Editorial: Baseline Drug Clearance Predicts Outcomes in Children With Inflammatory Bowel Disease Treated With Vedolizumab

Abstract

The pharmacokinetics of IBD biologics in children differ from adults. Differences are thought to be related to physiological (e.g., differences in body surface area and a higher rate of hypoalbuminemia), developmental (immature immune processing and higher prevalence of anti-drug antibody formation) and disease-related (e.g., severity and extent of inflammation) factors [1, 2]. Therapeutic drug monitoring (TDM), both reactive and proactive, has become a cornerstone for managing children with IBD, and higher biologic concentrations are often needed to achieve and sustain response [3]. For instance, standard vedolizumab dosing (300 mg [or 10 mg/kg for < 30 kg patients] every 8 weeks) was predicted to achieve maintenance target concentrations in fewer than 50% of paediatric patients, whereas dosing every 4 weeks was predicted to meet targets in 85%–100% [4]. In the HUBBLE trial, a phase II paediatric study, vedolizumab was effective and safe, and drug exposure increased in a dose-proportional manner, but no clear dose–response relationship was observed [5].

In a post hoc analysis, Stein et al. utilised data from the VedoKids study, a multicentre cohort of 129 children, to examine the association between baseline (pre-treatment) drug clearance, trough drug concentrations during early therapy and deep biochemical remission at Week 30 [6]. Their primary aim was to evaluate baseline drug clearance as a predictor of deep biochemical remission at Week 30 (defined by normalised CRP and ESR and clinical remission). While they did not find a statistically significant association for this primary aim, increased baseline drug clearance was negatively associated with achieving a faecal calprotectin < 100 μg/g and < 250 μg/g at Week 30 in the subset with available data. Importantly, Week 2, Week 6 and Week 14 trough concentrations were strongly associated with deep biochemical remission, offering valuable guidance for future dosing guidelines. Finally, the pharmacokinetic model parameter estimates were similar to adult studies, while patient weight, serum albumin and prior biologic use (although confounded) influenced vedolizumab clearance.

This study underscores the critical importance of proactive TDM in children with IBD to identify altered vedolizumab clearance early and optimise future dosing to enhance clinical outcomes. However, some limitations warrant consideration. Most patients had received at least one biologic before starting vedolizumab, indicating a more refractory cohort. The lack of endoscopic data limits the ability to link drug concentrations or baseline clearance to mucosal healing, a critical therapeutic goal. Furthermore, while baseline drug clearance is an important pharmacokinetic measure, the study did not demonstrate clear advantages over trough concentrations, which were more strongly associated with deep biochemical remission.

The findings highlight the need for large, multicentre, real-world pharmacokinetic studies of advanced IBD therapies in children. Future investigations should focus on identifying novel covariates of drug clearance to reduce unexplained interindividual variability and on defining concentration cut-points associated with clinical, biochemical, transmural and endoscopic remission in children. Since there are fewer FDA-approved treatment options for children than adults with IBD, these future investigations are essential for refining paediatric dosing guidelines, informing clinical decision dashboards and ultimately enhancing the durability of advanced therapies in children.