Neonatal pharmacotherapy is a field ripe with opportunity. Efficacy and toxicity is unpredictable and varies greatly for many drug classes commonly used. Weight-based dosing continues to be the standard of care as individualized drug markers are lacking. To better understand variability in drug response, the focus must shift from drug dosing to drug exposure.
Tamorah Lewis, MD, neonatologist and clinical pharmacologist, joins us to discuss how pharmacotherapy and individualized medicine can transform care for critically ill newborns.
Selected Podcast
Precision Therapeutics in the NICU
Featured Speaker:
Learn more about Tamorah Lewis, MD, Phd
Tamorah Lewis, MD, Phd
Tamorah Lewis, MD, PhD, is a Neonatologist at Children’s Mercy Kansas City and an Assistant Professor at the University of Missouri-Kansas City School of Medicine. She completed a combined fellowship in Neonatal/Perinatal Medicine and Clinical Pharmacology at the Johns Hopkins University School of Medicine. She is a clinical neonatologist with a research interest in clinical pharmacology, drug development and optimizing clinical trial designs. Her research interests include population pharmacokinetic and pharmacodynamic investigations in neonates, pertaining to both drugs in common use and drugs under development. The intersection between ontogeny and pharmacogenetic effects on the PK and PD of drugs in infants and neonates is also a future direction of her research.Learn more about Tamorah Lewis, MD, Phd
Transcription:
Precision Therapeutics in the NICU
Dr. Michael Smith: Our topic today is precision therapeutics in the NICU. My guest is Dr. Tamorah Lewis. Dr. Lewis is a neonatologist at Children’s Mercy Kansas City and an assistant professor at the University of Missouri Kansas City School of Medicine. Welcome to the show.
Dr. Tamorah Lewis, MD, PhD.: Thank you for having me.
Dr. Smith: Obviously, we know that the NICU is a very special place. It has a lot of complicated cases. Tell us a little bit, as someone that works in the NICU all the time, about the challenges of pharmacotherapy in the NICU.
Dr. Lewis: I think one of the biggest challenges about drug use and sick babies in the NICU is most of the medications that we use on sick newborns were not developed for that patient population. These are medicines that were developed for adult diseases. All of the studies were done in adult populations, and based on things like weight or size, the doses are modified to treat newborns. There are a few exceptions, a few drugs, that have been developed specifically for the newborn population but that really is the exception to the rule of us borrowing drugs from adult studies. As a neonatologist and clinical pharmacologist, in my mind, the biggest issue is that a lot of the drugs we use in the NICU have not been sufficiently studied in the newborn population, especially if you think about preterm newborns who are very small and fragile. For many of the drugs we use, we haven't done enough studies to know about the efficacy to know about the toxicity or safety concerns and we’re not sure if we’re using the right dose. We’re in an ICU and we have sick patients, so we do the best we can with the drugs that we have, but I believe as a pharmacologist that we can do much better for our patients.
Dr. Smith: Without the clinical research in this population of patients, what can we do? How do we overcome the limitations of just dosing by weight and really get it down to that individualized patients? What's the plan to move this forward?
Dr. Lewis: I think there's a growing recognition among the medical field and the administration of the country that neonates are therapeutic orphans, which means there's not an effort to improve drug therapy in this population. Recently, the Food and Drug Administration, or the FDA, has passed laws that mandate drug study in newborns. The National Institutes of Health, or the NIH, have made concerted efforts to fund research programs that are looking at drug use in newborns. Increasingly, pharmaceutical companies are realizing that they cannot continue to ignore the newborn population and their drug studies. There is a national recognition in a push to change drug study in newborns and do more thorough studies and to make sure that we're not using drugs off-label in the newborn population so often. One of the major success stories in this arena is something called the international neonatal consortium, or the INC, and I'm a member of this consortium and it's basically getting all of the stakeholders in the same room that have an invested interest in newborn pharmacology or newborn pharmacotherapy. You have the FDA, the NIH, the pharmaceutical companies and academic researchers such as myself all working together to prioritize diseases, to prioritize drugs and get these very thorough important studies done in the newborn population. I believe there is hope and I think there is actual movement for the first time in a very long time to get drug adequately studied in newborns and to know what we need to know to do the best for our patients.
Dr. Smith: This is great news and I agree with you. That’s good to hear that there's this effort now in studying pharmacology in the neonate, but of course, you're working in the NICU today. If weight is not the best way to dose, what are you doing right now? This is this idea of precision therapeutics. What is that really mean and what are you doing in the NICU today that’s different than other doctors in NICUs?
Dr. Lewis: In general, when you treat a patient with a medicine, you take what's called a population-based dosing approach, meaning no matter who the baby is, no matter their race, no matter their sex, no matter their age, you give every baby the same weight-based dose. What we know from the studies that have been done is that if you give a population of infants the same weight-based dose, the drug concentrations in their body vary widely. If you give all babies the same dose, there will be a large range of drug exposure inside their body and a large range of clinical outcomes. Some babies respond, some babies don't respond, some babies have toxicity, some babies don't have toxicity. The issue is precision therapeutics is trying to understand specific characteristics of a baby that would allow you to modify the dose in order to get a standard drug exposure or in order to predict precisely what the concentrations will be in the baby's body and what the outcomes will be both efficacy and toxicity.
My entire research program at Children’s Mercy is trying to understand what are the variables that we can use to dose medications differently in sick newborns so that we decrease that variability and drug exposure and decrease the unpredictability of clinical response. The work I'm doing is modeled after a lot of precision therapeutic works that has already been done in the adult population, looking at things like different disease endotypes, looking at pharmacogenetics, looking at patient-specific factors that we know in adults modify the dose of drug they need and modify the expected outcomes based on the dose of drug that you give. Just bringing those concepts into the NICO population is really the basics of my research program.
Dr. Smith: In your research right now in determining those factors that determine drug exposure, how far along are you and what have you found so far?
Dr. Lewis: We’re looking at a few different very commonly used drugs in the NICU and we chose drugs that have very unpredictable outcomes. You give the standard population weight-based dose of a drug and you really cannot predict what the baby is going to do – will the drug be efficacious or not? Will the drug be toxic or not? We pick those drugs that we clearly can improve upon and we are looking at what I believe are the two most important determinants of what I’ll call the dose exposure relationship. One of those is age and development because you can imagine that a preterm baby born at 24 weeks has the ability to metabolize a drug a certain way, but even seven days later, 14 days later, that preterm baby’s drug metabolism has changed so much just in that short time because of rapid development that the same weight-based dose days later is going to lead to a vastly different drug exposure. One thing I'm studying is the effect of gestational age at first and post-natal age in the NICU and how that changes the drug dose exposure relationship.
The other important variable is pharmacogenetics. Even beyond a baby's individual development of drug metabolism, they have a genotype or based on their DNA, their drug metabolizing enzymes are different from baby to baby. A great example is the drug metabolizing enzyme cytochrome P4502D6, or CYP2D6. We know from adult studies there's a wide range of genetic function of that drug-metabolizing enzyme. Some humans have no functional enzymes and if you give them a drug metabolized to that pathway, it will not be cleared at all. Some humans have what's called ultra-rapid function of that enzyme, so even more than you would expect in the average adult, but the problem is these genetic changes and drug metabolism have not been sufficiently studied in newborns. A newborn’s individual genetics will also be important in how the dose you give results in a certain drug exposure in their body. My studies focus on those two important variables – age and development – and pharmacogenetics. What we have found so far is very interesting. For example, we’re studying the non-steroid anti-inflammatory drug Indomethacin, which is very commonly used in preterm infants. I would say at least 30% of preterm infants are exposed to Indomethacin at some points in their NICU stay, depending on which NICU you're in and which country you're in.
Just based on preliminary pilot data, in a very homogenous group of preterm infants, less than 29 weeks at first, less than a month of age, who all received Indomethacin, if you look very closely at these factors, there are clearly distinct metabolic groups that we've never known about before, meaning some of the babies metabolize the drug a certain way, some of the babies metabolize the drug a very different way and there's a third group that metabolizes the drug even a different way. If you treat preterm infants as a homogeneous population and give them all the same dose of Indomethacin, you're going to get 14- or 20-fold variability in drug concentrations. If you look at this baby individually and say which metabolic group do you fall into, knowing that and should we modify your dose in this way, you can really decrease the variability in drug exposure and the ultimate goal is to decrease the variability in clinical outcomes and improve the care of these babies. That’s the preliminary data that we’re starting to see.
Dr. Smith: It's fascinating work. The end goal of all this is to be able to take an individualized neonate and say ‘here's your genetics and how you metabolize, here's your gestational age or your postnatal age and here's how we put that together, and this is how we can perfectly treat you.' That sounds awesome and fantastic and that obviously will improve outcomes and safety. This is a fascinating topic to me. I just want to hear it from you. What is it you want people to know about therapy in a NICU and this idea of precision therapeutics?
Dr. Lewis: As a researcher who’s really trying to move this field, one thing I really want people to know is that although NICU doctors are doing their best, we need to be more transparent with families about how little we know because most parents in the NICU do not know that 90% of the drugs we give NICU babies are off-label, meaning the FDA has never approved this drug at this dose for this patient population. Parents do not know that. I think the reason we are not more transparent is because we don't want to scare parents, but I think we've done ourselves a disservice as a profession because now parents don't want to sign their babies up for pharmacology studies. I think as parents knew more about how much we need to learn to use these drugs optimally, they would be more willing to sign up and consent for research studies about drug efficacy and toxicity. One push in the INC that I mentioned earlier is to be more transparent with NICU families about the work that needs to be done and how every baby in the NICU can contribute to furthering knowledge and optimizing pharmacotherapy for neonates. The other thing that I would say is that we need more young neonatology trainees, fellows, and junior faculty to get excited and passionate about this type of research because neonatology has a really strong foundation and pulmonary development and surfactant deficiency research or hypoxic brain injury research, but we don’t have a good history of hardcore bread and butter pharmacology research among neonatologists. As a niche of research within the field of neonatology, personalized medicine or precision therapeutics I'm hoping really grows as a research focus in the field of neonatology because we can understand more and more about these disease processes and that’s important. The real question is ‘can we treat these diseases optimally using the drugs that are currently in our wheelhouse, and, even better, drugs that are going to be developed in the future?’ Those are my big take-home messages.
Dr. Smith: This is fantastic. There's the call. Calling all neonatologists, come into this precision therapeutic research, and I agree with you. I think it’s not even in pediatrics; it’s also in the adult population. This is where we’re headed, being able to really individualize our care and outcomes can only be better. I think that’s clear and I want to 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.
Precision Therapeutics in the NICU
Dr. Michael Smith: Our topic today is precision therapeutics in the NICU. My guest is Dr. Tamorah Lewis. Dr. Lewis is a neonatologist at Children’s Mercy Kansas City and an assistant professor at the University of Missouri Kansas City School of Medicine. Welcome to the show.
Dr. Tamorah Lewis, MD, PhD.: Thank you for having me.
Dr. Smith: Obviously, we know that the NICU is a very special place. It has a lot of complicated cases. Tell us a little bit, as someone that works in the NICU all the time, about the challenges of pharmacotherapy in the NICU.
Dr. Lewis: I think one of the biggest challenges about drug use and sick babies in the NICU is most of the medications that we use on sick newborns were not developed for that patient population. These are medicines that were developed for adult diseases. All of the studies were done in adult populations, and based on things like weight or size, the doses are modified to treat newborns. There are a few exceptions, a few drugs, that have been developed specifically for the newborn population but that really is the exception to the rule of us borrowing drugs from adult studies. As a neonatologist and clinical pharmacologist, in my mind, the biggest issue is that a lot of the drugs we use in the NICU have not been sufficiently studied in the newborn population, especially if you think about preterm newborns who are very small and fragile. For many of the drugs we use, we haven't done enough studies to know about the efficacy to know about the toxicity or safety concerns and we’re not sure if we’re using the right dose. We’re in an ICU and we have sick patients, so we do the best we can with the drugs that we have, but I believe as a pharmacologist that we can do much better for our patients.
Dr. Smith: Without the clinical research in this population of patients, what can we do? How do we overcome the limitations of just dosing by weight and really get it down to that individualized patients? What's the plan to move this forward?
Dr. Lewis: I think there's a growing recognition among the medical field and the administration of the country that neonates are therapeutic orphans, which means there's not an effort to improve drug therapy in this population. Recently, the Food and Drug Administration, or the FDA, has passed laws that mandate drug study in newborns. The National Institutes of Health, or the NIH, have made concerted efforts to fund research programs that are looking at drug use in newborns. Increasingly, pharmaceutical companies are realizing that they cannot continue to ignore the newborn population and their drug studies. There is a national recognition in a push to change drug study in newborns and do more thorough studies and to make sure that we're not using drugs off-label in the newborn population so often. One of the major success stories in this arena is something called the international neonatal consortium, or the INC, and I'm a member of this consortium and it's basically getting all of the stakeholders in the same room that have an invested interest in newborn pharmacology or newborn pharmacotherapy. You have the FDA, the NIH, the pharmaceutical companies and academic researchers such as myself all working together to prioritize diseases, to prioritize drugs and get these very thorough important studies done in the newborn population. I believe there is hope and I think there is actual movement for the first time in a very long time to get drug adequately studied in newborns and to know what we need to know to do the best for our patients.
Dr. Smith: This is great news and I agree with you. That’s good to hear that there's this effort now in studying pharmacology in the neonate, but of course, you're working in the NICU today. If weight is not the best way to dose, what are you doing right now? This is this idea of precision therapeutics. What is that really mean and what are you doing in the NICU today that’s different than other doctors in NICUs?
Dr. Lewis: In general, when you treat a patient with a medicine, you take what's called a population-based dosing approach, meaning no matter who the baby is, no matter their race, no matter their sex, no matter their age, you give every baby the same weight-based dose. What we know from the studies that have been done is that if you give a population of infants the same weight-based dose, the drug concentrations in their body vary widely. If you give all babies the same dose, there will be a large range of drug exposure inside their body and a large range of clinical outcomes. Some babies respond, some babies don't respond, some babies have toxicity, some babies don't have toxicity. The issue is precision therapeutics is trying to understand specific characteristics of a baby that would allow you to modify the dose in order to get a standard drug exposure or in order to predict precisely what the concentrations will be in the baby's body and what the outcomes will be both efficacy and toxicity.
My entire research program at Children’s Mercy is trying to understand what are the variables that we can use to dose medications differently in sick newborns so that we decrease that variability and drug exposure and decrease the unpredictability of clinical response. The work I'm doing is modeled after a lot of precision therapeutic works that has already been done in the adult population, looking at things like different disease endotypes, looking at pharmacogenetics, looking at patient-specific factors that we know in adults modify the dose of drug they need and modify the expected outcomes based on the dose of drug that you give. Just bringing those concepts into the NICO population is really the basics of my research program.
Dr. Smith: In your research right now in determining those factors that determine drug exposure, how far along are you and what have you found so far?
Dr. Lewis: We’re looking at a few different very commonly used drugs in the NICU and we chose drugs that have very unpredictable outcomes. You give the standard population weight-based dose of a drug and you really cannot predict what the baby is going to do – will the drug be efficacious or not? Will the drug be toxic or not? We pick those drugs that we clearly can improve upon and we are looking at what I believe are the two most important determinants of what I’ll call the dose exposure relationship. One of those is age and development because you can imagine that a preterm baby born at 24 weeks has the ability to metabolize a drug a certain way, but even seven days later, 14 days later, that preterm baby’s drug metabolism has changed so much just in that short time because of rapid development that the same weight-based dose days later is going to lead to a vastly different drug exposure. One thing I'm studying is the effect of gestational age at first and post-natal age in the NICU and how that changes the drug dose exposure relationship.
The other important variable is pharmacogenetics. Even beyond a baby's individual development of drug metabolism, they have a genotype or based on their DNA, their drug metabolizing enzymes are different from baby to baby. A great example is the drug metabolizing enzyme cytochrome P4502D6, or CYP2D6. We know from adult studies there's a wide range of genetic function of that drug-metabolizing enzyme. Some humans have no functional enzymes and if you give them a drug metabolized to that pathway, it will not be cleared at all. Some humans have what's called ultra-rapid function of that enzyme, so even more than you would expect in the average adult, but the problem is these genetic changes and drug metabolism have not been sufficiently studied in newborns. A newborn’s individual genetics will also be important in how the dose you give results in a certain drug exposure in their body. My studies focus on those two important variables – age and development – and pharmacogenetics. What we have found so far is very interesting. For example, we’re studying the non-steroid anti-inflammatory drug Indomethacin, which is very commonly used in preterm infants. I would say at least 30% of preterm infants are exposed to Indomethacin at some points in their NICU stay, depending on which NICU you're in and which country you're in.
Just based on preliminary pilot data, in a very homogenous group of preterm infants, less than 29 weeks at first, less than a month of age, who all received Indomethacin, if you look very closely at these factors, there are clearly distinct metabolic groups that we've never known about before, meaning some of the babies metabolize the drug a certain way, some of the babies metabolize the drug a very different way and there's a third group that metabolizes the drug even a different way. If you treat preterm infants as a homogeneous population and give them all the same dose of Indomethacin, you're going to get 14- or 20-fold variability in drug concentrations. If you look at this baby individually and say which metabolic group do you fall into, knowing that and should we modify your dose in this way, you can really decrease the variability in drug exposure and the ultimate goal is to decrease the variability in clinical outcomes and improve the care of these babies. That’s the preliminary data that we’re starting to see.
Dr. Smith: It's fascinating work. The end goal of all this is to be able to take an individualized neonate and say ‘here's your genetics and how you metabolize, here's your gestational age or your postnatal age and here's how we put that together, and this is how we can perfectly treat you.' That sounds awesome and fantastic and that obviously will improve outcomes and safety. This is a fascinating topic to me. I just want to hear it from you. What is it you want people to know about therapy in a NICU and this idea of precision therapeutics?
Dr. Lewis: As a researcher who’s really trying to move this field, one thing I really want people to know is that although NICU doctors are doing their best, we need to be more transparent with families about how little we know because most parents in the NICU do not know that 90% of the drugs we give NICU babies are off-label, meaning the FDA has never approved this drug at this dose for this patient population. Parents do not know that. I think the reason we are not more transparent is because we don't want to scare parents, but I think we've done ourselves a disservice as a profession because now parents don't want to sign their babies up for pharmacology studies. I think as parents knew more about how much we need to learn to use these drugs optimally, they would be more willing to sign up and consent for research studies about drug efficacy and toxicity. One push in the INC that I mentioned earlier is to be more transparent with NICU families about the work that needs to be done and how every baby in the NICU can contribute to furthering knowledge and optimizing pharmacotherapy for neonates. The other thing that I would say is that we need more young neonatology trainees, fellows, and junior faculty to get excited and passionate about this type of research because neonatology has a really strong foundation and pulmonary development and surfactant deficiency research or hypoxic brain injury research, but we don’t have a good history of hardcore bread and butter pharmacology research among neonatologists. As a niche of research within the field of neonatology, personalized medicine or precision therapeutics I'm hoping really grows as a research focus in the field of neonatology because we can understand more and more about these disease processes and that’s important. The real question is ‘can we treat these diseases optimally using the drugs that are currently in our wheelhouse, and, even better, drugs that are going to be developed in the future?’ Those are my big take-home messages.
Dr. Smith: This is fantastic. There's the call. Calling all neonatologists, come into this precision therapeutic research, and I agree with you. I think it’s not even in pediatrics; it’s also in the adult population. This is where we’re headed, being able to really individualize our care and outcomes can only be better. I think that’s clear and I want to 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.