Causes of Treatment Failure in Children With Inflammatory Bowel Disease Treated With Infliximab: A Pharmacokinetic Study

Samuele Naviglio, Doriana Lacorte, Marianna Lucafò, Adriana Cifù, Diego Favretto, Eva Cuzzoni, Tania Silvestri, Martina Pozzi Mucelli, Oriano Radillo, Giuliana Decorti, Martina Fabris, Matteo Bramuzzo, Andrea Taddio, Gabriele Stocco, Patrizia Alvisi, Alessandro Ventura, Stefano Martelossi

Research output: Contribution to journalArticle

Abstract

OBJECTIVES: Anti-tumor necrosis factor antibodies have led to a revolution in the treatment of inflammatory bowel diseases (IBD); however, a sizable proportion of patients does not respond to therapy. There is increasing evidence suggesting that treatment failure may be classified as mechanistic (pharmacodynamic), pharmacokinetic, or immune-mediated. Data regarding the contribution of these factors in children with IBD treated with infliximab (IFX) are still incomplete. The aim was to assess the causes of treatment failure in a prospective cohort of pediatric patients treated with IFX. METHODS: This observational study considered 49 pediatric (median age 14.4) IBD patients (34 Crohn disease, 15 ulcerative colitis) treated with IFX. Serum samples were collected at 6, 14, 22 and 54 weeks, before IFX infusions. IFX and anti-infliximab antibodies (AIA) were measured using enzyme linked immunosorbent assays. Disease activity was determined by Pediatric Crohn's Disease Activity Index or Pediatric Ulcerative Colitis Activity Index. RESULTS: Clinical remission, defined as a clinical score <10, was obtained by 76.3% of patients at week 14 and by 73.9% at week 54. Median trough IFX concentration was higher at all time points in patients achieving sustained clinical remission. IFX levels during maintenance correlated also with C-reactive protein, albumin, and fecal calprotectin. After multivariate analysis, IFX concentration at week 14 >3.11 μg/mL emerged as the strongest predictor of sustained clinical remission. AIA concentrations were correlated inversely with IFX concentrations and directly with adverse reactions. CONCLUSIONS: Most cases of therapeutic failure were associated with low serum drug levels. IFX trough levels at the end of induction are associated with sustained long-term response.

Original languageEnglish
Pages (from-to)37-44
Number of pages8
JournalJournal of Pediatric Gastroenterology and Nutrition
Volume68
Issue number1
DOIs
Publication statusPublished - Jan 1 2019

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Treatment Failure
Inflammatory Bowel Diseases
Pharmacokinetics
Anti-Idiotypic Antibodies
Pediatrics
Infliximab
Serum
Ulcerative Colitis
Crohn Disease
Observational Studies
Therapeutics
Tumor Necrosis Factor-alpha
Enzyme-Linked Immunosorbent Assay
Antibodies
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Gastroenterology

Cite this

Causes of Treatment Failure in Children With Inflammatory Bowel Disease Treated With Infliximab : A Pharmacokinetic Study. / Naviglio, Samuele; Lacorte, Doriana; Lucafò, Marianna; Cifù, Adriana; Favretto, Diego; Cuzzoni, Eva; Silvestri, Tania; Pozzi Mucelli, Martina; Radillo, Oriano; Decorti, Giuliana; Fabris, Martina; Bramuzzo, Matteo; Taddio, Andrea; Stocco, Gabriele; Alvisi, Patrizia; Ventura, Alessandro; Martelossi, Stefano.

In: Journal of Pediatric Gastroenterology and Nutrition, Vol. 68, No. 1, 01.01.2019, p. 37-44.

Research output: Contribution to journalArticle

Naviglio, Samuele ; Lacorte, Doriana ; Lucafò, Marianna ; Cifù, Adriana ; Favretto, Diego ; Cuzzoni, Eva ; Silvestri, Tania ; Pozzi Mucelli, Martina ; Radillo, Oriano ; Decorti, Giuliana ; Fabris, Martina ; Bramuzzo, Matteo ; Taddio, Andrea ; Stocco, Gabriele ; Alvisi, Patrizia ; Ventura, Alessandro ; Martelossi, Stefano. / Causes of Treatment Failure in Children With Inflammatory Bowel Disease Treated With Infliximab : A Pharmacokinetic Study. In: Journal of Pediatric Gastroenterology and Nutrition. 2019 ; Vol. 68, No. 1. pp. 37-44.
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T1 - Causes of Treatment Failure in Children With Inflammatory Bowel Disease Treated With Infliximab

T2 - A Pharmacokinetic Study

AU - Naviglio, Samuele

AU - Lacorte, Doriana

AU - Lucafò, Marianna

AU - Cifù, Adriana

AU - Favretto, Diego

AU - Cuzzoni, Eva

AU - Silvestri, Tania

AU - Pozzi Mucelli, Martina

AU - Radillo, Oriano

AU - Decorti, Giuliana

AU - Fabris, Martina

AU - Bramuzzo, Matteo

AU - Taddio, Andrea

AU - Stocco, Gabriele

AU - Alvisi, Patrizia

AU - Ventura, Alessandro

AU - Martelossi, Stefano

PY - 2019/1/1

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N2 - OBJECTIVES: Anti-tumor necrosis factor antibodies have led to a revolution in the treatment of inflammatory bowel diseases (IBD); however, a sizable proportion of patients does not respond to therapy. There is increasing evidence suggesting that treatment failure may be classified as mechanistic (pharmacodynamic), pharmacokinetic, or immune-mediated. Data regarding the contribution of these factors in children with IBD treated with infliximab (IFX) are still incomplete. The aim was to assess the causes of treatment failure in a prospective cohort of pediatric patients treated with IFX. METHODS: This observational study considered 49 pediatric (median age 14.4) IBD patients (34 Crohn disease, 15 ulcerative colitis) treated with IFX. Serum samples were collected at 6, 14, 22 and 54 weeks, before IFX infusions. IFX and anti-infliximab antibodies (AIA) were measured using enzyme linked immunosorbent assays. Disease activity was determined by Pediatric Crohn's Disease Activity Index or Pediatric Ulcerative Colitis Activity Index. RESULTS: Clinical remission, defined as a clinical score <10, was obtained by 76.3% of patients at week 14 and by 73.9% at week 54. Median trough IFX concentration was higher at all time points in patients achieving sustained clinical remission. IFX levels during maintenance correlated also with C-reactive protein, albumin, and fecal calprotectin. After multivariate analysis, IFX concentration at week 14 >3.11 μg/mL emerged as the strongest predictor of sustained clinical remission. AIA concentrations were correlated inversely with IFX concentrations and directly with adverse reactions. CONCLUSIONS: Most cases of therapeutic failure were associated with low serum drug levels. IFX trough levels at the end of induction are associated with sustained long-term response.

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