Research Award Recipients

Model-informed precision dosing of mycophenolic acid in pediatric kidney transplant recipients

Co-Applicant(s): Chia Wei Teoh, Lorraine Hamiwka, Lusine Tonoyan, Michelle Ruhl, Tom Blydt-Hansen

Lay Abstract

BACKGROUND: The drug mycophenolic acid (MPA) is prescribed to almost all pediatric kidney transplant recipients to prevent their bodies from rejecting their transplanted kidney. Unfortunately, even when taking consistent doses of this medication, many patients have large variations in the levels of MPA in their blood during the first 6 months after transplantation. This can cause severe side effects such as reduced white blood cell count (i.e., cells that help your body fight infections) and even the loss of the organ. Almost a third of pediatric patients stop taking MPA within 2 years of their kidney transplant because they cannot tolerate the medication. These patients tend to experience worse organ survival (likely due to lack of sufficient anti-rejection effects), underscoring the urgent need to better understand appropriate dosing for this important drug. We still do not know why so many patients have variable MPA blood levels, and doctors do not know how to manage this problem effectively. Adding to the problem, the current method for monitoring and dosing MPA was adapted from studies in adult patients and does not account for the unique drug actions (i.e., how the body handles the drug and how the drug affects the body) in pediatric patients. It is also not clear what threshold of MPA blood levels will lead to the development of side effects, and MPA dose-adjustments are sometimes made in patients who may already have experienced bad outcomes without a way to account for each patient’s demographics, medical history, and unique clinical presentations. Recently, our lab reported several potential strategies for improving the monitoring and dosing MPA, which require understanding MPA pharmacokinetics (drug actions) specifically in this population. We have also published a sophisticated population-based model that describes important patient factors that may affect MPA actions in children.

PURPOSE: From this work, we think that there are specific patient factors that could affect MPA levels in the body, and we can develop a predictive clinical tool to accurately dose MPA, precisely estimate its blood levels, and effectively minimize the severe side effects.

METHOD: Using state-of-the-art “bench-to-bedside” methods, we will answer these important research questions using samples collected from children at several time points within 6 months after their kidney transplantations. We will work with transplant centres across Canada (i.e., Vancouver, Calgary, Edmonton, Toronto) to ensure we have a diverse sample of subjects that represent different geographical regions and ethnicities. More specifically, we will determine the important patient factors (e.g., biological sex, time after transplant, the patient’s overall kidney function, age, ethnicity, and others) which may influence the movement of MPA through the liver, kidneys, and blood; characterize how the blood levels of MPA are associated with side effects; and create strategies to proactively prevent the negative effects of MPA. Our lab has extensive expertise in describing the complex MPA drug actions using established drug measurement and modelling methods.

ANTICIPATED OUTCOMES: If we are correct, this work will create powerful tools that healthcare professionals can use to actively manage the blood levels of MPA, which will greatly reduce the chances of MPA-associated negative side effects, prevent transplant rejection, and improve quality of life.

PATIENT ENGAGEMENT: We will actively engage patients and their parents/caregivers across Canada (i.e. not just those participating in the study) at multiple stages of the research through the Alberta Transplant Institute and the Canadian Donation and Transplantation Research Program to communicate the nature of our experiments and the relevance of our findings.

RELEVANCE TO PATIENTS/COMMUNITY: Our research will help clinicians better prescribe MPA, which will improve care in this fragile population of pediatric transplant recipients.

CONCLUSION: It is very difficult to obtain a lifesaving kidney transplant. We believe our research will lead to immediate improvements in how doctors dose and monitor MPA so that we can better preserve the transplanted organ, reduce unwanted drug effects, and improve outcomes in pediatric patients.