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Optimal Use of 5-HT3 Antagonists in CINV

Panelists:Lee S. Schwartzberg, MD, FACP, University of Tennessee Health Science Center;Rebecca Clark-Snow, RN, BSN, OCN, University of Kansas Cancer Center;Charles L. Loprinzi, MD, Mayo Clinic;James Natale, PharmD, BCOP, UPMC Cancer Center;Eric Roeland, MD, University of California, San Diego
Published: Monday, Aug 15, 2016


Transcript:

Lee S. Schwartzberg, MD:
Let’s move on to how the landscape of CINV therapies has have changed in the last few years. I think if you look at the whole field, we started in the 1980s with the first drug that was developed that helped CINV, and that was high-dose metoclopramide. It’s not a drug that we use anymore. It had a lot of toxicity, but at least it made an impact. And then came the 5-HT3 receptor antagonists, which truly transformed the field in the early 90s. Over the last 10 years, there’s been some additional advances, and we want to talk about those with our audience. So, Jim, you want to talk to us about the 5-HT3 receptor antagonists and some of the drugs we have available now?

James Natale, PharmD, BCOP: I’ll start with what most commonly we refer to as first- or second-generation 5-HT3’s. The first-generation agents being ondansetron, granisetron, and dolasetron, with the second-generation agent being palonosetron. I think palonosetron or, Aloxi, has made an impact in the control and prevention of CINV on a number of different levels from a both a pharmacokinetic and pharmacokinetic standpoint. It certainly has a longer half-life; it sticks around longer. There are at least some lab studies that show they may have different binding parameters to the receptors. In clinical trials, it’s been compared to the first-generation agents both in MEC and HEC, MEC being moderately emetogenic and HEC being highly emetogenic chemotherapies. It shows better control in the delayed phase, as well as overall phases, and equivalent efficacy in the acute phase.

Lee S. Schwartzberg, MD: So, in your institution, are you predominantly using palonosetron?

James Natale, PharmD, BCOP: We are.

Lee S. Schwartzberg, MD: Eric, what do you think?

Eric Roeland, MD: I favor palonosetron, as well, from the patient perspective. But, I think something that’s really important for everyone out there to realize, and I see this happening all the time, is they’ll get palonosetron as their prophylactic medication. And, then, for breakthrough, I’m unfortunately seeing people given ondansetron. So, once that 5-HT3 receptor is saturated, adding more Zofran or ondansetron, on top of that, doesn’t work. I think it’s important for when you’re thinking about your breakthrough medications that you’re thinking about a different class of medication. In the same way, when you approach like, blood pressure, you’re going to take hydrochlorothiazide. If that’s not working, you’re going to take a different class of medication not just keep adding the same. But, the advantage of that is that you just get that one time with palonosetron and you’re pretty much protected for 72 hours, which is really nice for the patient.

Lee S. Schwartzberg, MD: That’s a really important point. Because we also know that with the first-generation agents, when they were given day after day, there was really very little effectiveness after day 1. So, there’s a difference, perhaps with the receptor occupancy, or the receptor interaction, as well as the long half-life. And, we see that in the clinical trial data. You’ve been involved in those clinical trials from the original palonosetron studies. Do you have any comments about that?

Rebecca Clark-Snow, RN, BSN, OCN: Actually, not the palonosetron. This goes way far back to the serotonin antagonists and metoclopramide trials.

Lee S. Schwartzberg, MD: You’ve been there from the beginning. That’s great.

Rebecca Clark-Snow, RN, BSN, OCN: Yes.

James Natale, PharmD, BCOP: It’s the same concept with the drugs themselves. If you look at a package insert on ondansetron, you’ll see it’s still the original dosing of 3 times a day. Nobody does that anymore, it’s all once-a-day dosing. It’s the same concept. You saturate the receptors, they’re saturated. They all have a plateau effect.

Eric Roeland, MD: I think we should point out though, the guidelines don’t really distinguish between the 5-HT3 receptor antagonist, except some guidelines prefer the palonosetron. But, in certain institutions where you’re restricted on which ones you can choose, the key is that you’re making sure that it is scheduled and not allow breakthrough in that highly emetogenic situation and moderate emetogenic situation.

Charles L. Loprinzi, MD: I might add in that I use palonosetron often, and it’s a good drug for that setting. If you’re using a moderately emetogenic and you happen to use an NK1 receptor antagonist, you probably don’t need the palonosetron in there. Because they’re both pretty expensive medications and we have to think about the financial implications for these things. But, the guidelines suggest if you’re going to a highly emetogenic chemotherapy where you use an NK1 receptor antagonist, you can use any of the 5-HT3 receptor antagonists in that particular setting. But, if you’re using it without an NK1, then the palonosetron is clearly better. So, I think we have to keep that into perspective.

Lee S. Schwartzberg, MD: Right, so we don’t have a lot. The data on palonosetron, either alone or with dexamethasone, which is given as the third group of agents that we typically use for prophylaxis for CINV, showed superiority, particularly in the late phase. We have limited data in the 3-drug regimen, but the data, as yet, do not support a clear-cut superiority.

Transcript Edited for Clarity
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Transcript:

Lee S. Schwartzberg, MD:
Let’s move on to how the landscape of CINV therapies has have changed in the last few years. I think if you look at the whole field, we started in the 1980s with the first drug that was developed that helped CINV, and that was high-dose metoclopramide. It’s not a drug that we use anymore. It had a lot of toxicity, but at least it made an impact. And then came the 5-HT3 receptor antagonists, which truly transformed the field in the early 90s. Over the last 10 years, there’s been some additional advances, and we want to talk about those with our audience. So, Jim, you want to talk to us about the 5-HT3 receptor antagonists and some of the drugs we have available now?

James Natale, PharmD, BCOP: I’ll start with what most commonly we refer to as first- or second-generation 5-HT3’s. The first-generation agents being ondansetron, granisetron, and dolasetron, with the second-generation agent being palonosetron. I think palonosetron or, Aloxi, has made an impact in the control and prevention of CINV on a number of different levels from a both a pharmacokinetic and pharmacokinetic standpoint. It certainly has a longer half-life; it sticks around longer. There are at least some lab studies that show they may have different binding parameters to the receptors. In clinical trials, it’s been compared to the first-generation agents both in MEC and HEC, MEC being moderately emetogenic and HEC being highly emetogenic chemotherapies. It shows better control in the delayed phase, as well as overall phases, and equivalent efficacy in the acute phase.

Lee S. Schwartzberg, MD: So, in your institution, are you predominantly using palonosetron?

James Natale, PharmD, BCOP: We are.

Lee S. Schwartzberg, MD: Eric, what do you think?

Eric Roeland, MD: I favor palonosetron, as well, from the patient perspective. But, I think something that’s really important for everyone out there to realize, and I see this happening all the time, is they’ll get palonosetron as their prophylactic medication. And, then, for breakthrough, I’m unfortunately seeing people given ondansetron. So, once that 5-HT3 receptor is saturated, adding more Zofran or ondansetron, on top of that, doesn’t work. I think it’s important for when you’re thinking about your breakthrough medications that you’re thinking about a different class of medication. In the same way, when you approach like, blood pressure, you’re going to take hydrochlorothiazide. If that’s not working, you’re going to take a different class of medication not just keep adding the same. But, the advantage of that is that you just get that one time with palonosetron and you’re pretty much protected for 72 hours, which is really nice for the patient.

Lee S. Schwartzberg, MD: That’s a really important point. Because we also know that with the first-generation agents, when they were given day after day, there was really very little effectiveness after day 1. So, there’s a difference, perhaps with the receptor occupancy, or the receptor interaction, as well as the long half-life. And, we see that in the clinical trial data. You’ve been involved in those clinical trials from the original palonosetron studies. Do you have any comments about that?

Rebecca Clark-Snow, RN, BSN, OCN: Actually, not the palonosetron. This goes way far back to the serotonin antagonists and metoclopramide trials.

Lee S. Schwartzberg, MD: You’ve been there from the beginning. That’s great.

Rebecca Clark-Snow, RN, BSN, OCN: Yes.

James Natale, PharmD, BCOP: It’s the same concept with the drugs themselves. If you look at a package insert on ondansetron, you’ll see it’s still the original dosing of 3 times a day. Nobody does that anymore, it’s all once-a-day dosing. It’s the same concept. You saturate the receptors, they’re saturated. They all have a plateau effect.

Eric Roeland, MD: I think we should point out though, the guidelines don’t really distinguish between the 5-HT3 receptor antagonist, except some guidelines prefer the palonosetron. But, in certain institutions where you’re restricted on which ones you can choose, the key is that you’re making sure that it is scheduled and not allow breakthrough in that highly emetogenic situation and moderate emetogenic situation.

Charles L. Loprinzi, MD: I might add in that I use palonosetron often, and it’s a good drug for that setting. If you’re using a moderately emetogenic and you happen to use an NK1 receptor antagonist, you probably don’t need the palonosetron in there. Because they’re both pretty expensive medications and we have to think about the financial implications for these things. But, the guidelines suggest if you’re going to a highly emetogenic chemotherapy where you use an NK1 receptor antagonist, you can use any of the 5-HT3 receptor antagonists in that particular setting. But, if you’re using it without an NK1, then the palonosetron is clearly better. So, I think we have to keep that into perspective.

Lee S. Schwartzberg, MD: Right, so we don’t have a lot. The data on palonosetron, either alone or with dexamethasone, which is given as the third group of agents that we typically use for prophylaxis for CINV, showed superiority, particularly in the late phase. We have limited data in the 3-drug regimen, but the data, as yet, do not support a clear-cut superiority.

Transcript Edited for Clarity
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