Pharmacokinetics, Pharmacodynamics Are More Complex, Essential in Cardio-Oncology

In an interview with Pharmacy Times, Jo Ellen Rodgers, PharmD, a clinical professor at the UNC Eshelman School of Pharmacy, discussed her presentation at the American College of Cardiology 2023 Scientific Session titled “Pharm 101: Practical Pharmacokinetic and Pharmacodynamics Considerations in Cancer Patients.” Although pharmacokinetics and dynamics can be complex, particularly in patients with cancer, pharmacists play a key role in the various considerations and treatment decisions.

Q: Can you discuss how pharmacokinetics and pharmacodynamics can be practical in everyday use?

Jo Ellen Rodgers, PharmD: Yeah, I think it's easy to get a little overwhelmed by the terms related to pharmacokinetics and dynamics; they sound like scary terms. You know, I think one of the major points of the program is to, one, raise awareness and make sure that people know that there are a lot of potential interactions on both the cardiovascular side and the oncology side of therapy. And it's really scary when those 2 sides come together, and they interact with one another. What we try to keep simple is just conceptually understanding the big buckets of how those PD, or pharmacodynamic, and PK, pharmacokinetic, interactions can occur. And just by raising awareness, knowing that we need to work as an interdisciplinary team to address them, because they're going to happen, there's a lot of ways we can look them up and search for how to address them. Unfortunately, a lot of times, there's not great data, so that makes it a little more complicated. But regardless, it just takes a lot of collaboration and making the right decision for the patient. Because oftentimes there's one great antiarrhythmic are anticoagulant and we want to use one most optimal. Similarly, there's a lot of times when there’s a most optimal cancer therapy and neither side on the street wants to give. So, how do we come together and use these therapies in the most effective and the safest way? How do we counsel the patient? What are we going to monitor? So, I don't think the right answer is always “Oh, we can't use these therapies together.” Although there are some absolute avoids, you can't use this combination, but more so how can we think creatively to make it a win-win for our patients?

Q: Patients with cancer can have very complex regimens. Can you discuss why this makes pharmacokinetics and pharmacodynamics more important and also more challenging?

Jo Ellen Rodgers, PharmD: Right, kind of rearing some of the key concepts earlier. Oftentimes, there is a best-case scenario for how we want to manage cancer patients, meaning you have better outcomes with therapy A than therapies B and C. Unfortunately, all of those therapies can potentially cause a variety of cardiovascular toxicities of varying degrees, and sometimes they can even cause different cardiac toxicities. One might cause tachycardia or atrial fibrillation, and the other one may cause bradycardia. And trying to then manage that with other complex medications or cardiovascular medications, which also have their own side effects, such as QT prolongation and tachycardia or bradycardia while we're trying to manage the patient's [atrial fibrillation], and very commonly the oral anticoagulants, and there's a whole host of other therapies that we have in our cardiovascular armamentarium. But, you know, they all have potential for interactions, and most of them are through drug metabolism. Most of them are through the cytochrome P450 system, but not all of them. Some of them affect absorption, some of them will have not pharmacokinetic effects or have pharmacodynamic effects. And when all of those therapies kind of collide, it can definitely make for some challenging decision making, that importantly requires team members from both disciplines. We need the oncologist kind of guiding us and saying, okay, are there alternative therapies or not, especially when you're in patients who are on their second or third line of cancer therapy, especially when they have metastatic disease and more end stage disease. You know, in that scenario, it doesn't matter that they're having some hypertension or some afib. It's okay, manage that so it doesn't bother the patient or affect their quality of life. But that's not going to be what impacts the patient's long-term outcome. It's going to be the cancer and the lack of adequate treatment. So oftentimes, the answer is, no, we don't want to reduce our antineoplastic. We don't want to stop it. We don't want to switch to another therapy. You've got to work with what we've got and figure it out. The good news is a lot of times there are maybe another anti-arrhythmic, maybe a different anticoagulant, alternative therapies that we can switch to, and the list goes on and on. A different ARB or a different statin and so on, where that interaction won't exist. Not always but a lot of times.

Q: What scenarios might you see in cardio-oncology?

Jo Ellen Rodgers, PharmD: Yeah, you know, that is a big focus of the programming we're doing. We have some pathology- and cardiology-minded individuals who brought some great everyday case examples, and those cases illustrate some of the complexities of cardiac toxicities that occur. Some of the ones that are highlighted include atrial fibrillation with our Bruton kinase inhibitors like ibrutinib, as well as hypertension with our VEGF inhibitors. And the VEGF inhibitors, especially the oral VEGF inhibitors, have exploded in practice with the number that are being used and the different cancer types that they're being used in. And so, when these side effects occur, and I think the BTK and BTK inhibitors are great example while you have afib, but now you have to decide, am I going to do rate control or rhythm control? Unfortunately, the rate controlling agents like diltiazem and verapamil can interact with maybe with the ibrutinib. The antiarrhythmics we may choose may interact or vice versa. In some scenarios, it's actually the ibrutinib that's affecting the metabolism of our cardiovascular agents. And interestingly, not only does ibrutinib have this incident, well, it can it not only can cause afib, but it can worsen hypertension. So, you're trying to potentially manage both, but when it causes afib it can which oftentimes trigger Oh, do I need a DOAC to prevent stroke or some type of anticoagulation? A lot of times, you know, we like to reach for DOACs for a variety of reasons. But DOACs, warfarin, you know, there's potential for a lot of drug interactions with both. The ibrutinib itself can increase bleeding risk directly by causing thrombocytopenia and then indirectly as well, and so there's this huge complex issue. Ibrutinib caused afib, now the patient's at risk of stroke, so we want to anticoagulant them, but it's also increasing their bleeding risk. And how do you balance that in a patient? Especially when there's a lot of drug interactions that are further complicating things. You know, do we dose reduce the DOAC empirically because of that increased bleeding risk? And oh, wait, we also just started diltiazem for rate control, and that might be increasing the bleeding risk. And that exercise alone just makes my head hurt.

Q: What are the key considerations that you review in your session?

Jo Ellen Rodgers, PharmD: Yeah, you know, it's the same thing I told our first-year pharmacy students today in class. When I'm thinking about these drug interactions, I never rely on 1 resource. I often will try to look at 2, if not 3 resources. You know, I like Micromedex, but I'll also check others and I'll see whether I’m getting the same answer and when am I getting conflicting answers? Unfortunately, I have to just sometimes look at the PK of the drugs and think about, okay, how are these drugs metabolized and excreted from the body? And are they substrates or inhibitors and inducers? Because sometimes, unfortunately, the drug interaction checkers will not catch something. For example, and this is kind of a gray area, you know, what if you have two mild or a mild and a moderate CYP3A4 inhibitor, does that equal a strong inhibitor? And so maybe those drugs alone wouldn't be flagged in Micromedex, maybe 1 of the 2 would be. Maybe 1 of the 2 would say there's a dose adjustment, but if you had a strong inhibitor, you know, the package insert (which is another great resource) and those resources would say, oh, avoid the drug. And so, you're like, okay, well, I don't have 1 strong inhibitor, but I have 2 moderate inhibitors, does that equate to a strong inhibitor? I don't know. And this drug interaction checker is not going to feel that. And, you know, the great thing is that's precisely when training as a pharmacist comes into play as far as your role on the on the health care team and it's great to relied upon that for that unique knowledge.

Q: Why are pharmacists crucial team members for cardio-oncology patients?

Jo Ellen Rodgers, PharmD: Yeah, you know, the patients are coming in, you know, on average, whether they have just cancer or just cardiovascular disease, with anywhere between, depending on which dataset you look, 9, sometimes even 10, 11, or 12 medications. And I feel like some of our most simple patients, that's an average. So clearly some people come with a few less, and some people come with more depending on what their comorbidities are, but I find the cardio-oncology patients can definitely get very complex. And the longer that list is, the more chance there are for pharmacodynamic and pharmacokinetic interactions and the greater the chances some of those interactions aren't so easy to detect with filling in a community pharmacy. And to be honest with you, a lot of these, especially the oral agents, may not be going through the same system as all their other medications. And is a computer going to find that, flag it in, and know that that's a medication that patient’s taking, and you should be looking for an interaction? So, yeah, I think as much as a second set of eyes to be very thoughtful about looking at the regimen and the complexity of it, the better overall patient care is achieved.

Q: Is there a key take-home message to leave attendees with?

Jo Ellen Rodgers, PharmD: Yeah, the one thing that I've come to enjoy most about cardio-oncology is the collaborative nature of it and the need to ask for input of other providers who have expertise. But then at the end of the day, to come to the table, to gather, to have a thoughtful discussion about the patient, and what's their best interest. And there oftentimes is a little bit of negotiation of, “oh, is this cardiovascular side effect is really going to hurt the outcome of the patient, the longevity of the patient, and very importantly, the quality of life? Or no, it's going to be the cancer.” And which of the 2 do we need to give more of a focus on? And to be honest with you with some of these, a lot of times it's pretty equal, but it takes very thoughtful clinicians who are willing to partner together.

One of our best examples of that is a new amyloidosis clinic where it's multidisciplinary and we have cardiology, hematology, neurology, and nephrology come together with pharmacy, hopefully in multiple places, you know, looking at those very complex patients to make decisions about their management of their amyloidosis and how it's impacting their heart, their kidneys, and their peripheral nervous system, which is most commonly why neurology is there. But also, the hematologist is selecting the chemotherapy and that complex decision making.

Q: Is there anything you want to add?

Jo Ellen Rodgers, PharmD: Yeah, I think that this is where medicine is going to go, is more multidisciplinary care involving more advanced practitioners who can supplement what our cardiologists and oncologists are doing. It simply takes a village these days to get really complex patients safely through our health care system.