter. So, teresa, what are the important take-home messages from this HABR article? Mg per kg. It led to significantly higher plasma concentrations compared to that EU canine modified release tablet at that same dose, a mg per kg. So specifically, we saw that the Cmax, or peak concentration, was approximately three times higher and the AUC, or the total systemic exposure, was 2.4 to 2.8 times greater.
Speaker 6:So this kind of indicates that these two formulations are not bioequivalent.
Speaker 6:The title of our article, as defined by the FDA, bioequivalence, means that two products are equally bioavailable, meaning equal in the rate and extent to which the active ingredient is absorbed and then becomes available at the site of the drug action. So this is really important because bioequivalence is the standard used by the FDA to determine whether a generic or alternative formulation can be expected to have the same clinical efficacy and safety profile as that original or reference product you're testing against. So in our case that's the EU modified release tablet. So if the do products aren't bioequivalent, we can't actually assume that they'll behave the same or have the same safety margins. And then so that brings us to safety. So imidexide is a P-glycoprotein or PGP substrate which is particularly important for dogs with NDR1 mutations. So these dogs lack a functioning PGP transporter, which normally keeps certain drugs out of the brain, and so, without it, drugs like emodepside can accumulate and cause neurotoxicity. So since we don't have an approved canine emodepside product here in the US, any off-label use of this feline topical formulation should be approached with caution.
Speaker 3:Yeah, really outstanding points that you highlighted from your article. So thank you for that really clear take-home message. Jeba, what sparked your research interest in this topic?
Speaker 4:So we first became interested in emodebsside because there was a study published in 2020 by our parasitology colleagues from the University of Georgia.
Speaker 4:In that study, Dr Jimenez-Castro and colleagues were working with resistant hookworms.
Speaker 4:Very specifically, they had isolated a hookworm from a greyhound and in control testing in their lab they found that this hookworm was multi-anthelmetic resistant, so it was resistant to fenbendazole, pyranthopamide and milbimicin oxime, and the only drug that worked in their trials was imodepside. So imodepside in that study had 99.6% efficacy and following that study they had sort of written this article in Clinician's Brief that suggested that in the case of multiple anthihelminthic resistance, Imodepcide could be used potentially to treat dogs that are infected. And now the only problem that has been that we don't know if a given dog that is brought to a veterinary clinic has hookworms that are resistant to all the different drug classes that are available on the market. And so that's where our interest in Imodev site sparked, because people read that article and they would then go and purchase this product and give it extra label. So they were giving the cat product, which is meant for topical use orally to dogs, and really that's what sparked my interest, because I was concerned about safety in all these different dogs that were being treated this way.
Speaker 3:Yeah, I can see why that would happen. Stephanie, we heard from Teresa some probably surprising findings, I would think based on Teresa's expression and her tone like, ooh, the area under the curve and the PK and all those things. But what did you find the most surprising thing from this article?
Speaker 5:Well, Truly, I expected that we were going to find overall higher concentrations when we gave the topical feline product orally to the dogs. Just because it's solubilized, it has accelerants like alcohols in it, as opposed to the EU formulation which is modified release and is going to require dissolution in order for it to be solubilized and be absorbed. I just did not know, or I was surprised. I guess that it was about threefold higher concentrations and I think just the magnitude difference for me was surprising. I was simply just not expecting it. And then, similarly, when we did give the topical formulation topically to the dogs, we had incredibly low concentrations and I suspected, just because of the physiological differences between skin for cats and dogs, I suspected it was not going to be as high, but I did not think it would be quite as low as we found. So I think just the magnitude was ultimately the between routes was quite surprising.
Speaker 3:Yeah, that actually speaks to safety as well.
Speaker 5:right, Like you know, we often think of safety as avoiding adverse events, but if the drug isn't being delivered and doesn't work, that's a safety issue as well, and I think it's a really great reminder for our veterinary community that, just you know, giving the same drug at the same dose with different formulations does not guarantee the same effect, and I think that's just sometimes we forget, and so it's a really great reminder. Yeah, excellent points.
Speaker 2:I come from the zoo world, where things often are, you know, extra label use trying to find indications of certain species, so always good information to keep in mind. So, teresa, what are next steps for research in this topic?
Speaker 6:Yeah, great question. So I think if a canine FDA-approved imidapside product remains unavailable here in the US and we continue to rely on this extra label use of the feline topical formulation as just kind of this last line treatment for these multi-antelmetic drug-resistant hookworms, then the next critical step would be to investigate whether lower doses of the feline topical product can achieve bioequivalence to the EUK9 product, and then ideally we would pair that with some clinical efficacy studies against multi-antelmetic drug-resistant hookworms to ensure it's both effective and safe for use in dogs. Very cool.
Speaker 2:Now this next question deals with AI, which is definitely a super interesting topic in veterinary medicine and for our listeners. If you haven't already, you should definitely read our new AJBR AI Supplemental Issue Artificial Intelligence in Veterinary Medicine from Barks to Bites. So, jeeva, do you see a role for AI in this area of?
Speaker 4:research. So in specifically pharmacokinetic research, in terms of how we did our study, probably not, although I would caution veterinarians and because I teach vet students, I caution them all the time about, you know, ethical use of AI, but also making sure that AI is accurate and what it is saying when it comes to diagnosis and treatment of our patients, because in some models of AI they're always not the most accurate. So, especially with extra label drug use like this, that's where my only caution is, especially with extra label drug use like this. That's where my only caution is. But in terms of research, I know it's coming. I unfortunately haven't quite read your AJBR article yet, but right now, in the pharmacokinetic aspects of the research, like we did it, I don't see a role for AI yet.
Speaker 3:Yeah, in the journals, what we do. I update our AI policies for lack of a better word quarterly because, as Sarah said, it's so rapidly evolving it's hard to keep up. But right now I rejected a manuscript. At least 75% of the references were fake, like completely fake, so you could tell that these authors one. I'm not sure that the whole manuscript wasn't faked, but we have programs that our copy editors run through everything to know so they can reformat the references and they get flagged like this isn't real. So I wrote back to the authors and I was like rejected flat out and please don't submit to us again. Because even if you did use AI and asked it to generate references, you should, and asked it to generate references, you should check them right.
Speaker 3:So just be you know, again, it has a great role. It's really tricky in scientific writing, and don't forget, too, anybody who does upload their information to AI. You don't know where that goes. So if you put your research article or your data into AI and ask it to interpret it, you've just lost control of it.
Speaker 4:Right. A long time ago some IT expert told me if the product is free to you, then you are the product. I've always taken that to heart.
Speaker 3:True Copyright's an issue.
Speaker 2:Yep, nothing's truly free. And for those of you just joining us, we're discussing how topical and oral imodepside formulations for last-line treatment of multi-anhylmetic drug-resistant hookworms, when given orally to dogs, are not bioequivalent with our guests Teresa Jeeva and Stephanie. So Jeeva, how did your training or previous work prepare you to write this article?
Speaker 4:Yeah, so I'm a veterinarian who trained in India. I got my advanced training in veterinary parasitology in the US and for my PhD I worked on toxic caracanis, the common dog ground worm. I worked on MDR-1, which is also known as PGP, and my special interest has been in drug-resistant hookworms. So when the hookworm resistance issues came around in 2019 and 2020, I was almost immediately interested. At the same time, I was starting as an assistant professor at Kansas State University, so I built my research program around resistance, identifying knowledge gaps that then I could fill. So this was a knowledge gap that I identified almost immediately because of safety issues. Because of safety issues, one, it triggered my PGP bells because Imodepside is a PGP substrate and in dogs that are mutant for MDR1, it could potentially cause neurological signs and it will cause neurological signs and so this kind of tied in my interests in pharmacology, zoonotic nematodes and then definitely the MDR1 piece.
Speaker 3:Yeah, really great. We like to ask this question of everybody, because veterinary medicine is such a fabulous career and you can go in a lot of different directions. So, stephanie, how about you? How did your training help you write this article?
Speaker 5:So my PhD training focused on bioanalytical method development, pharmacokinetics and regulatory science, which is the foundation of this work. And then during my postdoc at the Program for Individualized Medicine at Washington State University's vet school, I gained a lot of hands-on experience conducting pharmacokinetic studies in client-owned dogs, which helped us with our recruiting at Kansas State. And then really through my entire career, from undergraduate until even now as an assistant professor at Utah State University's brand new vet school, I've been partnering with veterinarians to really tackle clinically relevant pharmacology questions, which was really kind of shaped how I've approached research like this.
Speaker 3:Fantastic Teresa. How about you Bring it home? How did your training help you write this article?
Speaker 6:Yeah, so as Dr Jeva's PhD student I'm kind of like building on her research with PGPs and toxic caricanis. So that kind of helped me, you know, understand the pharmacological and molecular mechanisms behind are relevant to emidexide. And then I also have a background in animal health regulatory affairs. So that kind of gave me good insight into how formulation, bioequivalence, drug safety, how that's all evaluated of the FDA. I also have my master's in public health and I'm certified in public health. So I think that training helped me like kind of critically assess drug use from a population health and safety perspective and then kind of helped frame that like in a clinical and regulatory implications for off-label use of imidapside in dogs.
Speaker 3:Fantastic, what great diversity and approach and opinion within one problem. That's awesome.
Speaker 2:Now, this next set of questions is going to be very important for our listeners, and the first one is going to deal with the veterinarian's perspective. So, jeba, what is one piece of information the veterinarian should know about? Emodepside in dogs.
Speaker 4:Okay. So veterinarians managing suspected multiple antihelminic drug resistance cases in hook webs should not directly jump to using Imodepside as their first line of treatment. First they should first focus on establishing that the dog that they're dealing with actually has resistant hookworms using properly timed diagnostic tests. Specifically in this case that would be a fecal egg count reduction test that they can perform or get that test done at any diagnostic lab that they work with. After that they should.
Speaker 4:After establishing resistance, they can then use a combination of Drontal Plus, which has Fabantyl Pyrantyl as the two actives that are going to work against the hookworms, and topical moxidectin, either Advantage Multi or Equivalent topical moxidectin, either Advantage Multi or Equivalent, and then, in case of failure with that treatment, again assess through an FECRT. Then they should reach out for this VLAN formulation of Imodevcide. But that should be the last line of treatment and while they do, if they do get to that step, they should exercise caution, making sure that their patient is not MDR1 mutant. And if they have an MDR1 mutant dog they should seek other lines of treatment. So amorepside should really be used as a last line of treatment after making sure that nothing else works. In addition, they should encourage owners to pick up after their animals so that they prevent reinfection, which is very, very important in dealing with hookworm cases.
Speaker 2:Yeah, I'm always surprised how many like dog droppings. I just see like around. I'm like this is such a public health concern, like pick up after your pets, please. It's always wild, but thank you for providing that decision to me too. And on the other side of the relationship, what's one thing that clients should know about this topic?
Speaker 4:So clients should know about this topic. So clients should definitely go to their veterinarians yearly, take their veterinarian's advice, especially as it relates to deworming schedules, and really read through the instructions that their veterinarian provides them or gives them orally, especially as it pertains to products. So there are some products that are monthly and they should be given monthly. There are some products that don't cover hookworms, that are not monthly, and so in that case they should consult with their veterinarians to understand which product their pet is on and, again, as a good owner, they should pick up after their dogs and dispose of the feces properly, because, like I just mentioned, it is a zoonotic parasite, meaning that hookworm larvae can penetrate human skin and cause what is known as cutaneous larval migraines in humans, and so they should be aware of that.
Speaker 5:I might also add and just reiterate what Jeb has said for owners, which is you must follow your veterinarian's written and oral instructions, especially with emodepside, and probably the most important thing for an owner to remember is not to feed your dog overnight. So keep your dog fasted overnight and then do not feed them for at least four hours after administration. So emodepside's absorption is markedly enhanced with food. Modepside's absorption is markedly enhanced with food, and so giving the feline topical formulation off-label, knowing already that we're getting about threefold higher concentrations, you can imagine giving that with food, we would be really concerned about toxicity. So I think again, just following instructions for owners, that's very important.
Speaker 3:I think again, just following instructions for owners. That's very important. Great points, Thank you, guys. This is very interesting. Stirs up lots of other ideas for our journal collections and other things for the One Health side of our veterinary profession. So as we wind down, we'd like to ask some fun facts. So, Jeeba, we'll start with you. What is your favorite animal fact?
Speaker 4:Right. So thank you for that question. So my favorite animal fact, which I think is really cute, is sea otters often hold hands while they sleep. This behavior is known as rafting, and because they spend so much of their time in water, they want to prevent, you know, floating away while they're at sea. So they often sleep either entangling themselves in kelp forest or by holding hands, and it's a good way to prevent drifting away from the group. That's adorable. It's cute to see as well.
Speaker 3:Teresa on a different subject. When you complete a puzzle, do you do the border exterior pieces or do you start with a color or a theme in the inside?
Speaker 6:So I do start with the border exterior and that's because I need like a satisfying sense of progress right away to keep going to finish.
Speaker 3:Yeah, same with me. I need some structure to get me going. Stephanie, on a different subject, what was the first concert you attended?
Speaker 5:That's a good question. I have a very eclectic taste and this is probably going to age me, but I went to a Weezer concert, so a rock band from the 90s.
Speaker 2:But yeah, that's awesome, they're actually coming back to Chicago in September, I believe.
Speaker 5:So I was actually looking at going yeah, it's a great show, they're a great band, so let's get to here.
Speaker 2:Thank you, and just thank you all again for being here today, for submitting your manuscript to AJBR and for sharing the findings with our listeners.
Speaker 5:Thank you, yeah, thank you again for having us, yeah.
Speaker 2:And to our listeners. You can read Teresa Jeeva's and Stephanie's article on AJBR. I'm Sarah Wright with Lisa Fortier. Be on the lookout for next week's episode and don't forget to leave us a rating and review on Apple Podcasts or whatever platform you listen to.
