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Michael S. Saag, MD: Hello. I'm Dr Michael Saag, a professor of medicine and infectious diseases at the University of Alabama at Birmingham. Welcome to season 2 of Medscape's InDiscussion series on HIV.
Today we're going to discuss the notion of anticipating and managing drug interactions. It's a complex challenge for all of us in medicine, but especially vexing at times for people with HIV and the patients we take care of.
First, let me introduce my guest, Dr Charlie Flexner, a physician trained in internal medicine, infectious diseases, and pharmacology, which he blends together to create a really unique expertise that places him at the heart of all drug development in HIV, hepatitis C, and many other conditions. Welcome to InDiscussion.
Charles W. Flexner, MD: Thanks, Michael.
Saag: Charlie, let's start with your background and how this all came together, because you really are the right person to help us untangle a lot of these complex interactions among medicines that patients take. How did you get into this realm of medicine?
Flexner: When I was a medical student, one of my favorite mentors used to say that we spend most of our time in medical school teaching students about the causes of disease and not very much time teaching them about the treatment of disease. But when a patient comes to the doctor's office, they don't care so much about learning the cause of their disease. Patients are really interested in learning about treatment. In most cases, that means pharmacotherapy or drug therapy. And it turns out that is a very complicated but interesting part of medical care. I was hooked when I began to learn about it and decided that's how I wanted to spend my career.
Saag: You specifically studied pharmacology in terms of these unique mechanisms of how drugs interacted with each other.
Flexner: HIV has given us a very unique and important opportunity for learning about the role that drug interactions play in patient management, particularly if you think about drugs like the HIV protease inhibitors, which can block many of our most important drug-metabolizing enzymes but also induce them. HIV protease inhibitors turn them up and turn them down at the same time. To put that all together and tell a healthcare provider what to do, it turns out, is often quite complex.
Saag: I'm going to tell a personal story about you and me. The AIDS Clinical Trials Group would have meetings twice a year, oftentimes in Washington, DC, at the old Renaissance Hotel. And on that lower level, there was a series of very small meeting rooms where subgroups would get together. I remember being in the room with you when John Leonard from Abbott was presenting some information about ritonavir, and it was in the early days. He made a comment that ritonavir was a very potent inhibitor of the cytochrome P450 (CYP) 3A4 isoenzyme. I remember the look on your face. You immediately paid attention and you said, "Could you say that again?" He did, and you said, "Oh my goodness." Because it dawned on you immediately that this drug, while it may have activity against HIV, also had enormous potential at being a boosting agent. Do you remember that time when it first dawned on you about ritonavir's power?
Flexner: I remember that well, Mike. John Leonard was a very good friend of mine. He was a year behind me in medical school and residency. I said to John, you should be thinking about using this drug to enhance or boost the pharmacokinetics of other cytochrome P450 substrates, not just develop it as an anti-HIV drug in its own right.
Saag: I think initially, appropriately, Abbott was a little resistant to that advice because they had developed the drug as an antiviral. But its role has really emerged as a very potent boosting agent that has been used with most all of these current HIV protease inhibitors and also, as we'll talk about in a minute, some other very important drugs, especially antivirals. Do you remember that conversation in terms of trying to convince them to think more about this as a way forward?
Flexner: At the time, it was hard to imagine a future in which a new prescription drug would be used solely to benefit the pharmacokinetics of other compounds, including compounds that might be made by one of your competitors. But it turns out that gave ritonavir new life as a drug because it was poorly tolerated at the high doses (600 mg twice a day) used for treatment of HIV in combination with other antiretrovirals.
Saag: In the early days, ritonavir could only be formulated as a liquid and had to be refrigerated. I remember stories from patients who, almost like Pavlov's dogs, when they opened up the refrigerator, they immediately got nauseated and had to close the refrigerator door. The dosage of 600 mg twice a day was quite intolerable.
Flexner: One of my patients described it as cherry-flavored motor oil.
Saag: With the nauseating component. Now it's used at 100 mg, mostly once daily as a boosting agent. That is one-twelfth the dose that was being pushed as an antiviral. One of the things we've noticed, though, with the remaining protease inhibitors that are currently used — which is mostly darunavir and maybe some of the atazanavir-type drug products — it is used as a booster and it does seem to have interactions with other drugs, especially TDF (tenofovir disoproxil fumarate). That seems to be one of the reasons that TDF was causing renal trouble. It didn't seem to happen as much with other drugs. Is that something that you've noticed?
Flexner: This is a complexity of a number of drugs like ritonavir that impact drug-metabolizing enzymes: That is, they also impact drug transport proteins. Drug transport proteins are responsible for getting drugs like tenofovir out of the plasma and into the urine through the kidneys. Ritonavir can block that process and increase plasma concentrations of drugs like tenofovir. When you use a drug like tenofovir in combination with ritonavir, that is why you need to reduce the dose of the tenofovir.
Saag: Is that true as much for TAF (the alafenamide formulation of tenofovir), or not quite as much?
Flexner: It's true almost exactly to the same extent with other tenofovir prodrugs. For example, with TAF tenofovir alafenamide, you reduce the dose from 25 mg/d to 10 mg/d, so a 60% or so reduction in dose.
Saag: It's probably worth taking a moment to talk about some of the basic science, because these transport moieties that you were just talking about in the kidney, often in the proximal tubular epithelial cells, is something that I didn't learn in medical school. I remember hearing a little bit about cytochrome P450, which is similar to CYP3A4, where ritonavir potently inhibits for the most part. But let's talk for a moment about some of these transporters. The ones that I'm aware of are organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) and their role in increasing creatinine excretion across the proximal tubular epithelial cells. Could you give us a tutorial on which are the key ones that you pay attention to?
Flexner: It's a complex field, and it's a relatively recent field in drug interactions. In fact, one of the ways the role of drug transport proteins and drug interactions came to light was in so-called unexpected interactions: That is, when you put two drugs together that should not have interacted with one another, but one drug significantly increased or decreased the concentration of the other drug. There are a number of these proteins that both transport substrates into the urine and then transport substrates back out of the urine in some cases. There are several of the so-called organic anion transport (OATP) proteins — the major ones are 1 and 3 — that are responsible for selective clearance of several substrates out of the plasma and into the urine. If you block those proteins as certain other agents can, then you can increase the concentration of a substrate drug.
Saag: One of the practical activities of some of these transporters is the excretion of creatinine, which we'd had no appreciation for. I was alluding to that earlier. We assumed that creatinine clearance was a direct function of glomerular activity, but there is some small component of excretion that also plays a role here, right?
Flexner: Yes. There are active transport proteins responsible for facilitating the transport of creatinine out of the plasma and into the urine. If you block those proteins with certain drugs, then you increase the serum creatinine and apparently decrease your creatinine clearance. So for example, drugs like dolutegravir but also cobicistat can block transport of creatinine into the urine and apparently decrease creatinine clearance to a small extent, although that's not associated with nephrotoxicity per se. It's simply a laboratory artifact that you're increasing your serum creatinine because of selective interference with this creatinine transport process.
Saag: And that's on the order of about 0.1 mg/dL or so?
Flexner: Correct. It's enough to measure, but not enough to really worry about.
Saag: Let's now apply this knowledge to some current situation. Let's take the drug Paxlovid. That is a protease inhibitor against SARS-CoV-2 that uses ritonavir as a co-formulated product release or taken at the same time to increase the levels of the active protease inhibitor. One of the questions that comes up all the time in taking care of patients with HIV is, how do we prescribe Paxlovid if somebody is already on ritonavir or cobicistat? What do you do in that setting?
Flexner: The recommendation for people, particularly HIV-infected people who are already taking ritonavir or cobicistat, is to not worry about it. If you have to take Paxlovid, just take it and don't modify your antiretroviral regimen. The reason that recommendation exists is because you're only taking Paxlovid in most cases for 5 days, and the potential harm of effectively doubling or in some cases tripling your ritonavir dose is balanced by the complexity of having to rework your antiretroviral regimen for only 5 days. Very few people would get into trouble, if you will, by simply taking those additional doses of ritonavir because the extent of treatment is so short.
Saag: It's been interesting that the HIV providers as a group had much less difficulty embracing Paxlovid because we'd had 20 years of experience dealing with common drug interactions with ritonavir, including some with some statins. Where is your go-to place if you want to look up a drug interaction quickly? What do you advise folks to do?
Flexner: I am a big fan of the University of Liverpool drug interaction websites. Full disclosure, I am on their external advisory board, so I do have some bias there, but I think it is a series of programs that are extremely easy to use. There is a smartphone and computer app that you can download, and all you need to do is plug in the drugs of interest and it will instantaneously give you a categorization of potential interactions between those drugs in pairs. It will tell you whether the interaction is green, meaning not to worry, go ahead; amber, meaning caution, because there is a potential interaction; or red, which means there is a clinically significant interaction potential and therefore avoid prescribing these drugs at the same time. There is also yellow, which means no information available, not sure what to do, but most drug combinations are green, amber, or red.
Saag: As you read the description of the green, amber, or red, it tells you precisely what that interaction is and what enzyme systems, if you really want to dig into that.
You work at Johns Hopkins, and now they have the John Bartlett clinic there. I'm sure a lot of the clinicians call you frequently with advice on how to manage different drug interactions. What would you say are the two common questions you get from providers directly or maybe even pharmacists who work in that clinic?
Flexner: For the past 9 months, the most common call I get relates to something we just discussed, which is drug interactions with Paxlovid. This is an area that most clinicians find exceedingly confusing, but particularly clinicians who do not care for HIV-infected patients. Our group, the HIV providers, have a much better handle on this, as you pointed out earlier, than do the non-HIV providers. I think this is the main reason why this otherwise exceedingly valuable drug is really being under prescribed, because care providers are worried about drug interactions and they don't want to harm their patient by co-prescribing a drug that contains ritonavir, a potent 3A4 blocker that might adversely affect the pharmacokinetics of other co-prescribed drugs.
Saag: I'm going to shift gears a little bit and focus not so much on where we are now but where we're going to be in the future. Everything in HIV drug development is trying to point to longer-acting medications. We now have cabotegravir that can be dosed after initial priming to every other month, and then a new drug called lenacapavir, which is a capsid inhibitor that can be used subcutaneously every 6 months in certain situations. As you see these new longer-acting drugs emerging, what are the issues and challenges you see, especially in terms of using these medications but in the realm of drug-drug interactions as well?
Flexner: I think this is the future, Mike. When we think about the pharmacokinetics of long-acting formulations, we're going to have to turn what we learned in medical school on its head, because the pharmacokinetics of these agents are very different from the pharmacokinetics of orally administered drugs. First and foremost, the rate-limiting step in determining systemic or plasma concentrations of drugs administered as long-acting formulations is not their rate of clearance or metabolism, but rather their rate of absorption from the site of delivery, which in the case of either subcutaneous or injectable intramuscular agents is the depot that's formed when these agents are given by injection. This is something that's been termed flip-flop kinetics, which is a term I despise because I think it's confusing. It implies that the drug is cleared before it's absorbed, which is not the case. I prefer a term I use called absorption-dependent kinetics. When you have a drug whose pharmacokinetics are determined by absorption dependence, you worry less about inhibition of metabolism of that drug because you can inhibit the metabolism all you want. But the drug continues to be delivered at such a low rate from its depot that changing that rate of metabolism, even 50% or 75%, is going to have very little impact on systemic concentrations of the drug.
Saag: In that regard, one of the concerns that we have about administering an injection, either depot in the subcutaneous space or in the intramuscular space, is that if there is some untoward event, it's there and it's going to be released over whatever period of time it was designed to do. What are some strategies in the future that we can use that might enable us to get the drug out once it's been administered, either subcutaneously or intramuscularly? Are there some tricks that you're thinking of or that the drug companies are considering?
Flexner: One important approach to this is changing the platform for drug delivery — for example, implants, particularly non-bioerodable implants like the polymer implants used to deliver hormonal contraceptives such as levonorgestrel. Those implants can be removed with a minor surgical procedure if you need to get the drug out immediately. That is one straightforward way to avoid long-acting adverse reactions to antiretroviral drugs, for example.
I think the major strategy that's being used, however, is to reserve long-acting delivery for drugs that already are felt to have essentially no or exceedingly rare adverse effects in humans. Sometimes it's hard to predict that, but our preclinical and early clinical testing is getting better. If you look at the success we've had with the three drugs you mentioned — cabotegravir, rilpivirine, and lenacapavir — I think we're doing a remarkably good job so far at avoiding significant toxicity with these agents.
Saag: I've got to say that the idea of an implantable [drug delivery device] that hopefully could remain active for 6 months to maybe a year and in a combination has strong appeal to me. But we'll see how it all pans out. Your points are extremely well taken.
As predicted, our time is rapidly flying by. I want to finish with a final question to you about what do you see developing in the next 5-10 years? If you had to give your crystal ball analysis, what do you expect we'll be doing in the way of antiretroviral therapy 7 years from now?
Flexner: I think 7 years from now, the majority of HIV-infected individuals are going to be treated with long-acting agents. The reason I say that is because if you look at other chronic conditions where we've moved from oral to injectable to implantable long-acting agents, the patients with these conditions, once they realize that it's possible to not have to take pills every day, seem to gravitate to long-acting therapy. I don't think our HIV-infected patients are going to be any different.
There are some amazing new ways of delivering long-acting antiretrovirals in development: for example, transdermal patches that have microneedles that dissolve under the skin but leave behind a nanoformulated depot for long-acting delivery of drugs like cabotegravir. I think we're going to be seeing more of those kinds of approaches to drug delivery. Approaches we would have considered to be science fiction just a few years ago are going to be science fact in the next 5-7 years.
Saag: I think you're exactly right. That's especially going to be true for prevention. Using these long-acting agents as prevention, I think, is going to revolutionize the effectiveness of preexposure prophylaxis (PrEP).
Flexner: I agree, Mike. It's going to be a very exciting time ahead of us.
Saag: Well, our time has gone by very quickly, and unfortunately, we're at the end of our conversation. Today we talked with Dr Charlie Flexner about a number of things, especially drug-drug interactions, the mechanisms of the drug interactions, the enzyme systems that we know can be inhibited [by drugs] like ritonavir and cobicistat that we've known and used for years. But we've also learned about transport mechanisms in the kidney itself, especially in the proximal tubular epithelial cells that can get drugs from the plasma and into the urine, and how we can take advantage of that knowledge. But especially looking to the future, we talked about the notion of longer-acting therapies that are just now coming around — some of their limitations, but mostly their promise and the ability for us to be able to use these drugs in the majority of patients in all likelihood over the next 3-7 years. I think that's going to be the future of HIV therapeutics, both in terms of treatment and prevention.
Charlie, thank you very much for joining us today. Thanks to everybody for tuning in. If you haven't already done so, please take a moment to download the Medscape app to listen and subscribe to this podcast series on HIV. This is Michael Saag for InDiscussion.
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Cite this: Anticipating and Managing Drug Interactions: Pharmacokinetics of Long-Acting HIV Treatment and Prevention Formulations - Medscape - Apr 11, 2023.