The right dose of research could help children, professor says

J. Steven Leeder

The challenge of finding the right dosage of medicines for young patients is complex and requires fresh thinking, J. Steven Leeder, Pharm.D., Ph.D., told the audience for the latest installment of the Health Sciences Deans’ Seminar Series.

Leeder, a professor of pediatrics and pharmacology at the UMKC School of Medicine, spoke Oct. 25 in the Health Sciences Building on Hospital Hill on “Exploring Inter-Individual Variability in Drug Response: Moving Beyond the Dose-Exposure Relationship.”

Leeder, who leads the pediatric clinical pharmacology group at Children’s Mercy Hospital, noted that many drugs are initially developed for adults and tested on them, making dosage calculations for children more difficult. On top of that, he said, the typical differences in how people respond to a drug can be magnified in children, given great differences in patient weight and in how rapidly different biological mechanisms in children can change during growth and development.

 The maturation of the brain, Leeder said, implies that receptors and transporters affecting drugs’ effectiveness may be changing in children and adolescents, but there’s relatively little research knowledge of these changes.

Given those challenges, he said, it makes sense to invert the usual sequence of “dose-exposure-response”:  administering a standard dosage of a drug and then seeing how much of that dosage is present in a patient’s body and how much the patient’s condition responded to the drug. Instead, he favors looking at “response-exposure-dose”: identifying the desired response or therapeutic outcome, and determining the amount of drug that needs to be in the body – the “exposure” — to achieve the desired response. Given that knowledge, he said, then a dosage can be tailored to the patient.

Leader, who practices at Children’s Mercy Hospital, noted that many drugs are initially developed for adults and tested on them, making dosage calculations for children more difficult. On top of that, he said, the typical differences in how people respond to a drug can be magnified in children, given great differences in patient weight and in how rapidly different biological mechanisms in children can change.

The maturation of the brain, Leeder said, means receptors and transporters that affect drugs’ effectiveness must be changing in children and adolescents, but there’s relatively little research knowledge of these changes.

Given those challenges, he said, it makes sense to invert the usual sequence of administering a standard dosage of a drug and then seeing how much of that dosage was used by a patient, and how much the patient’s condition responded to the drug. Instead, he favors looking at the response or outcome that’s desired, and then trying to gauge how well an individual patient’s system will use a drug. Given that knowledge, he said, then a dosage can be tailored to the patient.

Such an approach, he said, might best use the “more information on everyone” being provided by the increase in genomics, bioinformatics and population-wide data from electronic health records.

Leeder holds the Marion Merrell Dow Endowed Chair in Pediatric Clinical Pharmacology and is division director for clinical pharmacology and therapeutic innovations. He earned his pharmacy degree at the University of Minnesota and his doctorate at the University of Toronto. He completed a fellowship in clinical pharmacology at the Hospital for Sick Children in Toronto.