Infliximab (IFX) is administered intravenously using weight-based dosing (5 mg/kg) in inflammatory bowel disease (IBD) patients. Our hypothesis is that especially young children need a more intensive treatment regimen than the current weight-based dose administration. We aimed to assess IFX pharmacokinetics (PK), based on existing therapeutic drug monitoring (TDM) data in IBD patients < 10 years. TDM data were collected retrospectively in 14 centres. Children treated with IFX were included if IFX was started as IBD treatment at age < 10 years (young patients, YP) and PK data were available. Older IBD patients aged 10-18 years were used as controls (older patients, OP). Two hundred and fifteen paediatric inflammatory bowel disease (PIBD) patients were eligible for the study (110 < 10 year; 105 ≥ 10 years). Median age was 8.3 years (IQR 6.9-8.9) in YP compared with 14.3 years (IQR 12.8-15.6) in OP at the start of IFX. At the start of maintenance treatment, 72% of YP had trough levels below therapeutic range (< 5.4 μg/mL). After 1 year of scheduled IFX maintenance treatment, YP required a significantly higher dose per 8 weeks compared with OP (YP; 9.0 mg/kg (IQR 5.0-12.9) vs. OP; 5.5 mg/kg (IQR 5.0-9.3); p < 0.001). The chance to develop antibodies to infliximab was relatively lower in OP than YP (0.329 (95% CI - 1.2 to - 1.01); p < 0.001), while the overall duration of response to IFX was not significantly different (after 2 years 53% (n = 29) in YP vs. 58% (n = 45) in OP; p = 0.56).Conclusion: Intensification of the induction scheme is suggested for PIBD patients aged < 10 years. What is Known? •Infliximab trough levels of paediatric IBD patients are influenced by several factors as dosing scheme, antibodies and inflammatory markers. •In 4.5-30% of the paediatric IBD patients, infliximab treatment was stopped within the first year. What is New? •The majority of young PIBD (< 10 years) have inadequate IFX trough levels at the start of maintenance treatment. •Young PIBD patients (< 10 years) were in need of a more intensive treatment regimen compared with older paediatric patients during 1 year of IFX treatment. •The chance to develop antibodies to infliximab was relatively higher in young PIBD patients (< 10 years).

Department of Biostatistics Erasmus Medical Center Rotterdam The Netherlands

Department of Paediatric Gastroenterology Amsterdam UMC Vrije Universiteit Emma Children's Hospital Amsterdam The Netherlands

Department of Paediatric Gastroenterology Erasmus Medical Center Sophia Children's Hospital Rotterdam The Netherlands

Department of Paediatric Gastroenterology Hepatology and Nutrition Hôpital Necker Enfants Malades Paris France

Department of Paediatric Gastroenterology Hôpital Robert Debré Paris France

Department of Paediatric Gastroenterology Our Lady's Children's Hospital and RCSI Dublin Ireland

Department of Paediatric Gastroenterology Shaare Zedek Medical Center Jerusalem Israel

Department of Paediatric Gastroenterology Tampere University Hospital and University of Tampere Tampere Finland and Children's Hospital University of Helsinki Helsinki Finland

Department of Paediatric Gastroenterology Universitair Ziekenhuis Ghent Belgium

Department of Paediatric Gastroenterology Utrecht Medical Center Wilhelmina Children's Hospital Utrecht The Netherlands

Department of Paediatrics Gastroenterology and Nutrition Unit University Hospital Motol Prague Czech Republic

Division of Paediatric Gastroenterology and Nutrition Edmonton Paediatric IBD Clinic University of Alberta Edmonton Canada

Institute of Paediatric Gastroenterology Schneider Children's Hospital affiliated to the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

Paediatric Gastroenterology unit Dana Dwek Children's Hospital Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

Paediatric Gastroenterology Unit Edmond and Lily Safra Children's Hospital Sheba Medical Center Ramat Gan and Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

Zobrazit více v PubMed

Ruemmele FM, Veres G, Kolho KL, Griffiths A, Levine A, Escher JC, Amil Dias J, Barabino A, Braegger CP, Bronsky J, Buderus S, Martín-de-Carpi J, de Ridder L, Fagerberg UL, Hugot JP, Kierkus J, Kolacek S, Koletzko S, Lionetti P, Miele E, Navas López VM, Paerregaard A, Russell RK, Serban DE, Shaoul R, van Rheenen P, Veereman G, Weiss B, Wilson D, Dignass A, Eliakim A, Winter H, Turner D, European Crohn’s and Colitis Organisation. European Society of Pediatric Gastroenterology, Hepatology and Nutrition Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn’s disease. J Crohns Colitis. 2014;8:1179–1207. doi: 10.1016/j.crohns.2014.04.005. PubMed DOI

European Medicines Agency (2009) Remicade: EPAR - Productinformation. https://www.ema.europa.eu/en/documents/rmp-summary/remicade-epar-risk-management-plan-summary_en.pdf

Dotan I, Ron Y, Yanai H, Becker S, Fishman S, Yahav L, Ben Yehoyada M, Mould DR. Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease: a population pharmacokinetic study. Inflamm Bowel Dis. 2014;20:2247–2259. doi: 10.1097/MIB.0000000000000212. PubMed DOI

Xu Z, Davis HM, Zhou H. Rational development and utilization of antibody-based therapeutic proteins in pediatrics. Pharmacol Ther. 2013;137:225–247. doi: 10.1016/j.pharmthera.2012.10.005. PubMed DOI

Fasanmade AA, Adedokun OJ, Blank M, Zhou H, Davis HM. Pharmacokinetic properties of infliximab in children and adults with Crohn’s disease: a retrospective analysis of data from 2 phase III clinical trials. Clin Ther. 2011;33:946–964. doi: 10.1016/j.clinthera.2011.06.002. PubMed DOI

Frymoyer A, Hoekman DR, Piester TL, de Meij TG, Hummel TZ, Benninga MA, Kindermann A, Park KT. Application of population pharmacokinetic Modeling for individualized infliximab dosing strategies in Crohn disease. J Pediatr Gastroenterol Nutr. 2017;65:639–645. doi: 10.1097/MPG.0000000000001620. PubMed DOI PMC

deBruyn JC, Jacobson K, El-Matary W, Carroll M, Wine E, Wrobel I, Van Woudenberg M, Huynh HQ. Long-term outcomes of infliximab use for Pediatric Crohn disease: a Canadian Multicenter clinical practice experience. J Pediatr Gastroenterol Nutr. 2018;66:268–273. doi: 10.1097/MPG.0000000000001672. PubMed DOI

Merras-Salmio L, Kolho KL. Clinical use of infliximab trough levels and antibodies to infliximab in Pediatric patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2017;64:272–278. doi: 10.1097/MPG.0000000000001258. PubMed DOI

Kelsen JR, Grossman AB, Pauly-Hubbard H, Gupta K, Baldassano RN, Mamula P. Infliximab therapy in pediatric patients 7 years of age and younger. J Pediatr Gastroenterol Nutr. 2014;59:758–762. doi: 10.1097/MPG.0000000000000533. PubMed DOI

Hyams J, Crandall W, Kugathasan S, Griffiths A, Olson A, Johanns J, Liu G, Travers S, Heuschkel R, Markowitz J, Cohen S, Winter H, Veereman-Wauters G, Ferry G, Baldassano R, Group RS Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology. 2007;132:863–873. doi: 10.1053/j.gastro.2006.12.003. PubMed DOI

Fasanmade AA, Adedokun OJ, Ford J, Hernandez D, Johanns J, Hu C, Davis HM, Zhou H. Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis. Eur J Clin Pharmacol. 2009;65:1211–1228. doi: 10.1007/s00228-009-0718-4. PubMed DOI PMC

Zitomersky NL, Atkinson BJ, Fournier K, Mitchell PD, Stern JB, Butler MC, Ashworth L, Hauenstein S, Heiner L, Chuang E, Singh S, Bousvaros A. Antibodies to infliximab are associated with lower infliximab levels and increased likelihood of surgery in Pediatric IBD. Inflamm Bowel Dis. 2015;21:307–314. doi: 10.1097/MIB.0000000000000284. PubMed DOI PMC

Hemperly A, Vande Casteele N. Clinical pharmacokinetics and pharmacodynamics of infliximab in the treatment of inflammatory bowel disease. Clin Pharmacokinet. 2018;57:929–942. doi: 10.1007/s40262-017-0627-0. PubMed DOI

Vande Casteele N, Ferrante M, Van Assche G, Ballet V, Compernolle G, Van Steen K, Simoens S, Rutgeerts P, Gils A, Vermeire S. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;148:1320–1329 e1323. doi: 10.1053/j.gastro.2015.02.031. PubMed DOI

Levine A, Griffiths A, Markowitz J, Wilson DC, Turner D, Russell RK, Fell J, Ruemmele FM, Walters T, Sherlock M, Dubinsky M, Hyams JS. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis. 2011;17:1314–1321. doi: 10.1002/ibd.21493. PubMed DOI

Haapamaki J, Roine RP, Sintonen H, Kolho KL. Health-related quality of life in paediatric patients with inflammatory bowel disease related to disease activity. J Paediatr Child Health. 2011;47:832–837. doi: 10.1111/j.1440-1754.2011.02034.x. PubMed DOI

Clarkston K, Tsai YT, Jackson K, Rosen MJ, Denson LA, Minar P. Development of infliximab target concentrations during induction in Pediatric Crohn disease patients. J Pediatr Gastroenterol Nutr. 2019;69:68–74. doi: 10.1097/MPG.0000000000002304. PubMed DOI PMC

van Hoeve K, Dreesen E, Hoffman I, Van Assche G, Ferrante M, Gils A, Vermeire S. Higher infliximab trough levels are associated with better outcome in paediatric patients with inflammatory bowel disease. J Crohns Colitis. 2018;12:1316–1325. doi: 10.1093/ecco-jcc/jjy111. PubMed DOI

van Hoeve K, Hoffman I, Vermeire S. Therapeutic drug monitoring of anti-TNF therapy in children with inflammatory bowel disease. Expert Opin Drug Saf. 2018;17:185–196. doi: 10.1080/14740338.2018.1413090. PubMed DOI

Bortlik M, Duricova D, Malickova K, Machkova N, Bouzkova E, Hrdlicka L, Komarek A, Lukas M. Infliximab trough levels may predict sustained response to infliximab in patients with Crohn’s disease. J Crohns Colitis. 2013;7:736–743. doi: 10.1016/j.crohns.2012.10.019. PubMed DOI

Yanai H, Hanauer SB. Assessing response and loss of response to biological therapies in IBD. Am J Gastroenterol. 2011;106:685–698. doi: 10.1038/ajg.2011.103. PubMed DOI

Ungar B, Glidai Y, Yavzori M, Picard O, Fudim E, Lahad A, Haberman Y, Shouval DS, Weintraub I, Eliakim R, Ben-Horin S, Weiss B (2018) Association between infliximab drug and antibody levels and therapy outcome in Pediatric inflammatory bowel diseases. J Pediatr Gastroenterol Nutr 67(4):507–512 PubMed

Singh N, Rosenthal CJ, Melmed GY, Mirocha J, Farrior S, Callejas S, Tripuraneni B, Rabizadeh S, Dubinsky MC. Early infliximab trough levels are associated with persistent remission in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2014;20:1708–1713. doi: 10.1097/MIB.0000000000000137. PubMed DOI

Ohem J, Hradsky O, Zarubova K, Copova I, Bukovska P, Prusa R, Malickova K, Bronsky J. Evaluation of infliximab therapy in children with Crohn’s disease using trough levels predictors. Dig Dis. 2018;36:40–48. doi: 10.1159/000477962. PubMed DOI

Steenholdt C, Bendtzen K, Brynskov J, Thomsen OO, Munck LK, Christensen LA, Pedersen G, Kjeldsen J, Ainsworth MA. Changes in serum trough levels of infliximab during treatment intensification but not in anti-infliximab antibody detection are associated with clinical outcomes after therapeutic failure in Crohn’s disease. J Crohns Colitis. 2015;9:238–245. doi: 10.1093/ecco-jcc/jjv004. PubMed DOI

Kennedy NA, Heap GA, Green HD, Hamilton B, Bewshea C, Walker GJ, Thomas A et al (2019) Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn’s disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol 4(5):341–353 PubMed

Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, Lichtiger S, D’Haens LG, Diamond RH, Broussard DL, Tang KL, van der Woude CJ, Rutgeerts P, Group SS Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–1395. doi: 10.1056/NEJMoa0904492. PubMed DOI

Frymoyer A, Piester TL, Park KT. Infliximab dosing strategies and predicted trough exposure in children with Crohn disease. J Pediatr Gastroenterol Nutr. 2016;62:723–727. doi: 10.1097/MPG.0000000000001123. PubMed DOI PMC

Greener T, Kabakchiev B, Steinhart AH, Silverberg MS. Higher infliximab levels are not associated with an increase in adverse events in inflammatory bowel disease. Inflamm Bowel Dis. 2018;24:1808–1814. doi: 10.1093/ibd/izy066. PubMed DOI

Drobne D, Kurent T, Golob S, Svegl P, Rajar P, Terzic S, Kozelj M, Novak G, Smrekar N, Plut S, Sever N, Strnisa L, Hanzel J, Brecelj J, Urlep D, Osredkar J, Homan M, Orel R, Stabuc B, Ferkolj I, Smid A. Success and safety of high infliximab trough levels in inflammatory bowel disease. Scand J Gastroenterol. 2018;53:940–946. doi: 10.1080/00365521.2018.1486882. PubMed DOI

Ungar B, Levy I, Yavne Y, Yavzori M, Picard O, Fudim E, Loebstein R, Chowers Y, Eliakim R, Kopylov U, Ben-Horin S. Optimizing anti-TNF-alpha therapy: serum levels of infliximab and Adalimumab are associated with mucosal healing in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2016;14:550–557 e552. doi: 10.1016/j.cgh.2015.10.025. PubMed DOI

El-Matary W, Walters TD, Huynh HQ, deBruyn J, Mack DR, Jacobson K, Sherlock ME, Church P, Wine E, Carroll MW, Benchimol EI, Lawrence S, Griffiths AM (2018) Higher Postinduction infliximab serum trough levels are associated with healing of Fistulizing perianal Crohn’s disease in children. Inflamm Bowel Dis 25(1):150–155 PubMed PMC

Yarur AJ, Kanagala V, Stein DJ, Czul F, Quintero MA, Agrawal D, Patel A, Best K, Fox C, Idstein K, Abreu MT. Higher infliximab trough levels are associated with perianal fistula healing in patients with Crohn’s disease. Aliment Pharmacol Ther. 2017;45:933–940. doi: 10.1111/apt.13970. PubMed DOI

Vande Casteele N, Buurman DJ, Sturkenboom MG, Kleibeuker JH, Vermeire S, Rispens T, van der Kleij D, Gils A, Dijkstra G. Detection of infliximab levels and anti-infliximab antibodies: a comparison of three different assays. Aliment Pharmacol Ther. 2012;36:765–771. doi: 10.1111/apt.12030. PubMed DOI

Malickova K, Duricova D, Bortlik M, Hind’os M, Machkova N, Hruba V, Lukas M, Zima T, Lukas M. Serum trough infliximab levels: a comparison of three different immunoassays for the monitoring of CT-P13 (infliximab) treatment in patients with inflammatory bowel disease. Biologicals. 2016;44:33–36. doi: 10.1016/j.biologicals.2015.09.005. PubMed DOI

Afonso J, Lopes S, Gonçalves R, Caldeira P, Lago P, Tavares de Sousa H, Ramos J, Gonçalves AR, Ministro P, Rosa I, Vieira AI, Coelho R, Tavares P, Soares J, Sousa AL, Carvalho D, Sousa P, da Silva JP, Meira T, Silva Ferreira F, Dias CC, Chowers Y, Ben-Horin S, Magro F, on behalf Portuguese IBDSG Detection of anti-infliximab antibodies is impacted by antibody titer, infliximab level and IgG4 antibodies: a systematic comparison of three different assays. Ther Adv Gastroenterol. 2016;9:781–794. doi: 10.1177/1756283X16658223. PubMed DOI PMC

Is It Useful to Monitor Thiopurine Metabolites in Pediatric Patients with Crohn's Disease on Combination Therapy? A Multicenter Prospective Observational Study