Why does one child respond to a medication, but another doesn’t?
What are the factors that influence how a child responds to a medication and how do those differ from adults?
Despite all the talk about “big pharma” and research, very little has been done about testing the safety and efficacy of medications for children.
Even with new FDA regulations in place, pediatric labeling is decreasing, not increasing.
The Clinical Pharmacology, Toxicology and Personalized Therapeutics program at Children’s Mercy is the largest and most comprehensive pediatric pharmacology program in North America and has been at the forefront of advocating and advancing research.
The GOLDILOKS initiative acknowledges that individual children are not small average adults; dosing of medications must include factors that make each child unique in order to deliver the dose of medication that is “just right” for each individual child.
Children’s Mercy faculty (trained in a pediatric subspecialty and clinical pharmacology) are looking at how this applies in several subspecialty areas including cardiology, infectious disease, asthma/allergy, rheumatology, gastroenterology, neonatology and hematology/oncology.
Steve Leeder, PharmD, PhD is here to discuss the best ways to keep your child and their medications safe.
Selected Podcast
GOLDILOKS: Getting Medication Dosage “Just Right” for Children
Featured Speaker:
Steve Leeder, PharmD, PhD
Dr. Leeder is the Marion Merrell Dow/Missouri Endowed Chair in Pediatric Clinical Pharmacology and Chief, Division of Clinical Pharmacology and Medical Toxicology, at Children’s Mercy Kansas City. He holds faculty appointments as Professor of Pediatrics and Pharmacology at the University of Missouri-Kansas City; Courtesy Professor of Pharmaceutical Chemistry in the School of Pharmacy at the University of Kansas; and Adjunct Professor of Pharmacology, Toxicology, and Therapeutics at the University of Kansas Medical Center. Dr. Leeder is board certified in Applied Pharmacology by the American Board of Clinical Pharmacology. He received his PhD in pharmacology at the University of Toronto, Toronto, ON. Prior to that, he received his PharmD from University of Minnesota. Following 14 years at The Hospital for Sick Children in Toronto, Dr. Leeder joined Children’s Mercy in 1996. He is an elected member of the American Pediatric Society and serves on the American Board of Clinical Pharmacology, as Past-Chair of the Drug Metabolism Division of the American Society for Pharmacology and Experimental Therapeutics, and as Treasurer of the Drug Metabolism Section of the International Union of Pharmacology. Transcription:
GOLDILOKS: Getting Medication Dosage “Just Right” for Children
Dr. Michael Smith (Host): Welcome to Transformational Pediatrics. I’m Dr. Mike Smith. Our topic, Goldilocks: kiddie medication dosages just right for kids. My guest is Dr. Steve Leeder. He’s the department chair in Pediatric Clinical Pharmacology and Chief of the Division of Clinical Pharmacology and Medical Toxicology. Dr. Leeder is board certified in applied pharmacology by the American Board of Clinical Pharmacology. Dr. Leeder, welcome to the show.
Dr. Steve Leeder (Guest): Thank you very much for having me.
Dr. Smith: Well, tell us about the mission and goals of what is called the Goldilocks initiative.
Dr. Leeder: Well, just to put it in a nutshell, it’s the dose that’s not too big, not too small, it’s just right for your child. Underlying that concept is the reality that individual children are not small average adults, which is the way that most dosing recommendations have been developed. Our program is trying to identify those factors that make each child unique and use those to help guide the doses that will ultimately be used for an individual child.
Dr. Smith: So the guidelines that might come out of this initiative, these guidelines are going to be used by general practitioners, maybe not pediatricians but maybe family practice physicians that are treating kids? Or I guess maybe who’s really the target for these guidelines that might come out of it?
Dr. Leeder: Well, I think initially we are working with partner pediatric subspecialists here within our own institution. But when it comes to actually disseminating the experiences that we have and making them more broadly applicable, we really would like to reach general pediatricians in the community, pediatric subspecialists at other institutions. And so what this means is that ultimately we are hoping to develop web-based dosing algorithms or web-based decision support tools that ultimately would be accessible to anyone who has an Internet connection.
Dr. Smith: So what subspecialties in pediatrics are you working with right now with the initiative?
Dr. Leeder: We actually have several pediatric subspecialists who have undergone formal Clinical Pharmacology Training and are embedded, defined as being physically located within our clinical pharmacology group. Probably the biggest opportunities right now are in the area of cancer, pediatric cancer. We see opportunities in developmental behavioral sciences, particularly in ADHD and perhaps the use of antipsychotics and antidepressants in children with autism, depression. We also have partners in cardiology, where we are anticipating increasing use of statin medications in children, and we would like to be preemptive in coming up with safe and effective dosing guidelines for that class of medications. Asthma is another area where we have faculty with a specific interest in improving drug treatment there. Neonatology is another one of our partners, and multiple opportunities there. GI, particularly in the field of inflammatory bowel disease, has lots of opportunities, where we are working. And then we also have an infectious disease specialist in our group who is looking at things from the perspective of minimizing adverse drug reaction. So we’ve probably got six or eight areas where we are fairly active right now.
Dr. Smith: So thinking back to my 3rd year medical school, Dr. Leeder, and we did our initial pediatric rotation and then we were able to do some electives and I chose a couple of pediatric subspecialties, one of the things that always just astounded me was how one child could have such a positive reaction to a drug, whether it was for asthma or even in certain chemotherapies. One child just has this amazing response. But what seems to be the same disease, same symptoms in a different child, that drug just doesn’t do anything. So why is it? Why is there such a difference in response from one child to another with the same medication?
Dr. Leeder: Well, I guess the most obvious answer to that is that each child is genetically distinct, for example, and has had different environmental exposures as they grow and develop. But I think you really have to look at the question from a couple of different perspectives. The first is those dosing guidelines that you were taught as a resident and where those doing guidelines came from. To be honest, those are largely empirical guidelines. And one of the major in pediatrics is the lack of an evidence base that can really associate the dose that a child should get with what the expected or desired therapeutic respond might be. And part of this is because the initial dosing guidelines that we have to work with are those that during the drug development process basically fell out of a drug development strategy; that sought to determine the dose that on average produced the desired therapeutic response in adults. And really, those types of dosing recommendations are directed at a population. We know within any given population, if you view a population of patients as a bell-shaped curve, you’ve got people at extremes of the population that are obviously quite different from each other. And the big problem when we start a child on medication is that we, generally speaking, don’t have any idea where within that population distribution they’re going to fall, yet they will all be started at a dose of the medication that’s really targeted for those individuals who fall under the hump of the bell curve. And really, to deal with the situation that you’re talking about, we really would like to have some sort of information before a child starts a drug that would allow us to have some sort of idea where within that population distribution they might fall so that one might start with a dose that may be more appropriate for their location within the population distribution. And so that’s where you know the Goldilocks program really comes into place that we’re trying to focus on those factors that make each child unique starting, with the G of Goldilocks, which is genomic, and the O, which refers to ontogeny or the stage of development. And I think that’s really the challenge is moving away from viewing the dose that’s going to be administered to a child a population perspective to one that is a little bit more individualized in nature. And it’s that challenge of moving away from the population perspective to that of the individual that really is the most difficult to do but also the most rewarding if we’re ever able to do it, accomplish those goals.
Dr. Smith: You mentioned that eventually, when this is released that there’s going to be a web-based application of the guidelines. What will that look like? What will be the user’s experience of that site?
Dr. Leeder: Well, first of all, this is largely conceptual in nature right now. But what we would be anticipating is something that looks like a dashboard and opportunities for people to enter the information that the research tells us is most important for determining the dose required in a given child to reach a particular exposure—and by exposure I mean the sort of product of drug concentration over time—with the assumption that the amount of drug in the body at a given period of time is going to be somewhat predictive of the response that one can anticipate. And the type of information that may be required to be entered will be dependent upon the particular medication, but it might be things like the child’s age, height, weight, hematocrit, albumin, the types of things that we suspect might influence drug disposition. The most important factor though would be genetic information for those medications that are subject to metabolism by a pathway that is known to be genetically variant within the population and for which that genetic variation plays a significant role in that dose exposure relationship. But again, the amount of information and the type of information will be dependent on the drug, but those factors that I mentioned would be sort of a minimum stat.
Dr. Smith: So Dr. Leeder, lastly, is there a timeline here when you’re looking to get the initiative and the guidelines complete, the website up?
Dr. Leeder: Well, right now we are working with one drug and one gene as our proof of principal project. The drug is atomoxetine, marketed Strattera. Most people probably know it as Strattera. And the genetic pathway is one that’s called cytochrome P4502D6. We have completed one study, where we investigated the pharmacokinetics of atomoxetine in a group of children with ADHD who had different or specific genotypes or combinations of variant forms of the cytochrome P4502D6 gene. And that study allowed us to characterize the extent of variability that we can anticipate within the population. In fact, we gave each child a dose of half a milligram per kilo, and we found that the amount of drug in the body over a 24-hour period ranged 50-fold between the child who had the slowest capacity to eliminate the drug and the most rapid capacity to eliminate the drug. And so, armed with that now, we’re designing a study to see if we have adequate knowledge with our model and the factors that contribute to variability in the amount of atomoxetine that’s in the system to see whether we can actually individualize the dose to produce the same exposure in any child that may be prescribed that drug with the intent of eventually looking at genetic variation in the drug target as being another source of variability in who responds or who doesn’t respond to the medication. So for that prototype, we are maybe a third of the way where we want to be right now.
Dr.: Smith: Okay, that’s nice. Well Dr. Leeder, I want to thank you for everything that you’re doing. It sounds like you’re on the right track here, and it sounds like you’re going to have some impressive results soon. Thank you for coming on the show. 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. Have a great day.
GOLDILOKS: Getting Medication Dosage “Just Right” for Children
Dr. Michael Smith (Host): Welcome to Transformational Pediatrics. I’m Dr. Mike Smith. Our topic, Goldilocks: kiddie medication dosages just right for kids. My guest is Dr. Steve Leeder. He’s the department chair in Pediatric Clinical Pharmacology and Chief of the Division of Clinical Pharmacology and Medical Toxicology. Dr. Leeder is board certified in applied pharmacology by the American Board of Clinical Pharmacology. Dr. Leeder, welcome to the show.
Dr. Steve Leeder (Guest): Thank you very much for having me.
Dr. Smith: Well, tell us about the mission and goals of what is called the Goldilocks initiative.
Dr. Leeder: Well, just to put it in a nutshell, it’s the dose that’s not too big, not too small, it’s just right for your child. Underlying that concept is the reality that individual children are not small average adults, which is the way that most dosing recommendations have been developed. Our program is trying to identify those factors that make each child unique and use those to help guide the doses that will ultimately be used for an individual child.
Dr. Smith: So the guidelines that might come out of this initiative, these guidelines are going to be used by general practitioners, maybe not pediatricians but maybe family practice physicians that are treating kids? Or I guess maybe who’s really the target for these guidelines that might come out of it?
Dr. Leeder: Well, I think initially we are working with partner pediatric subspecialists here within our own institution. But when it comes to actually disseminating the experiences that we have and making them more broadly applicable, we really would like to reach general pediatricians in the community, pediatric subspecialists at other institutions. And so what this means is that ultimately we are hoping to develop web-based dosing algorithms or web-based decision support tools that ultimately would be accessible to anyone who has an Internet connection.
Dr. Smith: So what subspecialties in pediatrics are you working with right now with the initiative?
Dr. Leeder: We actually have several pediatric subspecialists who have undergone formal Clinical Pharmacology Training and are embedded, defined as being physically located within our clinical pharmacology group. Probably the biggest opportunities right now are in the area of cancer, pediatric cancer. We see opportunities in developmental behavioral sciences, particularly in ADHD and perhaps the use of antipsychotics and antidepressants in children with autism, depression. We also have partners in cardiology, where we are anticipating increasing use of statin medications in children, and we would like to be preemptive in coming up with safe and effective dosing guidelines for that class of medications. Asthma is another area where we have faculty with a specific interest in improving drug treatment there. Neonatology is another one of our partners, and multiple opportunities there. GI, particularly in the field of inflammatory bowel disease, has lots of opportunities, where we are working. And then we also have an infectious disease specialist in our group who is looking at things from the perspective of minimizing adverse drug reaction. So we’ve probably got six or eight areas where we are fairly active right now.
Dr. Smith: So thinking back to my 3rd year medical school, Dr. Leeder, and we did our initial pediatric rotation and then we were able to do some electives and I chose a couple of pediatric subspecialties, one of the things that always just astounded me was how one child could have such a positive reaction to a drug, whether it was for asthma or even in certain chemotherapies. One child just has this amazing response. But what seems to be the same disease, same symptoms in a different child, that drug just doesn’t do anything. So why is it? Why is there such a difference in response from one child to another with the same medication?
Dr. Leeder: Well, I guess the most obvious answer to that is that each child is genetically distinct, for example, and has had different environmental exposures as they grow and develop. But I think you really have to look at the question from a couple of different perspectives. The first is those dosing guidelines that you were taught as a resident and where those doing guidelines came from. To be honest, those are largely empirical guidelines. And one of the major in pediatrics is the lack of an evidence base that can really associate the dose that a child should get with what the expected or desired therapeutic respond might be. And part of this is because the initial dosing guidelines that we have to work with are those that during the drug development process basically fell out of a drug development strategy; that sought to determine the dose that on average produced the desired therapeutic response in adults. And really, those types of dosing recommendations are directed at a population. We know within any given population, if you view a population of patients as a bell-shaped curve, you’ve got people at extremes of the population that are obviously quite different from each other. And the big problem when we start a child on medication is that we, generally speaking, don’t have any idea where within that population distribution they’re going to fall, yet they will all be started at a dose of the medication that’s really targeted for those individuals who fall under the hump of the bell curve. And really, to deal with the situation that you’re talking about, we really would like to have some sort of information before a child starts a drug that would allow us to have some sort of idea where within that population distribution they might fall so that one might start with a dose that may be more appropriate for their location within the population distribution. And so that’s where you know the Goldilocks program really comes into place that we’re trying to focus on those factors that make each child unique starting, with the G of Goldilocks, which is genomic, and the O, which refers to ontogeny or the stage of development. And I think that’s really the challenge is moving away from viewing the dose that’s going to be administered to a child a population perspective to one that is a little bit more individualized in nature. And it’s that challenge of moving away from the population perspective to that of the individual that really is the most difficult to do but also the most rewarding if we’re ever able to do it, accomplish those goals.
Dr. Smith: You mentioned that eventually, when this is released that there’s going to be a web-based application of the guidelines. What will that look like? What will be the user’s experience of that site?
Dr. Leeder: Well, first of all, this is largely conceptual in nature right now. But what we would be anticipating is something that looks like a dashboard and opportunities for people to enter the information that the research tells us is most important for determining the dose required in a given child to reach a particular exposure—and by exposure I mean the sort of product of drug concentration over time—with the assumption that the amount of drug in the body at a given period of time is going to be somewhat predictive of the response that one can anticipate. And the type of information that may be required to be entered will be dependent upon the particular medication, but it might be things like the child’s age, height, weight, hematocrit, albumin, the types of things that we suspect might influence drug disposition. The most important factor though would be genetic information for those medications that are subject to metabolism by a pathway that is known to be genetically variant within the population and for which that genetic variation plays a significant role in that dose exposure relationship. But again, the amount of information and the type of information will be dependent on the drug, but those factors that I mentioned would be sort of a minimum stat.
Dr. Smith: So Dr. Leeder, lastly, is there a timeline here when you’re looking to get the initiative and the guidelines complete, the website up?
Dr. Leeder: Well, right now we are working with one drug and one gene as our proof of principal project. The drug is atomoxetine, marketed Strattera. Most people probably know it as Strattera. And the genetic pathway is one that’s called cytochrome P4502D6. We have completed one study, where we investigated the pharmacokinetics of atomoxetine in a group of children with ADHD who had different or specific genotypes or combinations of variant forms of the cytochrome P4502D6 gene. And that study allowed us to characterize the extent of variability that we can anticipate within the population. In fact, we gave each child a dose of half a milligram per kilo, and we found that the amount of drug in the body over a 24-hour period ranged 50-fold between the child who had the slowest capacity to eliminate the drug and the most rapid capacity to eliminate the drug. And so, armed with that now, we’re designing a study to see if we have adequate knowledge with our model and the factors that contribute to variability in the amount of atomoxetine that’s in the system to see whether we can actually individualize the dose to produce the same exposure in any child that may be prescribed that drug with the intent of eventually looking at genetic variation in the drug target as being another source of variability in who responds or who doesn’t respond to the medication. So for that prototype, we are maybe a third of the way where we want to be right now.
Dr.: Smith: Okay, that’s nice. Well Dr. Leeder, I want to thank you for everything that you’re doing. It sounds like you’re on the right track here, and it sounds like you’re going to have some impressive results soon. Thank you for coming on the show. 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. Have a great day.