Kansas City,
04
June
2018
|
05:26 PM
Europe/Amsterdam

Improving Patient Outcomes Through Individualized Drug Therapy

Leeder

Pharmacogenomics is quickly becoming the standard of care for certain medication-gene pairs, and huge advancements have been made in individualized drug therapy.

Steve Leeder, Pharm.D., PhD, is Associate Chair in the Department of Pediatrics and Deputy Director of the Children’s Research Institute at Children’s Mercy. He won the 2018 Department of Pediatrics Research Team Award for his work on GOLDILOKS, a research program designed to implement precision therapeutics in pediatrics, ensure that children receive the dose of medication that is “just right” for them.

Dr. Leeder will be present the GOLDILOKS initiative at the Precision Medicine World Conference June 6-7, 2018 at the University of Michigan.

We spoke with Dr. Leeder about how taking an individualized approach of treatment helps improve patient outcomes.

Tell us more about the GOLDILOKS initiative and the research you’re working on right now.

Dr. Leeder: My research focuses on characterizing the relative contributions of genetic variation and changes due to growth and development to observed variability in drug response in children. These efforts have coalesced into the GOLDILOKS initiative, which stands for Genomic- and Ontogeny-Linked Dose Individualization and cLinical Optimization for Kids.

There are several factors that contribute to how a child responds to a medication. Some of these factors relate to the relationship between the dose that is administered and how the amount of medication in the body changes over time, and other factors determine the nature of the response that occurs when the medication interacts with its intended target in the body. Our goal is to better understand how each patient’s unique characteristics influence that individual’s response to medication or treatment.

For instance, you can give a group of kids the same dose of medication and find the amount of drug in the system - or the ‘exposure’ - varies greatly. Most people pay little attention to the actual exposure following a given dose, but here’s why it matters. We did a study where we gave the same dose of ADHD medication to a group of children with ADHD and found a fifty-fold difference between the patients who had the highest exposure compared to the person with the lowest exposure – all given the same weight-based dose. It turns out that genetic differences in the pathway responsible for elimination of the medication from the body was largely responsible for the amount of variability in exposure that we observed in this study. However, the most valuable lesson we learned related to the potential clinical consequences of extreme variability to this (or any other) medication: some children may have side effects at low doses of the medication whereas others may not respond to it simply due to inadequate exposure even at the maximum recommended dose. The GOLDILOKS research program focuses on developing decision support tools to assist clinicians in selecting the optimum dose for an individual patient.

The GOLDILOKS clinic focuses on therapeutic dilemmas. Clinicians who have trouble managing a child’s medications will refer the child to our clinic. Most of the patients we see tend to have neurodevelopmental disorders, which can be difficult to treat because a child is being treated with multiple medications targeting the central nervous system.

When thinking about the field you’re working in, what are some recent breakthroughs that are propelling the field forward and how will they impact healthcare?

Dr. Leeder: Most of the discoveries are being made in the area of cancer, specifically looking at gene expression patterns and the implications for a particular choice of drug. Researchers are starting to ask the question, “Could a drug that works in colon cancer be used for brain cancer or lung cancer if the tumor has the same signature of gene expression?” For example, if people are looking at drugs to inhibit specific pathways, and if that pathway is present in a different type of tumor and the drug can get to where it needs to be, maybe it'll work for that cancer as well.

Gene expression patterns could be used in other diseases too, because not all asthma is the same, not all inflammatory bowel disease is the same. Similarly, conditions like ADHD or anxiety and depression may have subgroups that be defined patterns of neurotransmitters, lipids and other types of endogenous biomarkers that can be measured using metabolomics analyses. We want to know if there are sub groups within each of these so-called complex diseases that have a signature and pattern that may be predictive of response, and if different patients share the same pattern is it reasonable to anticipate that each will experience a similar clinical response, assuming we can get the exposure right?

What makes Children’s Mercy healthcare service unique?

Dr. Leeder: What makes our program unique is we have so many pediatric subspecialists who now think in a similar manner. They understand it's not so much the dose, but how much drug is in the body and its relationship to response that is more relevant. So all our teams, whether neonatology, infectious diseases, cardiology, hematology, oncology, allergy, rheumatology, can all interact with one another and learn from others’ experience related to variability in the response to medications within the different patient populations.

The GOLDILOK program is changing the standard. When a sample is sent for pharmacogenetic analysis and the results come back, all it will say is change in dosage is required. To me, that’s not helpful. Clinicians need to know by how much the dose should be changed. What we’re doing is providing the tools that help clinicians know how the dose should be individualized for a particular child to get the appropriate exposure. Given the targets of drug action are subject to genetic variation and that expression of targets may change with growth and development, we expect to have more information in future regarding the level of exposure that is optimal for each child, depending on their unique characteristics.

What advice do you have for your colleagues based on your research?

Dr. Leeder: We need to change the way we think about how a medication will be used in clinic. The classic thought process is comparing the relationship between dose, exposure and response. Perhaps we should be starting with the response - considering the desired therapeutic goal we would like to achieve with the medication that is to be prescribed. Then we need to look at what exposure is going to be necessary to achieve that therapeutic response and finally how does the dose need to be individualized to get that exposure.

It's completely reverse in how we think about drug development. The FDA and drug companies are asking what dose, on average, is safe and effective for a population. The question we need to ask, in the context of precision therapeutics, is what dose is needed to give individual patients the exposure they need to have the desired therapeutic response.

What excites you most about your work?

Dr. Leeder: My role as the Deputy Director of the Children’s Research Institute is focused on precision therapeutics and studying how variable children are in terms of how they respond to medications, across all pediatric subspecialties. While the genetic component of how children (and adults) eliminate medications from their bodies is relatively easy to study and is may be a significant factor, it only accounts for a fraction of the overall variability in overall response to medications. Relatively speaking, we know very little about the effects of genetic variation in the targets of drug action, or the role of growth and development on the expression of drug targets. For instance, a drug target may change during the child’s development, which will impact how we treat the patient at two years old, versus eight years old, versus 12 years old, versus 18 years old, versus adulthood.

As an industry, we need to get away from this idea that giving everybody the same dose works. Instead we need to give the right exposure and target of drug that will work for a particular individual, not what works on the “average” population.

At the end of day, individualized patient dosing means better and quicker treatment. Right now, physicians prescribe a medication and wait for a period of time to determine if the medication works or not. What’s going to be a game-changer is knowing how a person is going to respond to a medication before that person ever takes the drug, and that really excites me.

 

Learn more about the Children's Research Insititue at Children's Mercy.