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 is Narrator - ? 00:12 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. Speaker 1 00:31 Welcome to HelixTalk. Episode 163 I'm your co host, Dr. Kane, I'm Dr. Patel, and we're excited to have a guest podcast host with us today. Dr. Katie Cunningham, Dr. Cunningham, maybe you could introduce yourself and just tell the audience a little bit about who you are and why you're here today. Speaker 2 00:49 Yes, thank you so much for having me today. I'm really excited to be here. I am one of the clinical faculty members at RFU. I practice at Northwestern Memorial Hospital in solid organ transplant. So I work on mostly the abdominal transplant team, but also have been a part of the lung transplant team as well. Speaker 1 01:08 We'll get more into your credentials in just a second. But of course, we need to tell the audience the title of today's episode, which is the two drug tango, a concise guide to tacrolimus and mycophenolate and organ transplantation. And before we get into the episode, I did want to mention that HelixTalk episode 162 which went live a couple weeks ago, that has a continuing education one hour of CE credit. So if you're a pharmacist and and you would like some CE credit, there's still time to do that. It will be open for a year since it was published, but you might as well take advantage of that now. So again, Episode 162 for a $5 fee, you can get an hour CE for that episode. So Doctor Cunningham, we, we've invited you today, clearly, for a transplant topic. What is it about April that makes this month a particularly notable month to have a transplant topic? Speaker 2 01:58 Yes, April is Donate Life Month. So it's really exciting nationally as we strive to get more people to be organ donors and register to be organ donors and raise awareness and honor those that that have donated and those that have received an organ transplantation. But really, you know, for all the organ donors out there, Speaker 1 02:18 as you mentioned earlier, you're involved in transplant, could you just tell the audience a little bit about your background in terms of how you got to the position Speaker 2 02:25 that you have today? Yeah, so I went to pharmacy school at UIC, and while I was on rotation there on the hepatology service, is when I was really introduced to transplant, and I just found that the pharmacist's role and involvement in the team was something that I had never thought existed. So then I went on to do my PGY one at Rush University Medical Center in Chicago, and did a rotation on the transplant team there. And that's when it solidified that I knew that that was what I wanted to do. And so then I went to do my PGY two and transplant up at the University of Wisconsin in Madison. I was drawn up there because they did all the organ types for transplant. So I spent a year up there, and then came back to Chicago at Northwestern and I started there back in 2014 and that's actually when we started our lung transplant program. So I was part of the inception of that and the growth of that program, which has made a lot of national headlines as we were the first institution in the United States to perform a transplant on a covid patient, and our numbers have just continued to grow. And then in 2017 I was lucky enough to have the opportunity to join RFU as clinical faculty. It wasn't something I ever thought was possible for a transplant pharmacist, but we do play a huge role in managing internal medicine type of disease states with our patient population. So I lecture a lot on other medicine related topics at the university, and it's really allowed me the opportunity to grow my career in a different way than I thought was possible, Dr. Khyati Patel 04:03 kind of setting the stage for, you know, what you do and why we are here to talk about transplant. Let's talk some numbers. These numbers are coming directly from organ donor.gov in the US, there's about 100,000 people they're in need of transplant. So we call this the, you know, waiting list, and about 60,000 of these patients are quote, unquote, active on the waiting list. Obviously, a lot of these are for kidney transplant, yes. Speaker 2 04:29 And one thing to note is that one organ donor can actually save up to eight lives and potentially enhance the lives of 75 more from one organ donor you can have, you can transplant one heart. There are two lungs. Sometimes we do single lung transplants, and some patients will need both lungs. There's one liver, there's one pancreas, two kidneys. And then some centers do do intestinal transplants as well. And we do about 40,000 transplants in the United States each. Year, with the majority being kidneys. Now. Speaker 1 05:02 Dr. Cunningham, one thing that I read about was that there has been an increase in the number of deceased donor transplants over the last couple of years. Can you maybe expand on that a little bit? Speaker 2 05:13 Yes, there's always, we are always looking for ways to increase the number of transplants, just because we know, based on those numbers, there are so many patients out there that are waiting for a transplant, and a lot of patients, unfortunately, do pass away while they are on the waiting list. The United Network of Organ Sharing will do different redistricting of regions to try to make things more equitable of where organs are being placed. We try to remove barriers for potential living donors, so that there's more opportunity for patients to donate one of their kidneys or even part of their liver to another patient. And then one big thing that's happened over the last five years or so was starting to transplant patients that have active hepatitis C. So the donor passed away with hepatitis C. So we know that we are, in fact, transmitting that virus to the organ recipient. But because of the new drugs that are out there that you've probably seen commercials for, because there are a lot of them, we can essentially cure that hepatitis C virus post transplant. So that has expanded our donor pool. Additionally, there's something called the Hope Act, where we've started transplanting HIV positive patients organs into HIV positive recipients. So that's another really exciting field that probably has much more room to grow. Speaker 1 06:34 Dr. Cunningham, so as people are listening to this episode, how do they either know that they're an organ donor, or how do they actually become an organ donor? Encourage other people to become organ donors, to help expand the availability of these organs when they pass away. Speaker 2 06:49 Yes, thank you for asking about that. I think most people think about it as being at the DMV, and that's where you sign up to be an organ donor, which you can but it's also much simpler than that, you can actually go to organ donor.gov each state has their own separate registration, but that website will let you connect to any individual state that you live in, and very simply, you can sign up to be an organ donor. You usually do have to put your driver's license or state ID number in with that, but it's a fairly simple process, but I think the other really important thing that goes along with that is making sure that your family knows that that's your wish. Because you know, in moments of crisis and grief, it's hard to process things such as, you know a family member passing away, but if your family member knows that that's ultimately what you want. It eases that process for them, and I Speaker 1 07:45 think that's so important for the listeners to hear and to think about in terms of organs. You mentioned the kinds of organs that are typically donated. One thing that I thought was interesting is that by far, like almost half of organ transplants are kidney transplants, and obviously we still do livers, hearts, a pancreas and lungs, but kidneys are by far the most common, right? Speaker 2 08:05 That's correct. Yeah, we do at Northwestern we're on track to do potentially up to 400 kidney transplants this year. Usually we do around 250 or so. And, you know, we also do combined transplants, a lot of them will be in combination with the kidney. So we'll do a liver and a kidney transplant together, a pancreas and kidney transplant, heart, kidney, lung, kidney, lung, liver, heart, liver, kind of any combination that you can think of. A lot of the surgeons out there have have Dr. Khyati Patel 08:34 done it. That is very neat to know. And I think something to know as well as there is living donor versus the disease donor based on the organ that's being transplanted. So, for example, kidney and liver can be both living donors. As we know, liver is kind of like the only organ that can regenerate. So it's possible to do donation out of a living donor. Speaker 2 08:55 Yeah, it's pretty incredible for the liver donors. It's a very invasive and significant operation, but the recipients and the donors do very well. The benefit for receiving a living donor liver transplant is that patients aren't necessarily as sick at the time of transplant as if they were waiting for a deceased donor or liver transplant and then kidneys, since you have two kidneys, you can live with just one. So you can donate one of your kidneys to, you know, a family or friend. And you know, one other thing I think that's really interesting is, even if you're not a match for, potentially, a family member or a friend, we do a lot of swaps where we can find another pair that maybe you're a match for and you can, you can swap your kidneys. And then really fun is that we'll have then sometimes all of those people meet together once everyone's home from the hospital and they can meet who their actual organ donor was. Speaker 1 09:54 That's very neat. And you know, we're focusing on organs, but tissues are also things that can be donated. It as well. Can you kind of describe what some of these less common tissues or other organs are? Speaker 2 10:05 Yeah, I think we kind of overlook this a lot when we talk about organ transplantation. But corneas are huge for transplant. Heart valves can be transplanted. A lot of bone and tissue and cartilage, tendons, ligaments, you know, things to help, you know, obviously, restore sight with a cornea transplant, help with covering burns and then fixing, you know, damaged connective tissues. And then, I think the most fascinating thing that's really come you know, more recently is uterine transplant. This is a very, very new field. We have not done this at Northwestern but there was a baby that was born from uterine transplant in the United States in 2017 Speaker 1 10:48 that's pretty crazy. And of course, in addition to these tissues and organs, you know, we're focusing on solid organ transplant, but other things can also be donated that are more for hematologic malignancies. So what are typical scenarios for that? Speaker 2 11:04 So patients that, yeah, they you can be a bone marrow transplant donor, which, you know, is just, usually just a cheek swab. I know that we've done a drive, I believe, here at RFU in the past, and you stay on that registry kind of forever in order to, you know, give patients that have potential blood type of cancers, an opportunity to have a cure. Dr. Khyati Patel 11:26 And just the audience knows this is a separate registry than the organ donor.gov. So this, this one for the marrow transplant. The registry is a little bit different. Speaker 1 11:37 So Dr. Cunningham, kind of, in celebration of April being Donate Life Month, we thought that really the focus of today's episode would be for the listener who isn't directly involved in transplant care, per se, but may encounter patients that have received solid organ transplants in the past, and then kind of clinical pearls and pitfalls related to their immunosuppression regimen. So the main three questions that we're going to be answering today are, why is it that we can't just use a one drug regimen, but oftentimes we have multiple drugs for immunosuppression? What are some of those clinical pearls and pitfalls of that regimen? And then, how do we determine the intensity? So anyone who's encountered a patient on tacrolimus in the hospital, for example, knows that we can get levels and different patients have different goal levels and things like that. Some patients are on three drug regimens or two drug regimens. What are some of the factors involved in the decision points of how intense that regimen needs to be? So why don't we at least start Dr. Cunningham in terms of, why is it that a typical immunosuppression regimen is not just one drug, but we need multiple drugs? Yeah. Speaker 2 12:39 So you know, one thing that's really interesting about a lot of the way that all of these drugs work is that they all really work on the T cell, but they work on different signals, essentially of activating T cells, which ultimately to further proliferation of those T cells and and B cells as well. And so we use these with different mechanism of action so that they can, all you know, target different parts of that T cell to really try to best prevent a patient from developing rejection. Because we know that that rejection can happen at any time point. Typically, we tend to worry the most in the first six months to a year, but it can happen years and years down the road. Additionally, if we were only to use one medication, such as tacrolimus, for example, we would probably need to use much, much higher doses than we currently do, and this would subject our patients to considerable toxicities from the drug itself, which we'll talk about in a little bit. But the adverse effects of these agents can be pretty significant, so using this multi drug regimen allows us to target lower doses and target these different mechanism of action on the T cell, Dr. Khyati Patel 13:47 and can take it back to the basics of immunosuppression for organ transplant, right? Dr. Cunningham, there's about three different phases of immunosuppression somebody who need we call it the induction. That's at the time of the transplant itself. What we are focusing on the maintenance phase. It's the quote, unquote, the chronic phase of discussion. And then there is, you know, different treatment for when the acute rejection is happening. So just for the audience purposes, you know what we are talking about today is that chronic maintenance phase of the immunosuppression, yes, Speaker 2 14:21 and hopefully that our patient won't progress to developing rejection that we need to treat. Speaker 1 14:26 And as our title suggested, the two drug tango, the most common regimen that a typical patient is going to be on is going to be a calcineurin inhibitor. That's typically going to be tacrolimus, but it could be cyclosporine, an anti metabolite, typically going to be mycophenolate, could be azathioprine, and then sometimes a steroid like prednisone will be added as a third drug. This kind of two to three drug regimen is common with basically all of the solid organs that you're going to think about, so kidney, liver, pancreas, Heart, Lung, and it's going to be continued lifelong for these patients. Doctor Cunningham, do you want to maybe comment a little bit especially on that steroid can. Opponent and any other facets of a two to three drug regimen? Speaker 2 15:03 Yes, there's a couple things I want to know. The only organ really that can be on mono therapy is the liver. You know, the liver can tolerate much lower doses of immunosuppression, where our patients don't necessarily progress to developing rejection. So depending on the etiology of their liver disease, sometimes we are able to get them down to just a calcineurin monotherapy type of regimen. And then secondly, the steroid. A lot of center transplant centers do utilize steroids, and I think that's just another thing that's interesting to note is that if you travel across town to get treated for an acute MI or COPD, you're you're probably going to get the same treatment at pretty much every hospital in the city. If you travel across town to get an organ transplant, the regimens are, can be completely different. Transplant, in my opinion, is still kind of a newer field, and there's so much research that's still ongoing and data that hopefully comes to help us. But you know, different providers have different nuances in the way they practice, and based on that induction that Dr. Patel kind of alluded to, sometimes we make different decisions about the maintenance regimen. Example, at Northwestern we are known as a steroid sparing center, so this is specifically for our kidney transplant recipients. We use a more potent induction agent at the time of transplant that has allowed us steroid avoidance long term, and that can be really appealing to patients, because most patients out there, while they may not be familiar with tacrolimus or mycophenolate, they usually know what prednisone is, and they've usually heard about some of the side effects that come along with that. So depending on where you are transplanted and what type of medications are utilized, it could allow for the avoidance of prednisone. But in our lung and our heart transplant patients, they typically will always be on a three drug regimen, Speaker 1 17:00 and of course, there are many other immuno suppressive therapies out there that we're not talking about today. Dr. Cunningham, could you just mention a couple of those that would be used, either in someone who has acute rejection despite their two to three door regimen, or if they have a side effect and they can't take tacrolimus anymore, for example, yeah. Speaker 2 17:17 So most commonly, it's when they have some type of adverse effect that we'll talk about kind of later on. Nephrotoxicity is the big one that we encounter with calcineurin inhibitors, and we try to switch them to other type of regimens that may be mammalian target of rapamycin or an mTOR should be sirolimus or everolimus. And then there's also belatacept. Belatacept, or Nulojix, is the newest kid on the block for transplant medications. It's an IV medication, and it's got a unique mechanism of action. It's a co-stimulation blocker working on that T cell, and it's rapidly rising in use in the pharmacist. We are super involved in converting those patients over. But still, kind of, you know, newer out there and gaining traction with that. So still, most commonly we're using the calcineurin inhibitors and the anti metabolites. Dr. Khyati Patel 18:13 And obviously, you know, using this two drug regimen with calcineurin inhibitor or anti metabolites, the idea here is to kind of walk a fine line where we are not over suppressing the patient, where no patient would have a higher risk of toxicities or risk for infection, but also not under immunosuppressed them, so they would have a risk of rejection. So it's kind of like walking a fine line. Unknown Speaker 18:37 Yeah, it's the balance we're always striving for. Speaker 1 18:40 So Dr. Cunningham, one of the objectives of today's episode was to think about clinical pearls and pitfalls for the clinician who, let's say, a patient who had a kidney transplant three years ago gets admitted for pneumonia, and now you're part of the team, and you have to know about their tacrolimus. You didn't start it, but you have to make sure that you don't mess it up too, right? So why don't we focus on the calcineurin inhibitors first? And tacrolimus, some people call this FK and cyclosporine CSA. How do these calcineurin inhibitors work? We'll start with that. Yeah. Speaker 2 19:11 So they really work on signal one of T cell activation, and they both essentially inhibit calcineurin, hence their name, but the complex that they create by binding to their protein. Each of them binds to a different protein, tacrolimus binds to FK-binding protein, and cyclosporine binds to cyclophilin. They inhibit the phosphatase activity of calcineurin, and that is actually calcineurin is an enzyme that's responsible for, you know, essentially different transcription or various cytokines. And what we're really striving for, again, is to prevent additional T cell activation and proliferation of those T cells, to kind of kind of halt them and prevent them from essentially infiltrating that graft, that organ, and causing damage to it, or causing rejection. Hmm. Dr. Khyati Patel 20:01 So Dr. Cunningham, you know, good to know how they work and stuff, but what are some of the pertinent kinetics? That's where I feel like the specialty of pharmacists come in. Maybe it's related to the drugs, how they work, or maybe even the drug interactions. Speaker 2 20:17 Yes, that is a huge role of what we we do, and I will actually say that we have a consult service at Northwestern now for the transplant pharmacist team. And the reason for that, even coming up, was due to a significant drug drug interaction, where a patient on tacrolimus was starting on another medication that interacted, and their level shot sky high, and it went for like, root cause analysis in the hospital. And that developed, then us having this consult service, which is actually pretty amazing, because then we really manage the immunosuppression while patients are in the hospital. But basically the calcineurin inhibitors are hepatically metabolized and go through the CYP3A4 family of enzymes, and this puts them at risk for substantial drug interaction. There's lots of different examples, if we wanted to get into some of them, yeah, I think a typical one, I would think, with the CYP3A4 mentioned Dr. Cunningham would be the antifungals, the azole antifungals, yes. So based on those azole antifungals being CYP3A4 inhibitors, we can see a significant increase in our tacrolimus levels, so much so that with particular azoles, because some of them have different levels of enzyme inhibition, we will empirically make, you know, 50 to 75% dose reductions in tacrolimus or cyclosporine when we start them, and depending on how long the patient may be on therapy, the other key is making sure that we increase that dose back up once they complete their azole treatment. So therapeutic drug monitoring, which we'll talk about in a little bit, plays a huge role here for us. Speaker 1 22:02 Then, of course, another drug class that comes to mind are macrolides, specifically chlorythromycin, which is typically only really seen with h pylori infection, where you're on this multi drug regimen for that for stomach ulcers, but you will still occasionally see that for things like sinus infections and upper respiratory tract infections, although azithromycin probably should be used in those cases instead. The good news is that azithromycin really is not a huge interactor, but Clarithromycin is the bad guy here. Speaker 2 22:30 That's actually the one that sparked the drug interaction that led to us developing our consult service, and it was being utilized for h pylori treatment. Dr. Khyati Patel 22:39 I just need to know, and I believe the non-dihydropyridine calcium channel blockers like diltiazem, would also end up increasing the levels. But on the flip side, the dihydropyridine calcium channel blockers like amlodipine, they do not interact. Speaker 2 22:54 Yeah, so we actually amlodipine, or nifedipine are usually one of our first line blood pressure agents, just because they are thought to hopefully counteract the vasoconstriction, leading to some of the nephrotoxicity that the calcineurin inhibitors cause. But they commonly pop up as a drug drug interaction in computer systems, and we tend to get frequent calls about that, but we try to avoid diltiazem and verapamil, but we do preferentially use amlodipine and nifedipine. Speaker 1 23:24 Then, of course, we have the pharmacist kryptonite, which is grapefruit juice. So calcineurin inhibitors are P-glycoprotein substrates, and grapefruit juice does inhibit that process, so you end up absorbing or not metabolizing off quickly in the GI tract, your tacrolimus or your cyclosporine. So any grapefruit juice is going to increase those drug levels. So patients need to be aware to either not do it, or if they do it in very small moderation, or if they always do it every day, that we're going to adjust their dose for whatever amount of grapefruit juice they drink, but they have to be very consistent Speaker 2 23:56 with it. Yes, most patients don't have a problem avoiding it, but we do tell all of them to avoid grapefruits and grapefruit juice, Dr. Khyati Patel 24:06 and then to think about, you know, the flip side of a CYP3A4 interaction. Let's talk about our inducers like carbamazepine or phenytoin. Because they're enzyme inducers, they end up decreasing the level of these calcium urine inhibitors. Speaker 2 24:22 Yes, we don't see these as much, I would say, in general, but when we do, we tend to up our monitoring of our tacrolimus or cyclosporine levels, and potentially empirically dose increase them when somebody is starting on one of those inducers. Speaker 1 24:37 So Dr. Cunningham, I want to pivot to statins for a second, and I'm bringing up statins for kind of one specific reason. So tacrolimus and cyclosporine, they are not inhibiting or inducing CYP3A4, and statins do not inhibit or induce CYP3A4. So theoretically, you feel like you should be good in terms of statin and your calcineurin inhibitors, but that's actually not the case. Can you walk us through this interaction a little bit? Speaker 2 25:01 yes, and we always, historically felt like it was both tacrolimus and cyclosporine. But after some more data came out, it really was more pinpointed on cyclosporine itself, and it's due to this inhibition of cyclosporine of OATP1B1, which is the organic anion transporting polypeptide, and statins are actually substrates of that protein, and so it can result in increased concentrations of statins, which could potentially lead to myopathies. So there are some contraindications. Simvastatin is contraindicated with cyclosporine, and then we max out rosuvastatin at a five milligram dose. Now we still feel a little bit cautious, even with our tacrolimus. So for patients that may not have an extensive cardiac history, we will sometimes still do a 50% dose reduction in their statin just because we do worry about those myopathies occurring. Dr. Khyati Patel 25:59 And I believe the newest interaction is with our new friend Paxlovid, which is a combination drug nirmatrelvir and ritonavir. And I believe the interaction kind of resides more on the ritonavir side itself. Speaker 2 26:14 Yeah, so that's the newest thing we've been seeing. And we actually do not start paxlovid In any of our transplant patients, but it tends to be patients that may be further out from transplant whose primary care physician has started it and isn't aware of the drug interaction. And so we've had a significant amount of hospitalizations over the past several months for Tacoma levels being above the threshold that we even detect. So we tend to worry about some of the more rare side effects, like seizures and neurotoxicities that can occur, but also the nephrotoxicity. So we have brought them in just for monitoring and just to make sure that their levels start trending down. Speaker 1 26:53 Dr. Cunningham, you kind of casually said this, but I just want to emphasize it, because it's a really big deal. So you said that there have been instances where Paxlovid was started and tacrolimus levels were undetectably high. Can you just give us some numbers here? So how high is too high to be detectable in the sense of, you can't quantify it, and what is a typical tacrolimus level? Just to give context to how insane that tacrolimus level is. Speaker 2 27:16 So for our for example, for our kidney transplant patients, for the first three months, we run them at a concentration of eight to 10 nanograms per milliliter. After three months, they typically run somewhere around five to seven long term, we see levels greater than 60, and that's our upper limit of, you know, of of threshold, yeah, so we don't actually know how high they really are, but we get nervous of a level, you know, of around 1718, 20. So this is, you know, way beyond what we are typically seeing in our patients, which, hence, is why we've brought them in to be admitted. Speaker 1 27:56 And then kind of last interaction of sorts, or kinetic interaction that I want to talk about is with renal impairment. And I think a common misconception is that, you know, we see acute kidney injury in the ICU all the time. Probably two thirds of ICU patients will have acute kidney injury. A common misconception is that to crawl on this has to be dose adjusted because of renal impairment. Why do you think this misconception exists in terms of that, there's a renal dose adjustment with the medication. Speaker 2 28:23 Yeah, it's a good question. And something I get called about all the time is asking if we need to dose reduce. I think because the calcineurin inhibitors can cause nephrotoxicity, they can be the ones that are actually resulting in the Aki. And so providers may feel like, you know, they need to pull back on the dosing because of that, but really it then we need to adjust the dose based on what their level is. But it's not necessarily that we have to adjust the dose because of the renal impairment, because again, they are hepatically metabolized. Dr. Khyati Patel 28:55 So aside from managing drug interaction, Dr. Cunningham, I imagine that there's a lot of safety issues that come along with these drugs too, where pharmacists may be involved. Can we kind of summarize the more common side effect of these inhibitors? Yes. Speaker 2 29:09 I mean, for you know, all immunosuppressive agents, as we kind of alluded to before, we're trying to walk this fine line so we know that there's risk of infection and malignancy in our patients long term, so we're trying to always balance that and minimize the immunosuppression as much as we can, to prevent rejection, but not to cause infections. But then you know, specifically for the calcineurin inhibitors, and probably the most difficult thing to have to tell a patient about is that they can be nephrotoxic, and this is really the biggest pitfall of our calcineurin inhibitors. They are so good at preventing rejection, specifically, you know, tacrolimus, but you know, we do know that they can cause both that acute kidney injury and long term structural damage to the kidneys Speaker 1 29:54 as well. And of course, I think we have to comment on the irony here that we're giving a drug and let's say a kid. Transplant patient to help them not reject their kidney, but the drug itself can cause kidney damage. There's some some amount of irony there that it's hard to not appreciate Absolutely. Speaker 2 30:11 And you know, we've had patients that have had to go on to either have another kidney transplant, if they were a kidney you know, initially, or we've had lung transplant patients that have developed chronic nephrotoxicity, and this is where some of those alternative regimens, and specifically the latter Sept, because it does not cause any nephrotoxicity, is really that's why it's really rising in use. So it Dr. Khyati Patel 30:34 seems like if there is a patient who developed nephrotoxicity with one of these agents, they are bound to have change in their regimen. Is that right? Yes. Speaker 2 30:43 So for a long time, what we would do was try to switch them over to that mTOR based regimen. But mtors are not without their long laundry list of adverse effects, and they can be very difficult to use. So with, you know, the belatacept approval that's come out, we are just seeing a significant rise in that because it does combat that nephrotoxicity. Now, the challenges of bladder soft utilization are that it's IV only. So you know, you need to have an infusion center. It's hard to get it approved for home health. Really patients either come to our clinic or we set them up at a local infusion center, but also getting insurance approval. Dr. Khyati Patel 31:23 But I think the bottom line here, Dr. Cunningham is, let's maintain those levels really nice in the in a good range, so we don't induce nephrotoxicity, because otherwise the options are kind of Speaker 2 31:33 not that great, yeah, just more challenging to use, for sure. So nephrotoxicity Speaker 1 31:38 toxicity is one of the main side effects, but there are a number of other side effects that come to mind. So some so some electrolyte abnormalities, like hyperkalemia and hypomagnesemia, where the kidney can actually waste magnesium or hold on to potassium. Then also, we kind of mentioned it earlier, we can see some other adverse effects, some of which are more common with tacrolimus versus cyclosporine, but really seen in both. And one of those is neurotoxicity, especially as those levels get really high, right? Speaker 2 32:04 Yeah, so tremor has always been it's a very fine tremor that patients tend to develop in their hands. It's always been a side effect that we've seen a lot with both cyclosporine and Taco Ms. And one thing that's been really nice is there's a newer extended release formulation called invarsis that has shown in a clinical trial to improve this neurotoxicity, and specifically to improve the tremor. So that is one nice thing of this formulation that's come out. Dr. Khyati Patel 32:33 Other concerns are hyperglycemia or nuance of diabetes or alopecia losing here, Speaker 2 32:39 yes, and alopecia you see with tacrolimus, and you actually see hirsutism with cyclosporine. So really interesting. And that can for, you know, for women particularly, that can be a significant reason why we may actually switch, Speaker 1 32:54 then to add on to some of the adverse effects more commonly associated with cyclosporine. So you mentioned the hirsutism, which is going to be male pattern facial hair growth, but we can also see hypertension, hyperlipidemia, the kind of a unique one that we see with phenytoin also is Gingival Hyperplasia, where you get this kind of overgrowth or bubbling of the gum line where the teeth meet. Speaker 2 33:13 Yes, I've only seen that a few times over the years, but it can be pretty significant. And so in order to manage these side effects, right? We got to maintain the levels of these drug and that's where the therapeutic drug monitoring comes in play, where pharmacists play a huge role. Can you walk us through a little bit about, you know, what do we measure, what kind of windows we are looking at, and what kind of nuances that go along with the monitoring? Yes, the therapeutic drug monitoring is really our bread and butter. We are fortunate at Northwestern where we we manage all of our abdominal transplant patients, trolling Med, cyclosporine, mTOR levels while they're in the hospital. The goal level is really dependent on what type of transplant the patient received, how far out from transplant they are, whether or not they've ever had rejection, and then, of course, their concomitant immunosuppressive regimens. So that's a big discussion that we talk about every day on rounds for our patients, and something that's addressed every clinic visit for all of our outpatients when they come back. And the frequency with which we obtain these levels, it's also dependent on all of those factors as well. So for brand new, fresh transplants, we're checking everyday levels for the extended release once daily products. We can sometimes get our providers to back off and just do three times a week. And then as patients get further and further out, and once they're on a really stable dose, then we can go to like monthly drug levels. Speaker 1 34:43 Dr. Cunningham, from a formulation standpoint, are there any kind of clinical pearls that you want to leave the audience with, with respect to tacrolimus, in terms of its dosage forms that may be seen in clinical practice? Speaker 2 34:53 Yes, we typically do not use IV tacrolimus at all. You'll see that in bone marrow transplant, but not in. Solid organ, as much it does come as various, you know, formulations, there are capsules, there are tablets, there are suspension, there are granules for suspension. And, you know, the newest formulation that's out there is actually the invarsis, which is extended release formulation, where it's just once a day administration, and that has a pretty advantageous PK profile, as I alluded to before. We definitely saw an improvement in the neurotoxicity symptoms, and that's really due to the reduced C max that we see with this product. But still, there's comparable AUC exposure compared to immediate release tacrolimus. And so you see a dose reduction overall in Envarsus which is beneficial for our patients. And then, you know, the other thing about it that providers, we sometimes go back and forth about is that potentially, since we know drug adherence is so important with our patient population, that if they're taking it once a day, at least, we know they're getting their whole calcineurin inhibitor dose in the morning, like, say they forget to take their Dr. Khyati Patel 36:03 meds at night. So we talked about the calcineurin inhibitor, but this is a two drug tango, so we got to talk about the other side of the tango, and that's the anti metabolite type drug, which is mycophenolic acid. Dr. Cunningham, can you walk us through, like, how this drug works? And kind of like any PK or ADRs that we need to be concerned with, Speaker 2 36:25 yeah, so the anti metabolites, based on their name, they work on a, you know, a different part of that T cell versus the calcineurin inhibitors, working on signal one. These really work on the cell cycle, and they're going to work on preventing that T cell proliferation by binding to inocyte monophysate dehydrogenase, which essentially is making guanosine nucleotides, and this is through a de novo pathway, which is actually pretty unique to T and B cells. Most other cells can use the salvage pathway for making nucleotides, but because the lymph the T cells and the B cells don't we're really targeting here by using mycophenolate with this unique mechanism of action. And you know, azathioprine technically also falls into this category as well, but we have seen, you know, improvements in rejection rates with mycophenolate, so that has really kind of taken over for the anti metabolite drug of choice, and I Dr. Khyati Patel 37:21 believe the mycophenolate is also not safe in pregnancy. It's, you know, due to the teratogenic effects. And so usually we will go ahead and consider changing it to azathioprine. Is it true? Yeah. Speaker 2 37:32 So when we tell our patients if they are starting to do some family planning, and we really recommend that they plan for this in advance, so that we can safely transition them, so we can transition them to azathioprine monitor to make sure that they don't develop any acute rejection before the you know, the female were to get pregnant. And then, depending on the patient, we may just keep them on azathioprine until they're done having children. And then we'll switch them back to mycophenolate afterwards. Speaker 1 38:01 In terms of side effects, I would view this as much more favorable than our calcineurin inhibitors. The main one that comes to my mind are gi in nature, and that's believed due to one of the metabolites of mycophenolate. But we're thinking nausea, vomiting, diarrhea. Is that the main one that comes to your mind? Speaker 2 38:17 Dr. Cunningham, yes, and we do see a considerable amount of Gi toxicity with mycophenolate, I usually tell patients, mostly it's going to be the diarrhea that can occur, and they don't usually have that problem. Post op, we usually are kind of in the opposite boat, but it can occur, you know, down the road, months into therapy. And I always tell patients, just don't ever stop your medication without talking to us. It could be an infectious process, but if we do find out that it is due to the medication itself, we do have some strategies. And one thing that has been actually kind of successful is spacing out their dosing. So instead of just taking it twice a day, we can do three times or even four times a day. And we have seen significant improvement with with that gi toxicity and then it looks like Dr. Khyati Patel 39:02 leukopenia could also be a common ADR, so something to monitor would be CDCs to go along Speaker 2 39:08 with that. Yeah, leukopenia can be pretty challenging for our patients based on usually kind of goes back to their induction agent. We also our patients are on medications to prevent certain types of infection that can cause leukopenia. So we are always striving to keep their white count, you know, up, but it can be pretty difficult sometimes. Speaker 1 39:28 Now, unlike our casino inhibitors, we don't typically check a drug level of mycophenolate as an example, it can be done, but that's not typical, correct? Speaker 2 39:37 That could be controversial, depending on who you ask, from the pharmacist perspective, no, we don't generally recommend monitoring them. Some of our providers do. Sometimes it can be useful if you're trying to figure out if their GI toxicity is, in fact, due to the mycophenolate. And you find that they do have a higher trough level kind of the gold standard for monitoring mycophenolate. Is through AUC monitoring, but that's logistically pretty challenging. So we do have some correlators and values that we can utilize for obtaining a trough level, but it's not typically standard practice. So in terms of kind of interesting formulations that some of the pharmacists can come across, what are some of the nuances with micro phenolate? Yeah, so there are two formulations. There's mycophenolate mofetil, which is commonly referred to as CellCept, and then there's mycophenolic acid, or mycophenolate sodium. And that's Myfortic, and that's the extended‑release product. So it's really the drug itself isn't stable in the, you know, acidic environment of the stomach, so you either need the pro drug, which is mycophenolate mofitel, which they will rapidly convert into mycophenolic acid, or the delayed release product. And what's really kind of interesting is that Myfortic was really developed to try to improve that GI toxicity profile of mycophenolate mofetil. But if you look closely into the studies, the data didn't really support that. However, we have also switched patients over to Myfortic if we feel like the spacing of the dosing out isn't working. And I don't know if it's placebo effect or really there maybe there is some improvements, but some patients do feel like it's more advantageous. Speaker 1 41:20 Dr. Cunningham, in my neck of the woods, when we have intubated patients, we have to crush their immunosuppression regimen. As an example, we obviously can't use that delayed release my fortic formulation, because that would destroy the delayed release component and the stomach acid would just degrade the product. So in those patients that we can't give an oral tablet or capsule that they swallow, we can either give an oral suspension or even IV to kind of get around the issue of having an extended release or a delayed release formulation of my Speaker 2 41:49 fortic, yes, and that does come up pretty frequently, where we will need to switch formulations based on the clinical status of the patient. Speaker 1 41:57 Then, of course, when we do that, because mycophenolate mofetil is a different molecular weight compared to mycophenol acid. There is a conversion there in terms of they're not one to one conversion, right, right? Speaker 2 42:08 So 250 milligrams of mycophenolate mo fatal, which is the smallest capsule size of that product, is equivalent to 180 milligrams of mycophenolate sodium, or my four deck. And so it's just a simple ratio that that we can calculate the equivalent dosage. Dr. Khyati Patel 42:26 And then Dr. Cunningham, I would think corticosteroids probably would come in the picture in the, you know, case of like acute rejection, cap off a scenario. But you did mention earlier that some centers do use corticosteroid for maintenance therapy as well. Can you quickly walk us through what's the place of therapy for these agents? Speaker 2 42:45 Yeah, and I should correct myself a bit in that we do use steroids for all of our transplant patients, they just don't stay on them long term. So all of our transplant patients will get at Northwestern will get 500 milligrams of methyl prednisolone in the operating room or pre op, they'll get 250 milligrams on post up day one, and then 125 milligrams on post update two, that's for our kidneys. And then they will be off for the other organ transplants. They may then continue to taper down so we can get to the lowest possible dose for that medication. And I always tell my patients, these are like the oldest immunosuppressive agents on the block. Their mechanism of action is pretty significantly and profound. We know that there's a huge involvement with cytokine inhibition and cell migration, for example, and they are very effective. But they come with them, you know, a multitude of adverse effects, which I'm sure you're both aware of, Speaker 1 43:40 things like increased appetite or lots of energy indigestion, but that leads to weight gain and having dysipedia and hyperglycemia, hypertension, edema, you know, lots of things can go wrong from a metabolic standpoint because of these medications. Speaker 2 43:57 Yes, and that's why, you know patients don't like them. You know, we they work really great, but, you know, it is very challenging to balance all their side effects. Unfortunately, if patients do go on to develop rejection, come back real fast, and they likely will then be on indefinitely based on how a patient Dr. Khyati Patel 44:18 does after that. So Deb, cutting them. You know, this was great information about the two drugs that Tango together for, you know, chronic or maintenance phase of immunosuppression. I'm not going to go back to highlight our organ donation month, the Donate Life month, month of April. And, you know, there, there's misconceptions out there, mostly from, you know, patron population perspective. You know, what are some of the common myths you've heard? And you know, what is the actual truth behind them? If you can cover them? Speaker 2 44:48 Yes, that's great. There are so many myths out there, and it's really important to highlight these. And really, you know, I just have to put a plug in to please sign up to be an organ donor if you're not already it. The impact that you can make on somebody's life and their family's life is so profound, and transplant is so exciting, and to see somebody get this life changing event is so incredible. So some of the myths, you know, some people think it's, it's really just better to let my family decide, and that is so difficult for to for family to go through at that time, if they're, if this is a, you know, something very sudden that's occurred, and they don't know what your wishes are for them to make that decision is really, you know, kind of agonizing. And so it's really better if you, if you feel like, you know, being an organ owner is something you want to do to make your family aware. I think everyone in my family knows, I mean, based on my position anyway, but that, that, that you know, is would be so important for me, you know. So just making sure that your family is aware, that you discuss it with them, that that's Dr. Khyati Patel 45:50 your choice. There's other myths out there that going under this organ donation will disfigure the body and they won't be able to have the open casket funeral. What do you say to that? Speaker 2 46:01 Well, so I have to say, and just when I was a resident, I went on a procurement and I flew up in a plane with the team to northern Wisconsin, and we and it was the one of the most incredible experiences that I've ever done. But I have to say, when, when we went in the operating room, the first thing the team did was had a moment of silence. They read a poem from the patient's significant other, and really just took a moment to, you know, acknowledge the impact of of this, and that we were teams from all these different transplant centers coming to get different organs, but that we were recognizing the gift that this family was giving to all of these patients out there, and the, you know, the procurement itself, it's a it's a surgery. So you have trained expert surgeons you know, that are procuring these organs, and patients are closed surgically. So the body is treated with the utmost respect the enclosed, you know, and with a typical surgical incision, so that, you know, a patient can have that the goodbye after they've, you know, passed away, and have that open casket funeral, if desired. Speaker 1 47:08 And religion sometimes may come up. Are there certain religions that would maybe conflict with organ transplant or not? Speaker 2 47:14 Not that I'm aware of. Every kind of major recognized religion out there is in support of organ donation, and I would just advise that if you were ever hesitant or had a question about it, to really go to you know, someone in your faith based organization, to speak with them, to you know, so that you can make that best decision for you and your family. Dr. Khyati Patel 47:37 Sometimes I've heard people say, Oh, I'm too old. My organs are too old to be donated. Is that a thing? Speaker 2 47:42 It depends. I mean it, but that's something that I would just say, let, let the team design. You know, we were the ones monitoring all the organ function, and how incredible, even if you are older, to be able to donate your organs. And I will just say that we still do. We do living donor kidney transplants on people in their 70s. So you know it is possible. Speaker 1 48:03 Then another myth is that whoever gets your organs is just going to be the richest person who can pay the most money for that organ, and you're just helping the wealthy people at that point. Is that a thing? Speaker 2 48:13 No, there is so much regulation that comes with the waiting list and matching patients and who is at the top of the list. And so I just cannot see how that could ever, you know, anyone could ever, like go to the top of the list based on their status. But I think the thing is, is that when celebrities or famous people are transplanted, it gets a lot of press, and people may not realize that they were sick. And so then it could be a misconception that they got this transplant right away, but really they were probably privately battling that illness. Dr. Khyati Patel 48:46 What about some of the financial concerns that patient may have and think, like, oh, yeah, I'm gonna sign up, but then my family is gonna have to, like, get stuck with the bill. Yeah. Speaker 2 48:55 So I think the misconception that comes here is that now while all of your care while you know you're in the ICU and where the team is, you know, working to save your life and everything that will still be built to your insurance. But once you know you proceed into being an organ donor, then none of that will actually be built to the donors insurance that actually all goes on the recipients. Dr. Khyati Patel 49:19 And that would make sense, yeah, because they're receiving the organs then, Speaker 1 49:24 Dr. Cunningham, the last myth that I want to cover is super common in the ICU, and it's the misconception that the ICU team, or whatever team, is taking care of a patient, once they know that a patient is a an organ donor, that they'll just give up and kind of go toward the organ donation side, as opposed to doing everything they can to save someone's loved one. I can confirm that that's a myth. But do you want to comment on that as well? Yeah. Speaker 2 49:49 And I mean, I think all of us, from healthcare provider standpoint, know that, that there's absolutely no truth to that and that in you know, as our profession dictates, really and. What we all are in this for is to really help people as much as we can. And so every medical team, no matter where they are, is going to pursue all efforts in order to preserve and sustain a meaningful life for a patient. And I can say even from the post transplant side, when our patients get sick, you know, our team does the same thing, and we never give up until, you know, it's absolutely comes to that point where we have to make that call and with, in conjunction with a patient's family. Speaker 1 50:31 Well, Dr. Cunningham, I love that. We've kind of wrapped up with some common myths. But why don't we go back to the beginning in terms of some key points that we covered in today's episode, I think one key thing is for any healthcare provider to recognize that a typical immunosuppression regimen is going to be two or three drugs, most commonly that's to Chrome this and mycophenolate, sometimes with a steroid. And if you encountered a patient who's only on a one drug regimen, that might be a red flag. You mentioned that there are some circumstances where that's okay, but that might also be an issue where the med history wasn't done appropriately, and they're actually on other drugs, and you have to maybe investigate just a little bit further to confirm their lack of a multi drug regimen for their organ transplant. Dr. Khyati Patel 51:14 And kind of going into the nuances of tacrolimus, you know, it's hepatically eliminated, as we talked about it, because of that, we have drug interactions to worry about, especially CIP, three, a, four and P glycoprotein drug interactions. And normally at higher drug concentration, we're gonna see nephrotoxicity and neurotoxicity, although there are other side effects to worry about. Speaker 1 51:38 So we mentioned mycophenolate as our two drug tango, right? So mycophenolate, it's important to note that it's unstable in the stomach acid. So there's two ways to get around that you can either have CellCept, which is a pro drug of mycophenolate Mo, where the liver actually converts it to the active compound, or my fortic, which is an enteric coded or delayed release formulation that allows for mycophenolic acid to be protected in the stomach, get into the small intestine, where then the drug formulation is released, and then it will be absorbed into the blood. Speaker 2 52:08 And then lastly, I would just say that you'll see a lot of variations in immunosuppressive regimens, which is determined by what type of transplant the patient received, where they were transplanted, when their transplant was, their rejection history, their adverse effect profile that they've encountered, and then other patient specific factors that play a role too. And if you're ever unsure and the patient was transplanted Northwestern, you can always reach out to me, because I think every transplant pharmacist everywhere is always more than happy to help answer questions and help manage patients when they're at other institutions. Well. Speaker 1 52:45 Dr. Cunningham, thank you so much for joining us and for your expertise. For the audience, if you want to check out, our show notes are available at HelixTalk.com this is episode 163 we're on Twitter at HelixTalk. We have a mailing list you can sign up on our website. So with that, I'm Dr. Kane. Dr. Khyati Patel 53:01 I'm Dr. Patel. Thank you so much again, Dr. Cunningham, for being here with us. Unknown Speaker 53:06 Thank you so much for having me Dr. Khyati Patel 53:08 and to the audience. Study hard, donate your organs and save lives. Thank you. Narrator - Dr. Abel 53:16 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 to Narrator - ? 53:27 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.