Baseline Drug Clearance Predicts Outcomes in Children With Inflammatory Bowel Disease Treated With Vedolizumab:
Ronen Stein1,2, Dan Turner3, Séamus Hussey4
1Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Insights
Vedolizumab dosing in children with IBD needs optimization. Higher drug clearance, influenced by albumin, predicts lower remission rates, especially in lower-weight children. Tailored dosing strategies are crucial for effective treatment.
Area of Science:
- Pharmacology
- Gastroenterology
- Paediatric Medicine
Background:
- Pharmacokinetics of biologic agents differ in paediatric inflammatory bowel disease (IBD) patients.
- This necessitates modified paediatric dosing strategies for effective treatment.
Purpose of the Study:
- To define the vedolizumab exposure-response relationship in paediatric IBD patients.
- To evaluate the effect of baseline clearance on deep biochemical remission at 30 weeks.
- To match adult and paediatric pharmacokinetic profiles using population pharmacokinetic models.
Main Methods:
- Developed a pharmacokinetic model using 312 serum vedolizumab concentrations from 129 children.
- Utilized a published adult model as a Bayesian prior.
- Performed exposure-response evaluations and simulated paediatric doses to match adult exposure.
Main Results:
- 81% of children remained on vedolizumab at 30 weeks; 31% achieved deep biochemical remission.
- Increased baseline drug clearance was linked to lower remission rates (p<0.05).
- Higher weight and lower serum albumin correlated with increased clearance; tiered fixed dosing matched adult concentrations in children ≤30kg.
Conclusions:
- Serum albumin significantly influences vedolizumab clearance.
- Baseline clearance predicts 30-week deep biochemical remission.
- Optimal dosing strategies, particularly for lower-weight children, require further investigation.
Background:
The pharmacokinetics of biologic agents can differ between children and adults with inflammatory bowel disease (IBD), often necessitating modified paediatric dosing strategies.
Aims:
To define the exposure-response relationship of vedolizumab in the paediatric IBD VedoKids cohort including the effect of baseline clearance on deep biochemical remission (normal C-reactive protein [CRP]/erythrocyte sedimentation rate [ESR] and steroid-free remission) at 30 weeks, and to use population pharmacokinetic models to find the best matches between adult and paediatric pharmacokinetic profiles.
Methods:
We sought a pharmacokinetic model on 312 serum vedolizumab concentrations from 129 children, assisted by a published adult model as a Bayesian prior. We employed the model for exposure-response evaluation and for investigating doses in paediatric patients to match the adult exposure at the labelled dose.
Results:
At Week 30, 104/129 (81%) children (53% female and 47% Crohn disease) remained on vedolizumab, of whom 39 (31%) in the exposure-response evaluation were in deep biochemical remission. Increased baseline drug clearance was associated with lower deep biochemical remission rates at Week 30 based on ESR/CRP (OR 0.47 [95% CI 0.2-1.05, p = 0.08]) and calprotectin < 100 μg/g (OR 0.13 [95% CI 0.1-0.79, p < 0.05]). Higher weight and lower serum albumin were associated with increased clearance (p < 0.001). Simulation models found that, for children ≤ 30 kg, tiered fixed dosing regimens best matched adult drug concentrations.
Conclusions:
Drug clearance was strongly influenced by serum albumin. Baseline clearance predicted deep biochemical remission at Week 30. Further investigation is needed to better understand optimal dosing strategies-especially for lower-weight children receiving vedolizumab.
More Related Videos
07:05Fluorescence-mediated Tomography for the Detection and Quantification of Macrophage-related Murine Intestinal Inflammation
Published on: December 15, 2017
08:27Dynamic Adhesion Assay for the Functional Analysis of Anti-adhesion Therapies in Inflammatory Bowel Disease
Published on: September 20, 2018
Related Concept Videos
01:29Drugs for Treatment of Ulcerative Colitis in IBD
01:29Drugs for Treatment of Crohn's Disease in IBD Using Immunomodulatory Agents
01:24Drugs for Treatment of Crohn's Disease in IBD Using Biologic Agents: Anti-TNF
01:21Drugs for Treatment of Crohn's Disease in IBD Using Glucocorticoids
01:23Pharmacokinetics in Pediatric Patients: Overview and Drug Absorption
01:26Pharmacokinetics in Pediatric Patients: Drug Excretion