BACKGROUND AND OBJECTIVES: Ustekinumab (USTE) and vedolizumab (VEDO) are increasingly used in paediatric patients with inflammatory bowel diseases (pIBD). However, data on the usefulness of therapeutic drug monitoring (TDM) in children are scarce. The primary objective of this study was to evaluate the association between disease activity, measured by faecal calprotectin (F-CPT), and serum trough levels (TLs) of USTE and VEDO. Secondary outcomes were to explore factors potentially associated with the outcome and exposure, to determine the optimal USTE or VEDO dose that predicts remission (defined as F-CPT < 250 µg/g), to validate our hypothesis using a proof-of-concept cohort (POCC) and to assess the occurrence of serum antibodies to USTE and VEDO. METHODS: This was a prospective single-centre observational study performed at the University Hospital Motol, Prague, Czech Republic. Of the 87 patients (51 Crohn's disease (CD), 30 ulcerative colitis (UC), and 6 IBD unclassified (IBD-U)), drug serum TLs and antibodies were measured in 282 observations (49 treatment courses) of USTE and 359 observations (38 courses) of VEDO. Serum and stool samples were collected before each study drug application during both the induction and maintenance phases of the treatment throughout the entire study period (January 2020 to June 2024). Clinical and laboratory data were obtained from the nationwide prospective registry CREdIT. Patients with perianal disease and those with previous major bowel surgery were not excluded from the study. As a POCC, we analysed a group of pIBD treated at our centre with anti-TNF agents-adalimumab or infliximab. RESULTS: In a linear multiple regression mixed model, an association was observed between logF-CPT levels and USTE treatment duration (β -0.0010, 95% confidence interval (CI) -0.0015 to -0.0006, p < 0.001) but not with USTE TLs (p = 0.12). VEDO TLs and logF-CPT levels were negatively associated both in the linear (β -0.0173, 95% CI -0.0292 to -0.0053, p = 0.005) and categorical models (p = 0.026), even after adjusting for time. A VEDO TL of 15.1 µg/mL showed the best, though still poor, combination of sensitivity (0.82) and specificity (0.32) to predict F-CPT < 250 µg/g (area under the curve (AUC) 0.56, 95% CI 0.49-0.63). Intensification, induction phase, undetectable TLs, and type of IBD (CD, UC, IBD-U) were not associated with logF-CPT. Slightly elevated anti-drug antibodies were detected in 5 USTE and 16 VEDO observations, with no clinical implications. CONCLUSIONS: TDM of USTE does not appear to be useful in pIBD. TDM of VEDO may assist in therapeutic strategy decisions, although establishing clinically useful cut-offs remains challenging.

Gastroenterology and Nutrition Unit Department of Paediatrics 2nd Faculty of Medicine Charles University and University Hospital Motol 5 Uvalu 84 15006 Prague Czech Republic

Zobrazit více v PubMed

Turner D, et al. Management of paediatric ulcerative colitis, part 1: ambulatory care-an evidence-based guideline from European Crohn’s and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018;67(2):257–91. PubMed DOI

van Rheenen PF, et al. The medical management of paediatric Crohn’s disease: an ECCO-ESPGHAN guideline update. J Crohns Colitis. 2020;15(2):171–94. DOI

An overview of Stelara and why it is authorised in the EU. https://www.ema.europa.eu/en/documents/overview/stelara-epar-medicine-overview_en.pdf . An overview of Stelara and why it is authorised in the EU. https://www.ema.europa.eu/en/documents/overview/entyvio-epar-summary-public_en.pdf . Accessed 22 May 2025.

Cai XC, et al. Efficacy and safety of biological agents for the treatment of pediatric patients with psoriasis: a Bayesian analysis of six high-quality randomized controlled trials. Front Immunol. 2022;13: 896550. PubMed DOI PMC

European Commission approves STELARA® (ustekinumab) for the treatment of moderately to severely active Crohn’s disease in paediatric patients. https://innovativemedicine.jnj.com/emea/european-commission-approves-stelara-ustekinumab-for-the-treatment-of-moderately-to-severely-active-crohns-disease-in-paediatric-patients . Accessed 22 May 2025.

Classen M, Hoerning A. Current role of monoclonal antibody therapy in pediatric IBD: a special focus on therapeutic drug monitoring and treat-to-target strategies. Children (Basel). 2023;10(4):634. PubMed

Dolinger MT, et al. Outcomes of children with inflammatory bowel disease who develop anti-tumour necrosis factor-induced skin reactions. J Crohns Colitis. 2022;16(9):1420–7. PubMed DOI

Fang S, et al. Effectiveness and safety of ustekinumab for pediatric inflammatory bowel disease: a systematic review. Paediatr Drugs. 2023;25(5):499–513. PubMed DOI

Hradsky O, et al. Sustainability of biologic treatment in paediatric patients with Crohn’s disease: population-based registry analysis. Pediatr Res. 2024;96(5):1283–91. PubMed DOI

Pujol-Muncunill G, et al. STEP-CD study: ustekinumab use in paediatric Crohn’s disease—a multicentre retrospective study from paediatric IBD Porto Group of ESPGHAN. Eur J Pediatr. 2024;183(8):3253–62. PubMed DOI

Yerushalmy-Feler A, et al. Safety and potential efficacy of escalating dose of ustekinumab in pediatric Crohn disease (the speed-up study): a multicenter study from the pediatric IBD Porto Group of ESPGHAN. J Pediatr Gastroenterol Nutr. 2022;75(6):717–23. PubMed DOI

Atia O, et al. Children included in randomised controlled trials of biologics in inflammatory bowel diseases do not represent the real-world patient mix. Aliment Pharmacol Ther. 2022;56(5):794–801. PubMed DOI PMC

Garcia-Romero R, et al. Safety and effectiveness of vedolizumab in paediatric patients with inflammatory bowel disease: an observational multicentre Spanish study. Eur J Pediatr. 2021;180(9):3029–38. PubMed DOI

Choi S, et al. Vedolizumab is safe and efficacious for the treatment of pediatric-onset inflammatory bowel disease patients who fail a primary biologic agent. J Korean Med Sci. 2022;37(37): e282. PubMed DOI PMC

Kakiuchi T, Yoshiura M. Vedolizumab as the first-line of biologicals for pediatric patients with ulcerative colitis. Clin Ther. 2022;44(7):1028–32. PubMed DOI

Patel H, Karam L, Kellermayer R. A single-center study of long-term effectiveness of vedolizumab in anti-tnf refractory pediatric inflammatory bowel disease. JPGN Rep. 2023;4(1): e276. PubMed DOI

Schneider AM, et al. Vedolizumab use after failure of TNF-alpha antagonists in children and adolescents with inflammatory bowel disease. BMC Gastroenterol. 2018;18(1):140. PubMed DOI PMC

Yokoyama K, et al. Safety and efficacy of vedolizumab in pediatric patients with ulcerative colitis: multicenter study in Japan. J Gastroenterol Hepatol. 2023;38(7):1107–15. PubMed DOI

Jongsma MME, et al. Infliximab in young paediatric IBD patients: it is all about the dosing. Eur J Pediatr. 2020;179(12):1935–44. PubMed DOI PMC

Alsoud D, Vermeire S, Verstockt B. Monitoring vedolizumab and ustekinumab drug levels in patients with inflammatory bowel disease: hype or hope? Curr Opin Pharmacol. 2020;55:17–30. PubMed DOI

Carman N, Mack DR, Benchimol EI. Therapeutic drug monitoring in pediatric inflammatory bowel disease. Curr Gastroenterol Rep. 2018;20(5):18. PubMed DOI

Dutt K, Vasudevan A. Therapeutic drug monitoring for biologic and small-molecule therapies for inflammatory bowel disease. Medicina (Kaunas). 2024;60(2):250. PubMed DOI

Nassar IO, et al. Proposed pathway for therapeutic drug monitoring and dose escalation of vedolizumab. Frontline Gastroenterol. 2022;13(5):430–5. PubMed DOI PMC

Pouillon L, Vermeire S, Bossuyt P. Vedolizumab trough level monitoring in inflammatory bowel disease: a state-of-the-art overview. BMC Med. 2019;17(1):89. PubMed DOI PMC

Vasudevan A, et al. Systematic review and meta-analysis: the association between serum ustekinumab trough concentrations and treatment response in inflammatory bowel disease. Inflamm Bowel Dis. 2024;30(4):660–70. PubMed DOI

Vootukuru N, Vasudevan A. Approach to loss of response to advanced therapies in inflammatory bowel disease. World J Gastroenterol. 2024;30(22):2902–19. PubMed DOI PMC

Ward MG, Sparrow MP, Roblin X. Therapeutic drug monitoring of vedolizumab in inflammatory bowel disease: current data and future directions. Ther Adv Gastroenterol. 2018;11:1756284818772786. DOI

Yacoub W, et al. Early vedolizumab trough levels predict mucosal healing in inflammatory bowel disease: a multicentre prospective observational study. Aliment Pharmacol Ther. 2018;47(7):906–12. PubMed DOI

Raine T, et al. ECCO guidelines on therapeutics in ulcerative colitis: medical treatment. J Crohns Colitis. 2022;16(1):2–17. PubMed DOI

Torres J, et al. ECCO guidelines on therapeutics in Crohn’s disease: medical treatment. J Crohns Colitis. 2020;14(1):4–22. PubMed DOI

Turner D, et al. STRIDE-II: an update on the selecting therapeutic targets in inflammatory bowel disease (STRIDE) initiative of the International Organization for the Study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD. Gastroenterology. 2021;160(5):1570–83. PubMed DOI

Levine A, et al. ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J Pediatr Gastroenterol Nutr. 2014;58(6):795–806. PubMed DOI

Bouhuys M, Mian P, van Rheenen PF. Ustekinumab trough levels in children with Crohn’s disease refractory to anti-tumor necrosis factor agents: a prospective case series of off-label use. Front Pharmacol. 2023;14:1180750. PubMed DOI PMC

Dayan JR, et al. Real world experience with ustekinumab in children and young adults at a tertiary care pediatric inflammatory bowel disease center. J Pediatr Gastroenterol Nutr. 2019;69(1):61–7. PubMed DOI PMC

Dhaliwal J, et al. One-year outcomes with ustekinumab therapy in infliximab-refractory paediatric ulcerative colitis: a multicentre prospective study. Aliment Pharmacol Ther. 2021;53(12):1300–8. PubMed DOI

Do P, et al. Augmented ustekinumab dosing is needed to achieve clinical response in patients with anti-TNF refractory pediatric Crohn’s disease: a retrospective chart review. F1000Res. 2020;9:316. PubMed DOI

Kim FS, et al. Experience using ustekinumab in pediatric patients with medically refractory Crohn disease. J Pediatr Gastroenterol Nutr. 2021;73(5):610–4. PubMed DOI PMC

Rosh JR, et al. Ustekinumab in paediatric patients with moderately to severely active Crohn’s disease: pharmacokinetics, safety, and efficacy results from UniStar, a phase 1 study. J Crohns Colitis. 2021;15(11):1931–42. PubMed DOI PMC

Turner D, et al. Ustekinumab in paediatric patients with moderately to severely active Crohn’s disease: UniStar study long-term extension results. J Pediatr Gastroenterol Nutr. 2024;79(2):315–24. PubMed DOI

Philipp S, et al. Ustekinumab for the treatment of moderate-to-severe plaque psoriasis in paediatric patients (≥ 6 to < 12 years of age): efficacy, safety, pharmacokinetic and biomarker results from the open-label CADMUS Jr study. Br J Dermatol. 2020;183(4):664–72. PubMed DOI

Cohen S, et al. Effectiveness and safety of ustekinumab in pediatric ulcerative colitis: a multi-center retrospective study from the pediatric IBD Porto Group of ESPGHAN. Paediatr Drugs. 2024;26(5):609–17. PubMed DOI PMC

Sunny J, et al. Hypersensitivity Reaction to ustekinumab in pediatric and young adult inflammatory bowel disease patients: a case series. JPGN Rep. 2022;3(2): e205. PubMed DOI PMC

Hyams JS, et al. Pharmacokinetics, safety and efficacy of intravenous vedolizumab in paediatric patients with ulcerative colitis or Crohn’s disease: results from the phase 2 HUBBLE study. J Crohns Colitis. 2022;16(8):1243–54. PubMed DOI PMC

Aardoom MA, et al. Vedolizumab trough levels in children with anti-tumor necrosis factor refractory inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2020;71(4):501–7. PubMed DOI

Colman RJ, et al. Real world population pharmacokinetic study in children and young adults with inflammatory bowel disease discovers novel blood and stool microbial predictors of vedolizumab clearance. Aliment Pharmacol Ther. 2023;57(5):524–39. PubMed DOI

Rowland P, et al. Proactive therapeutic drug monitoring and vedolizumab dose optimization in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2024;78(4):853–61. PubMed DOI

Ungaro RC, et al. Higher trough vedolizumab concentrations during maintenance therapy are associated with corticosteroid-free remission in inflammatory bowel disease. J Crohns Colitis. 2019;13(8):963–9. PubMed DOI PMC

Hemming-Harlo M, et al. Drug levels of VEDOLIZUMAB in patients with pediatric-onset inflammatory bowel disease in a real-life setting. Eur J Pediatr. 2024;183(1):313–22. PubMed DOI

Atia O, et al. Outcomes, dosing, and predictors of vedolizumab treatment in children with inflammatory bowel disease (VEDOKIDS): a prospective, multicentre cohort study. Lancet Gastroenterol Hepatol. 2023;8(1):31–42. PubMed DOI

Atia O, et al. Maintenance treatment with vedolizumab in paediatric inflammatory bowel disease (VEDOKIDS): 54-week outcomes of a multicentre, prospective, cohort study. Lancet Gastroenterol Hepatol. 2025;10(3):234–47. PubMed DOI

Stein R, et al. Baseline drug clearance predicts outcomes in children with inflammatory bowel disease treated with vedolizumab: results from the vedokids prospective multicentre study. Aliment Pharmacol Ther. 2025;61(6):1000–10. PubMed DOI PMC

Outtier A, et al. Effect of vedolizumab dose intensification on serum drug concentrations and regain of response in inflammatory bowel disease patients with secondary loss of response. GastroHep. 2021;3(2):63–71. DOI

Ungar B, et al. Association of vedolizumab level, anti-drug antibodies, and alpha4beta7 occupancy with response in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2018;16(5):697-705e7. PubMed DOI