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Monitoring Azole Levels in Transplant Patients

Panelists: Harry Erba, MD, PhD, University of Alabama at Birmingham; Roy Chemaly, MD, MPH, MD Anderson Cancer Center; Mark Levis, MD, PhD, Sidney Kimmel Comprehensive Cancer Center
Published: Monday, Jan 23, 2017


Transcript:

Harry Erba, MD, PhD:
I’d like the 2 of you to comment on the particular aspect of the use of posaconazole that I’ve heard at my own institution. In AML, I do believe there are data showing a survival benefit of posaconazole in patients undergoing induction chemotherapy. But, one of the concerns that some of my colleagues have about posaconazole is the GI absorption, requiring food and making the case that patients are often not eating during this. They have mucositis. And so, they say, “Well, maybe we should use another drug that might be absorbed better.” On the other hand, in that very same population, we have randomized data showing a benefit. How do you deal with that?

Roy Chemaly, MD, MPH: So, actually, maybe a few years ago, we had been using the oral suspension of posaconazole where it can interact with food and you have to take it with high-fat meal diet, and absorption was an issue. Now with the new formulation actually, we don’t see this impact.

Mark Levis, MD, PhD: Yes, we made the leap. The randomized study showing the survival benefit with posaconazole was, in fact, the suspension. So, when the oral formulation came out, we sat down and said, “Are we going to allow this extrapolation to occur?” We were having such problems with voriconazole and its concomitant side effects. We made the leap 2 years ago, and we’ve been very satisfied with the results.

Roy Chemaly, MD, MPH: Especially when you look at the levels that we’re actually seeing in the blood with the new formulations. They are pretty high. It happened, it’s quite predictable.

Mark Levis, MD, PhD: Yes. We’re pretty confident that they’re getting good levels of posaconazole. And it is important to remember, we do like monitoring levels of azoles. Having a good assay at your institution, or available to you so you can follow azole levels in these patients, is important.

Roy Chemaly, MD, MPH: Right, especially when you treat it. Because it’s a predictable kind of level that you’re going to achieve. But, therefore, absolutely for treatment, or when you have a breakthrough infection, you always look at the level—was it really a failure of the triazoles or is it the infection is so invasive?

Harry Erba, MD, PhD: In my AML population, I found that a little bit hard to apply because the turnaround time, from commercial labs at least, has been a while. Is that an issue?

Roy Chemaly, MD, MPH: I think now within 48 hours, you can get the result of the level. Depends which lab you send it to and who’s doing it. So, it can guide you actually.

Mark Levis, MD, PhD: A trickier thing with the azoles, particularly with posaconazole, we’re forced to become pharmacologists because they do have drug interaction issues. The patients are routinely on calcineurin inhibitors. So, I have patients where I’m controlling their graft-versus-host (GVH) disease with a calcineurin inhibitor at a certain level. And it’s the azole that’s keeping it at that level. If I decide it’s time to pull the azole out, the tacrolimus level goes down and you get a flare of GVH.

Roy Chemaly, MD, MPH: Absolutely. You have to keep a close observation.

Harry Erba, MD, PhD: So, not only are you rounding with the ID guys, you have your pharmacist on service.

Roy Chemaly, MD, MPH, and Mark Levis, MD, PhD: Absolutely, we do.

Harry Erba, MD, PhD: Because, you have to in this situation. And of these drugs that we use, my recollection is itraconazole was the one with the more variable metabolic profile.

Roy Chemaly, MD, MPH: Yes. Actually, with itraconazole, it used to be the main oral drug for mold-active infection in the past—more than 10 years ago. Because of the anthracycline, either the lipid formulation or without the lipid formulation, it is a toxic drug. The issue with itraconazole is we didn’t have a great experience with this drug. First, it wasn’t active as a prophylaxis as much as we would like it to, and treatment levels were not predictable. And also, there were side effects. When you go with a higher dose of itraconazole, it’s pretty common and could be serious sometimes. So, I don’t think anyone is using itraconazole anymore.

Mark Levis, MD, PhD: No, I have not seen that used in well over a decade.

Harry Erba, MD, PhD: But, of the drugs we talked about—posaconazole, fluconazole, and voriconazole—there is a fourth drug that I’ve heard of, an oral antifungal. Can you tell us more about that?

Roy Chemaly, MD, MPH: Isavuconazole is probably what you’re alluding to. It’s a newly approved drug. Actually, it has an indication for invasive aspergillosis, as well as for mucormycosis, although according to the data, it’s for a small cohort of patients. And based on my experience with it, it’s still a good drug. There are not much of clinical data published already on it.

Mark Levis, MD, PhD: That’s the problem.

Harry Erba, MD, PhD: This is the issue.

Mark Levis, MD, PhD: Yes. One advantage that’s been brought up is potentially less of the FLT3 and FLT4 interaction effect. So, maybe it’s not going to drive my Taxol up so high.

Roy Chemaly, MD, MPH: But, we’re waiting for more data.

Mark Levis, MD, PhD: The simple truth is we’ve gotten very comfortable with posaconazole since that came out. The oral formulation, not the suspension.

Harry Erba, MD, PhD: So, I think we’ve covered what I wanted to cover for invasive fungal infection, unless there are any other comments that you want to bring up.

Mark Levis, MD, PhD: I would just say, going back, that I know you know this is true from 15 or 20 years ago when fungal infections were killing our patients: it’s not a problem anymore, is it?

Harry Erba, MD, PhD: It really isn’t a problem anymore. I’ll tell you the biggest problem that I see in my AML population is diagnosis. You have a patient with persistent fevers. You have pulmonary infiltrates that are suspicious for invasive fungal infection. I think it’s because we use so much prophylaxis—I can’t remember the last time I had a positive BAL (bronchoalvelar lavage)—and yet, we sent all of these patients, when they have low counts and they’re sick, for bronchoscopy. So, what do you think about that?

Roy Chemaly, MD, MPH: I think what we’re seeing now actually is that the ones who will get into trouble with invasive fungal infection are the ones who are not on prophylaxis, and for many reasons. It could be either toxicity or they thought the patient was not at high risk for fungal.

Mark Levis, MD, PhD: And the third one is their insurance didn’t cover it.

Roy Chemaly, MD, MPH: Absolutely, unfortunately. It happens more often than we like to see.

Harry Erba, MD, PhD: OK.

Transcript Edited for Clarity
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Transcript:

Harry Erba, MD, PhD:
I’d like the 2 of you to comment on the particular aspect of the use of posaconazole that I’ve heard at my own institution. In AML, I do believe there are data showing a survival benefit of posaconazole in patients undergoing induction chemotherapy. But, one of the concerns that some of my colleagues have about posaconazole is the GI absorption, requiring food and making the case that patients are often not eating during this. They have mucositis. And so, they say, “Well, maybe we should use another drug that might be absorbed better.” On the other hand, in that very same population, we have randomized data showing a benefit. How do you deal with that?

Roy Chemaly, MD, MPH: So, actually, maybe a few years ago, we had been using the oral suspension of posaconazole where it can interact with food and you have to take it with high-fat meal diet, and absorption was an issue. Now with the new formulation actually, we don’t see this impact.

Mark Levis, MD, PhD: Yes, we made the leap. The randomized study showing the survival benefit with posaconazole was, in fact, the suspension. So, when the oral formulation came out, we sat down and said, “Are we going to allow this extrapolation to occur?” We were having such problems with voriconazole and its concomitant side effects. We made the leap 2 years ago, and we’ve been very satisfied with the results.

Roy Chemaly, MD, MPH: Especially when you look at the levels that we’re actually seeing in the blood with the new formulations. They are pretty high. It happened, it’s quite predictable.

Mark Levis, MD, PhD: Yes. We’re pretty confident that they’re getting good levels of posaconazole. And it is important to remember, we do like monitoring levels of azoles. Having a good assay at your institution, or available to you so you can follow azole levels in these patients, is important.

Roy Chemaly, MD, MPH: Right, especially when you treat it. Because it’s a predictable kind of level that you’re going to achieve. But, therefore, absolutely for treatment, or when you have a breakthrough infection, you always look at the level—was it really a failure of the triazoles or is it the infection is so invasive?

Harry Erba, MD, PhD: In my AML population, I found that a little bit hard to apply because the turnaround time, from commercial labs at least, has been a while. Is that an issue?

Roy Chemaly, MD, MPH: I think now within 48 hours, you can get the result of the level. Depends which lab you send it to and who’s doing it. So, it can guide you actually.

Mark Levis, MD, PhD: A trickier thing with the azoles, particularly with posaconazole, we’re forced to become pharmacologists because they do have drug interaction issues. The patients are routinely on calcineurin inhibitors. So, I have patients where I’m controlling their graft-versus-host (GVH) disease with a calcineurin inhibitor at a certain level. And it’s the azole that’s keeping it at that level. If I decide it’s time to pull the azole out, the tacrolimus level goes down and you get a flare of GVH.

Roy Chemaly, MD, MPH: Absolutely. You have to keep a close observation.

Harry Erba, MD, PhD: So, not only are you rounding with the ID guys, you have your pharmacist on service.

Roy Chemaly, MD, MPH, and Mark Levis, MD, PhD: Absolutely, we do.

Harry Erba, MD, PhD: Because, you have to in this situation. And of these drugs that we use, my recollection is itraconazole was the one with the more variable metabolic profile.

Roy Chemaly, MD, MPH: Yes. Actually, with itraconazole, it used to be the main oral drug for mold-active infection in the past—more than 10 years ago. Because of the anthracycline, either the lipid formulation or without the lipid formulation, it is a toxic drug. The issue with itraconazole is we didn’t have a great experience with this drug. First, it wasn’t active as a prophylaxis as much as we would like it to, and treatment levels were not predictable. And also, there were side effects. When you go with a higher dose of itraconazole, it’s pretty common and could be serious sometimes. So, I don’t think anyone is using itraconazole anymore.

Mark Levis, MD, PhD: No, I have not seen that used in well over a decade.

Harry Erba, MD, PhD: But, of the drugs we talked about—posaconazole, fluconazole, and voriconazole—there is a fourth drug that I’ve heard of, an oral antifungal. Can you tell us more about that?

Roy Chemaly, MD, MPH: Isavuconazole is probably what you’re alluding to. It’s a newly approved drug. Actually, it has an indication for invasive aspergillosis, as well as for mucormycosis, although according to the data, it’s for a small cohort of patients. And based on my experience with it, it’s still a good drug. There are not much of clinical data published already on it.

Mark Levis, MD, PhD: That’s the problem.

Harry Erba, MD, PhD: This is the issue.

Mark Levis, MD, PhD: Yes. One advantage that’s been brought up is potentially less of the FLT3 and FLT4 interaction effect. So, maybe it’s not going to drive my Taxol up so high.

Roy Chemaly, MD, MPH: But, we’re waiting for more data.

Mark Levis, MD, PhD: The simple truth is we’ve gotten very comfortable with posaconazole since that came out. The oral formulation, not the suspension.

Harry Erba, MD, PhD: So, I think we’ve covered what I wanted to cover for invasive fungal infection, unless there are any other comments that you want to bring up.

Mark Levis, MD, PhD: I would just say, going back, that I know you know this is true from 15 or 20 years ago when fungal infections were killing our patients: it’s not a problem anymore, is it?

Harry Erba, MD, PhD: It really isn’t a problem anymore. I’ll tell you the biggest problem that I see in my AML population is diagnosis. You have a patient with persistent fevers. You have pulmonary infiltrates that are suspicious for invasive fungal infection. I think it’s because we use so much prophylaxis—I can’t remember the last time I had a positive BAL (bronchoalvelar lavage)—and yet, we sent all of these patients, when they have low counts and they’re sick, for bronchoscopy. So, what do you think about that?

Roy Chemaly, MD, MPH: I think what we’re seeing now actually is that the ones who will get into trouble with invasive fungal infection are the ones who are not on prophylaxis, and for many reasons. It could be either toxicity or they thought the patient was not at high risk for fungal.

Mark Levis, MD, PhD: And the third one is their insurance didn’t cover it.

Roy Chemaly, MD, MPH: Absolutely, unfortunately. It happens more often than we like to see.

Harry Erba, MD, PhD: OK.

Transcript Edited for Clarity
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