Targeted therapy for pediatric Crohn’s disease: Tissue levels of medications and cytokines

Project start date and end date: 2023 - 2025

Background:

Children with Crohn's disease, despite treatment with immune-suppressive medications, can develop severe complications throughout their intestine, leading to complications and potentially surgery. Therapeutic drug monitoring has been used to target medication levels in the blood to improve the patient's responses, but this does not work for everyone. What is unknown, however, is if these medications are delivered to the intestines at the same levels for all children, and if differences in medication delivery to the bowel can explain why some children still develop complications from Crohn's disease despite adequate levels of medications in the blood.

Objectives:

• Aim 1: To compare the tissue versus serum medication levels for evaluating unexplained disease activity among children with Crohn’s disease undergoing colonoscopy
• Aim 2: To determine the variation between inflamed and non-inflamed tissue with a given surgical resected intestinal specimen
• Aim 3: To propose a novel subgroup classification for children with Crohn’s disease by differences in tissue medication penetration and cytokine levels

Research Topics & Methods:

In this study, tissue levels of medications and other markers of the immune system will be measured from biopsy samples routinely obtained from pediatric patients with Crohn's disease. The tissue drug levels and immune markers will then be compared to the blood drug levels to better understand why some children do not respond adequately to standard medical therapy.

Implications:

Anti-tumor necrosis factor-a (anti-TNFa) medications have dramatically improved outcomes and quality of life for children with Crohn’s disease. Weight-based dosing guidelines informed by population pharmacokinetic studies do not work for many children, especially young children, due to variable drug clearance. Serum-level monitoring of medication dosing improves outcomes for some children with rapid clearance, however, many still have refractory disease despite high serum drug levels. Preliminary evidence suggests active Crohn’s disease in the face of high serum levels may be the result of poor tissue drug delivery. However, the status quo is that we currently cannot measure tissue drug levels in clinical practice, and we do not have the evidence base to understand how tissue-level drug delivery or cytokine levels impact disease activity. Consequently, patients discontinue medications that may have potential to be efficacious if we could optimize dosing to improve tissue medication levels. In this proposal, we will use real-time assessment of tissue-level medication and cytokine monitoring to evaluate and classify reasons for failure to respond among children with Crohn’s disease on anti-TNFa therapy.

Funder:

This project is funded by the Department of Pediatrics Charles Woodson Collaborative Research Award.

Collaborators:

Samir Gadepalli, MD, MSc, MBA, Assistant Professor in Surgery, Michigan Medicine

David Frame, PharmD, Clinical Assistant Professor in Pharmacy, Michigan Medicine

Katsuo Kurabayashi, PhD, Professor in Mechanical Engineering, University of Michigan