The medications used to treat gastroesophageal reflux (GERD) in children ignore one BIG factor – obesity. Obesity is a known risk factor for GERD in children, but the proton pump inhibitor (PPI) pantoprazole commonly used to treat GERD has no dosing guidelines for overweight and obese children.
Dr. Shakhnovich is here to explain that through her research, she has found that giving overweight children larger doses, a recently suggested practice with adults, could actually cause more harm than good and predispose children to unwanted side-effects from unintentional systemic overexposure to PPIs.
Selected Podcast
The GERD, The Bad, The Ugly: When Dosing Guidelines Ignore A BIG Problem
Featured Speaker:
Learn more about Valentina Shakhnovich, MD
Valentina Shakhnovich, MD
Valentina Shakhnovich, MD, is an Assistant Professor of Pediatrics and Associate Program Director for Gastroenterology Fellowship Research Program at Children’s Mercy Kansas City. Dr Shakhnovich is one of two double fellowship trained pediatric gastroenterologist and clinical pharmacologist in the nation. She completed her residency in pediatrics at the University of Wisconsin School of Medicine in 2011 followed by a fellowship in Clinical Pharmacology and Pediatric Gastroenterology at Children’s Mercy Kansas City in 2015.Learn more about Valentina Shakhnovich, MD
Transcription:
The GERD, The Bad, The Ugly: When Dosing Guidelines Ignore A BIG Problem
Dr. Michael Smith (Host): Alright, so our topic today is the GERD, The Bad, The Ugly: When Dosing Guidelines Ignore a Big Problem. My guest is Dr. Valentina Shakhnovich. She is an assistant professor of pediatrics and associate program director for gastroenterology fellowship research program at Children's Mercy Kansas City. Dr. Shakhnovich, welcome to the show.
Dr. Valentina Shakhnovich (Guest): Thank you, Dr. Mike!
Dr. Smith: You said I could call you Dr. Tina, right, moving forward?
Dr. Shakhnovich: Yes, absolutely.
Dr. Smith: Alright, well, let's talk about this, right. So, we know reflux disease has always been common in the adult world -- medicine world, but what about in children? What kind of -- how many cases are we dealing with nowadays in children with GERD?
Dr. Shakhnovich: So, GERD is a very common problem in children, not just an infant, but in older children as well. One of the reasons GERD is on the rise is just like in the adult population, GERD is associated with obesity in the pediatric population as well, so as the number of obese children increases, unfortunately, we're seeing a rise in pediatric GERD and the need to treat this condition.
Dr. Smith: One of the things that you are really looking at, though, within this, right, is the fact that in an obese child, right, when they have GERD simply increasing dose of those PPIs is not necessarily the best thing to do, right? So, that's been really your focus in this, is how we are really treating that specific case of GERD with obesity, right?
Dr. Shakhnovich: Absolutely. Absolutely. What we were interested in is figuring out what is the appropriate dose of proton pump inhibitors for obese children with GERD, and I think a lot of us -- out of the best intentions -- have the knee jerk reaction in pediatrics if we see a 10-year old who is twice the size of an average 10-year-old -- maybe we should double the dose of the medication. What our line of research has shown in two separate studies – is that's actually probably not the best thing to do for obese kids as it appears that they actually require lower doses of proton pump inhibitors on a per kilogram basis than their non-obese counterparts.
Dr. Smith: That's pretty fascinating to find out, right, because that goes kind of counterintuitive to everything we, at least -- we think we know about pharmacology, right?
Dr. Shakhnovich: Right. Absolutely, it has tremendous implications potentially when we think about some of the side effect profile information that's coming out about proton pump inhibitors as a drug class. These drugs have been around for three decades now, and when they first came on the market, they were really intended for short-term use of acid suppression. They were very safe from that standpoint, had a favorable side effect profile, and what we've learned now almost 30 years later is we are seeing some unexpected long-term potential side effects like lower bone density leading to osteopenia, osteoporosis, fractures, mineral and vitamin deficiencies that really we weren't anticipating, and I think of the consequence of using the drugs for longer periods of time which unfortunately some of our pediatric patients need --
Dr. Smith: Yeah...
Dr. Shakhnovich: -- I think not overdosing the chubby kids and minimizing the potential for side effects associated with high dose meds that's going to be key.
Dr. Smith: Yeah, yeah, because what's -- if you think about it -- so a child maybe say 5, 6 years old whose overweight is placed on a PPI, I mean, if they're going to be on that for an extended period of time, the consequences of that could be quite alarming, right? Because who knows how long they might stay on that PPI, right? So, what are you proposing then? Is there a new approach to this? Is there a new dosing practice that you'd like to see pediatricians follow?
Dr. Shakhnovich: Absolutely. This is the first step in defining what the appropriate dosing guidelines are for medications for children who are obese. What we hope to accomplish with the report that we just submitted to the FDA for approval is to actually include a statement in the label for pantoprazole, the PPI we started with, saying that obese children do not need to have dose escalation of this medication based on weight but, in fact, they can be dosed using the same dosing guidelines as non-obese peers, and if we increase their dose arbitrarily, we may actually be causing them more harm than good --
Dr. Smith: Yeah.
Dr. Shakhnovich: -- I think that's a good starting point. I think some of the next steps are going to be figuring out does this hold true for all other proton pump inhibitors or is there a different dosing paradigm depending on which of the PPI agents we're prescribing?
Dr. Smith: Yeah, so, how are you going to get this message out then, right? So, I know there's a lot of general practitioners, nurse practitioners, general pediatricians, that have an obese patient, they have GERD, and they're starting them on those higher doses. They're not -- how are we going to disseminate this information? Is there a plan for that?
Dr. Shakhnovich: Absolutely. I think educating the community is going to be key because the prescribers are the front lines, right? If they don't have the most up-to-date information, then we're all sort of sunk. That's exactly why we targeted our data first and foremost in our FDA report because ultimately, we look up dosing guidelines for the medications we prescribe, and we feel much more confident in our prescribing practices when there is an upfront statement for obese pediatric patients --please consider dose reduction or, you know, a particular dosing algorithm, which is precisely what we’re proposing to the FDA. So, we're optimistic that that technique is actually what’s going to allow us to disseminate this message quickly and effectively.
Dr. Smith: Yeah, this makes me wonder now, Dr. Tina, though, so we're specifically talking about GERD, PPIs, dosing in obese kids; what we've discovered and learned is not necessarily what we thought -- or how it should work, right? We should increase dose in a heavier kid. Is this true for other classes of medications, you think? I mean do we really need to look at, you know, better dosing guidelines in obese kids across the board?
Dr. Shakhnovich: We absolutely need to look at dosing guidelines specific to obese children. The reality is approximately one in six children is obese. One in three is overweight, so we can't keep ignoring this large population of kids who are getting prescribed medication frequently for obesity-related comorbidities. I think it's essential to start including obese patients in clinical trials upfront so that we're not trying to guess at the correct dose, and we're not trying to play catch up. I think the million dollar question is, what are the mechanisms that are responsible for the altered processing of medication in children who are overweight and obese, and once we figure out what those mechanisms are, I think we're going to be much better off at extrapolating what the appropriate dosing regimen is for obese children or drugs other than PPIs, and that's exactly where the next line of research for us here at Children's Mercy is headed.
Dr. Smith: Yeah. When you speak with researchers, organization that fund the clinical research, and you mention this -- that we almost need an obesity arm in all of these trials, what's the response to that?
Dr. Shakhnovich: Well, you know, fortunately, we now have organizations like the Pediatric Trials Network, who are very aware of this problem. So, the Pediatric Trials Network, the PTN, is sponsored by the NIH, and really their mission has been to make sure that we represent underrepresented populations of kids including kids who are obese. That's actually how we were able to fund one of the studies that really demonstrated that -- hey guys -- we're overdosing obese kids with PPIs.
Dr. Smith: Yeah. So let's do this. Let's end this way, Dr. Tina. So, right now, you know, a lot of community physicians listen to the show. You have a listening audience, what would you like to say to them about obese kids with GERD, and you’re about to write that prescription for a PPI?
Dr. Shakhnovich: You know, I think, until the clear dosing guidelines come from the FDA, the best practice, at least, in my opinion, is to think twice before dose escalating just because a child is obese. From our data, it certainly seems like for pantoprazole, at least, there really is no need to dose escalate for obese children.
Dr. Smith: It’s great. Dr. Tina, thank you for the work that you're doing at Children's Mercy and thank you for coming on the show today. You're listening to Transformational Pediatrics with Children's Mercy Kansas City. For more information you can go to childrensmercy.org. That's childrensmercy.org. I'm Dr. Mike Smith, thanks for listening.
The GERD, The Bad, The Ugly: When Dosing Guidelines Ignore A BIG Problem
Dr. Michael Smith (Host): Alright, so our topic today is the GERD, The Bad, The Ugly: When Dosing Guidelines Ignore a Big Problem. My guest is Dr. Valentina Shakhnovich. She is an assistant professor of pediatrics and associate program director for gastroenterology fellowship research program at Children's Mercy Kansas City. Dr. Shakhnovich, welcome to the show.
Dr. Valentina Shakhnovich (Guest): Thank you, Dr. Mike!
Dr. Smith: You said I could call you Dr. Tina, right, moving forward?
Dr. Shakhnovich: Yes, absolutely.
Dr. Smith: Alright, well, let's talk about this, right. So, we know reflux disease has always been common in the adult world -- medicine world, but what about in children? What kind of -- how many cases are we dealing with nowadays in children with GERD?
Dr. Shakhnovich: So, GERD is a very common problem in children, not just an infant, but in older children as well. One of the reasons GERD is on the rise is just like in the adult population, GERD is associated with obesity in the pediatric population as well, so as the number of obese children increases, unfortunately, we're seeing a rise in pediatric GERD and the need to treat this condition.
Dr. Smith: One of the things that you are really looking at, though, within this, right, is the fact that in an obese child, right, when they have GERD simply increasing dose of those PPIs is not necessarily the best thing to do, right? So, that's been really your focus in this, is how we are really treating that specific case of GERD with obesity, right?
Dr. Shakhnovich: Absolutely. Absolutely. What we were interested in is figuring out what is the appropriate dose of proton pump inhibitors for obese children with GERD, and I think a lot of us -- out of the best intentions -- have the knee jerk reaction in pediatrics if we see a 10-year old who is twice the size of an average 10-year-old -- maybe we should double the dose of the medication. What our line of research has shown in two separate studies – is that's actually probably not the best thing to do for obese kids as it appears that they actually require lower doses of proton pump inhibitors on a per kilogram basis than their non-obese counterparts.
Dr. Smith: That's pretty fascinating to find out, right, because that goes kind of counterintuitive to everything we, at least -- we think we know about pharmacology, right?
Dr. Shakhnovich: Right. Absolutely, it has tremendous implications potentially when we think about some of the side effect profile information that's coming out about proton pump inhibitors as a drug class. These drugs have been around for three decades now, and when they first came on the market, they were really intended for short-term use of acid suppression. They were very safe from that standpoint, had a favorable side effect profile, and what we've learned now almost 30 years later is we are seeing some unexpected long-term potential side effects like lower bone density leading to osteopenia, osteoporosis, fractures, mineral and vitamin deficiencies that really we weren't anticipating, and I think of the consequence of using the drugs for longer periods of time which unfortunately some of our pediatric patients need --
Dr. Smith: Yeah...
Dr. Shakhnovich: -- I think not overdosing the chubby kids and minimizing the potential for side effects associated with high dose meds that's going to be key.
Dr. Smith: Yeah, yeah, because what's -- if you think about it -- so a child maybe say 5, 6 years old whose overweight is placed on a PPI, I mean, if they're going to be on that for an extended period of time, the consequences of that could be quite alarming, right? Because who knows how long they might stay on that PPI, right? So, what are you proposing then? Is there a new approach to this? Is there a new dosing practice that you'd like to see pediatricians follow?
Dr. Shakhnovich: Absolutely. This is the first step in defining what the appropriate dosing guidelines are for medications for children who are obese. What we hope to accomplish with the report that we just submitted to the FDA for approval is to actually include a statement in the label for pantoprazole, the PPI we started with, saying that obese children do not need to have dose escalation of this medication based on weight but, in fact, they can be dosed using the same dosing guidelines as non-obese peers, and if we increase their dose arbitrarily, we may actually be causing them more harm than good --
Dr. Smith: Yeah.
Dr. Shakhnovich: -- I think that's a good starting point. I think some of the next steps are going to be figuring out does this hold true for all other proton pump inhibitors or is there a different dosing paradigm depending on which of the PPI agents we're prescribing?
Dr. Smith: Yeah, so, how are you going to get this message out then, right? So, I know there's a lot of general practitioners, nurse practitioners, general pediatricians, that have an obese patient, they have GERD, and they're starting them on those higher doses. They're not -- how are we going to disseminate this information? Is there a plan for that?
Dr. Shakhnovich: Absolutely. I think educating the community is going to be key because the prescribers are the front lines, right? If they don't have the most up-to-date information, then we're all sort of sunk. That's exactly why we targeted our data first and foremost in our FDA report because ultimately, we look up dosing guidelines for the medications we prescribe, and we feel much more confident in our prescribing practices when there is an upfront statement for obese pediatric patients --please consider dose reduction or, you know, a particular dosing algorithm, which is precisely what we’re proposing to the FDA. So, we're optimistic that that technique is actually what’s going to allow us to disseminate this message quickly and effectively.
Dr. Smith: Yeah, this makes me wonder now, Dr. Tina, though, so we're specifically talking about GERD, PPIs, dosing in obese kids; what we've discovered and learned is not necessarily what we thought -- or how it should work, right? We should increase dose in a heavier kid. Is this true for other classes of medications, you think? I mean do we really need to look at, you know, better dosing guidelines in obese kids across the board?
Dr. Shakhnovich: We absolutely need to look at dosing guidelines specific to obese children. The reality is approximately one in six children is obese. One in three is overweight, so we can't keep ignoring this large population of kids who are getting prescribed medication frequently for obesity-related comorbidities. I think it's essential to start including obese patients in clinical trials upfront so that we're not trying to guess at the correct dose, and we're not trying to play catch up. I think the million dollar question is, what are the mechanisms that are responsible for the altered processing of medication in children who are overweight and obese, and once we figure out what those mechanisms are, I think we're going to be much better off at extrapolating what the appropriate dosing regimen is for obese children or drugs other than PPIs, and that's exactly where the next line of research for us here at Children's Mercy is headed.
Dr. Smith: Yeah. When you speak with researchers, organization that fund the clinical research, and you mention this -- that we almost need an obesity arm in all of these trials, what's the response to that?
Dr. Shakhnovich: Well, you know, fortunately, we now have organizations like the Pediatric Trials Network, who are very aware of this problem. So, the Pediatric Trials Network, the PTN, is sponsored by the NIH, and really their mission has been to make sure that we represent underrepresented populations of kids including kids who are obese. That's actually how we were able to fund one of the studies that really demonstrated that -- hey guys -- we're overdosing obese kids with PPIs.
Dr. Smith: Yeah. So let's do this. Let's end this way, Dr. Tina. So, right now, you know, a lot of community physicians listen to the show. You have a listening audience, what would you like to say to them about obese kids with GERD, and you’re about to write that prescription for a PPI?
Dr. Shakhnovich: You know, I think, until the clear dosing guidelines come from the FDA, the best practice, at least, in my opinion, is to think twice before dose escalating just because a child is obese. From our data, it certainly seems like for pantoprazole, at least, there really is no need to dose escalate for obese children.
Dr. Smith: It’s great. Dr. Tina, thank you for the work that you're doing at Children's Mercy and thank you for coming on the show today. You're listening to Transformational Pediatrics with Children's Mercy Kansas City. For more information you can go to childrensmercy.org. That's childrensmercy.org. I'm Dr. Mike Smith, thanks for listening.