The role of proactive therapeutic drug monitoring in guiding infliximab therapeutic optimization in pediatric patients with Crohn’s disease: A retrospective study

Abstract

Therapeutic drug monitoring (TDM) plays an important role in guiding treatment plan adjustments and clinical outcomes in Crohn’s disease. To evaluate the role of TDM-guided optimization of infliximab dosage in patients with pediatric Crohn’s disease. Medical records of patients with pediatric Crohn’s disease who were treated with infliximab and had proactive TDM from June 2020 to June 2022 at the Children’s Hospital of Chongqing Medical University were included. Baseline influencing factors for infliximab trough concentration (TC) and clinical outcomes before and after the treatment change were analyzed to assess the value of adjusting treatment in the patients. Forty-six patients (male-to-female ratio = 1.55:1, age <18 years) were included. Univariate and multivariate analyses showed that hormone exposure (odds ratio: 0.042, 95% confidence interval: 0.002–0.924, p = 0.044), perianal lesions (5.813, 0.984–34.349, p = 0.052), simplified endoscopic score for Crohn’s disease (1.656, 1.065–2.577, p = 0.025), and total protein (TP) (0.851, 0.749–0.967, p = 0.014) were correlated with infliximab TC. Shortening the treatment interval increased the infliximab TC (pre vs. post = 1.69 ± 0.8 vs. 12.03 ± 6.64, p = 0.001, n = 12) after 93.9 ± 37.47 days, decreased the pediatric Crohn’s disease activity index and simplified endoscopic score for Crohn’s disease, and increased the biochemical remission, clinical remission, endoscopic remission, and endoscopic response rates; however, there was no statistical significance. Hormone exposure, perianal lesions, simplified endoscopic score for Crohn’s disease, and TP levels before the first infliximab use affected the infliximab TC. Shortening the treatment interval can improve infliximab TC levels and clinical outcomes.

Keywords

Crohn’s disease / infliximab / pediatric / therapeutic drug monitoring

References

[1] AlkhatryM, Al-Rifai A, AnneseV, et al. First United Arab Emirates consensus on diagnosis and management of inflammatory bowel diseases: a 2020 Delphi consensus. World J Gastroenterol. 2020; 26(43):6710-6769.

[2] RosenMJ, DhawanA, SaeedSA. Inflammatory bowel disease in children and adolescents. JAMA Pediatr. 2015; 169(11):1053-1060.

[3] Van LimbergenJ, Haskett J, GriffithsAM, et al. Toward enteral nutrition for the treatment of pediatric Crohn disease in Canada: a workshop to identify barriers and enablers. Can J Gastroenterol Hepatol. 2015; 29(7):351-356.

[4] CosnesJ, CattanS, BlainA, et al. Long-term evolution of disease behavior of Crohn’s disease. Inflamm Bowel Dis. 2002; 8(4):244-250.

[5] HillR, Lewindon P, MuirR, et al. Quality of life in children with Crohn disease. J Pediatr Gastroenterol Nutr. 2010; 51(1):35-40.

[6] Van LimbergenJ, Russell RK, DrummondHE, et al. Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology. 2008; 135(4):1114-1122.

[7] KelsenJ, Baldassano RN. Inflammatory bowel disease: the difference between children and adults. Inflamm Bowel Dis. 2008; 14(Suppl l l_2): S9-S11.

[8] van RheenenPF, AloiM, AssaA, et al. The medical management of paediatric Crohn’s disease: an ECCO-ESPGHAN guideline update. J Crohns Colitis. 2020:jjaa161.

[9] Subspecialty Group of Gastroenterology, the Society of Pediatrics, Chinese Medical Association, Subspecialty Group of Clinical Nutrition, the Society of Pediatrics, Chinese Medical Association. Expert consensus on the diagnosis and management of pediatric inflammatory bowel disease. Chin J Pediatr. 2019; 57(7):501-507.

[10] SzymanskaE, Dadalski M, Sieczkowska-GolubJ, et al. Premedication does not influence the incidence of infliximab infusion reactions in pediatric patients with inflammatory bowel disease-a single center case-control study. J Clin Med. 2021; 10(14):3177.

[11] CheifetzAS, AbreuMT, AfifW, et al. A comprehensive literature review and expert consensus statement on therapeutic drug monitoring of biologics in inflammatory bowel disease. Am J Gastroenterol. 2021; 116(10):2014-2025.

[12] Giráldez-MonteroJM, Gonzalez-LopezJ, Campos-Toimil M, Lamas-DíazMJ. Therapeutic drug monitoring of anti-tumour necrosis factor-α agents in inflammatory bowel disease: limits and improvements. Br J Clin Pharmacol. 2021; 87(5):2216-2227.

[13] Marquez-MegiasS, Nalda-Molina R, Sanz-ValeroJ, et al. Cost-effectiveness of therapeutic drug monitoring of anti-TNF therapy in inflammatory bowel disease: a systematic review. Pharmaceutics. 2022; 14(5):1009.

[14] SyedN, Tolaymat M, BrownSA, SivasailamB, CrossRK. Proactive drug monitoring is associated with higher persistence to infliximab and adalimumab treatment and lower healthcare utilization compared with reactive and clinical monitoring. Crohns Colitis 360. 2020; 2(3):otaa050.

[15] PapamichaelK, ChachuKA, VajraveluRK, et al. Improved long-term outcomes of patients with inflammatory bowel disease receiving proactive compared with reactive monitoring of serum concentrations of infliximab. Clin Gastroenterol Hepatol. 2017; 15(10):1580-1588.e3.

[16] VaughnBP, Martinez-Vazquez M, PatwardhanVR, MossAC, Sandborn WJ, CheifetzAS. Proactive therapeutic concentration monitoring of infliximab may improve outcomes for patients with inflammatory bowel disease: results from a pilot observational study. Inflamm Bowel Dis. 2014; 20(11):1996-2003.

[17] Sánchez-HernándezJG, RebolloN, Martin-Suarez A, CalvoMV, MuñozF. A 3-year prospective study of a multidisciplinary early proactive therapeutic drug monitoring programme of infliximab treatments in inflammatory bowel disease. Br J Clin Pharmacol. 2020; 86(6):1165-1175.

[18] PapamichaelK, Juncadella A, WongD, et al. Proactive therapeutic drug monitoring of adalimumab is associated with better long-term outcomes compared with standard of care in patients with inflammatory bowel disease. J Crohns Colitis. 2019; 13(8):976-981.

[19] BurgessCJ, ReillyC, Steward-HarrisonL, BalouchF, Lewindon PJ. Utility of proactive infliximab levels in paediatric Crohn’s disease. Arch Dis Child. 2019; 104(3):251-255.

[20] GuidiL, Pugliese D, Panici TonucciT, et al. Therapeutic drug monitoring is more cost-effective than a clinically based approach in the management of loss of response to infliximab in inflammatory bowel disease: an observational multicentre study. J Crohns Colitis. 2018; 12(9):1079-1088.

[21] YanaiH, DotanI. Therapeutic drug monitoring is more cost-effective than a clinically based approach in the management of loss of response to infliximab in inflammatory bowel disease: an observational multicentre study. J Crohns Colitis. 2019; 13(5):539-540.

[22] KellyOB, Donnell SO, StempakJM, SteinhartAH, Silverberg MS. Therapeutic drug monitoring to guide infliximab dose adjustment is associated with better endoscopic outcomes than clinical decision making alone in active inflammatory bowel disease. Inflamm Bowel Dis. 2017; 23(7):1202-1209.

[23] MartinsCA, GarciaKS, QueirozNSF. Multi-utility of therapeutic drug monitoring in inflammatory bowel diseases. Front Med. 2022; 9:864888.

[24] LevineA, Griffiths A, MarkowitzJ, et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis. 2011; 17(6):1314-1321.

[25] Inflammatory Enterology Group, Gastroenterology Branch, Chinese Medical Association. Expert consensus on monitoring of therapeutic drugs for inflammatory bowel disease in China. Chin J Inflamm Bowel Dis. 2018; 2(4):253-259.

[26] BaumanLE, XiongY, MizunoT, et al. Improved population pharmacokinetic model for predicting optimized infliximab exposure in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2020; 26(3):429-439.

[27] van HoeveK, Dreesen E, HoffmanI, et al. Higher infliximab trough levels are associated with better outcome in paediatric patients with inflammatory bowel disease. J Crohns Colitis. 2018; 12(11):1316-1325.

[28] KangB, ChoiSY, ChoiYO, et al. Infliximab trough levels are associated with mucosal healing during maintenance treatment with infliximab in paediatric Crohn’s disease. J Crohns Colitis. 2019; 13(2):189-197.

[29] FaubionWA, Dubinsky M, RuemmeleFM, et al. Long-term efficacy and safety of adalimumab in pediatric patients with Crohn’s disease. Inflamm Bowel Dis. 2017; 23(3):453-460.

[30] HyamsJ, Crandall W, KugathasanS, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology. 2007; 132(3):863-873.quiz 1165-1166.

[31] VuittonL, Marteau P, SandbornWJ, et al. IOIBD technical review on endoscopic indices for Crohn’s disease clinical trials. Gut. 2016; 65(9):1447-1455.

[32] VuittonL, Peyrin-Biroulet L, ColombelJF, et al. Defining endoscopic response and remission in ulcerative colitis clinical trials: an international consensus. Aliment Pharmacol Ther. 2017; 45(6):801-813.

[33] Peyrin-BirouletL, Sandborn W, SandsBE, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE):determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015; 110(9):1324-1338.

[34] PapamichaelK, Cheifetz AS, MelmedGY, et al. Appropriate therapeutic drug monitoring of biologic agents for patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2019; 17(9):1655-1668.e3.

[35] VermeireS, Dreesen E, PapamichaelK, DubinskyMC. How, when, and for whom should we perform therapeutic drug monitoring? Clin Gastroenterol Hepatol. 2020; 18(6):1291-1299.

[36] LylesJL, Mulgund AA, BaumanLE, et al. Effect of a practice-wide anti-TNF proactive therapeutic drug monitoring program on outcomes in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2021; 27(4):482-492.

[37] Vande CasteeleN, Ferrante M, Van AsscheG, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015; 148(7):1320-1329.e3.

[38] AssaA, MatarM, TurnerD, et al. Proactive monitoring of adalimumab trough concentration associated with increased clinical remission in children with Crohn’s disease compared with reactive monitoring. Gastroenterology. 2019; 157(4):985-996.e2.

[39] CaoW-T, HuangR, LiuS, et al. Infliximab trough level combined with inflammatory biomarkers predict long-term endoscopic outcomes in Crohn’s disease under infliximab therapy. World J Gastroenterol. 2022; 28(23):2582-2596.

[40] NandaKS, Cheifetz AS, MossAC. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD):a meta-analysis. Am J Gastroenterol. 2013; 108(1):40-47.quiz48.

[41] MooreC, Corbett G, MossAC. Systematic review and meta-analysis: serum infliximab levels during maintenance therapy and outcomes in inflammatory bowel disease. J Crohns Colitis. 2016; 10(5):619-625.

[42] SantacanaE, Rodríguez-Alonso L, PadullésA, et al. Predictors of infliximab trough concentrations in inflammatory bowel disease patients using a repeated-measures design. Ther Drug Monit. 2020; 42(1):102-110.

[43] GrinmanAB, de Souza MDGC, BouskelaE, CarvalhoATP, de Souza HSP. Clinical and laboratory markers associated with anti-TNF-alpha trough levels and anti-drug antibodies in patients with inflammatory bowel diseases. Medicine. 2020; 99(10):e19359.

[44] HofmeklerT, BerthaM, McCrackenC, et al. Infliximab optimization based on therapeutic drug monitoring in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2017; 64(4):580-585.

[45] DeoraV, KozakJ, El-KallaM, Huynh HQ, El-MataryW. Therapeutic drug monitoring was helpful in guiding the decision-making process for children receiving infliximab for inflammatory bowel disease. Acta Paediatr. 2017; 106(11):1863-1867.

[46] LegaS, PhanBL, RosenthalCJ, et al. Proactively optimized infliximab monotherapy is as effective as combination therapy in IBD. Inflamm Bowel Dis. 2019; 25(1):134-141.

[47] SunX-L, ChenS-Y, TaoS-S, Qiao L-C, ChenH-J, YangB-L. Optimized timing of using infliximab in perianal fistulizing Crohn’s disease. World J Gastroenterol. 2020; 26(14):1554-1563.

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2024 The Author(s). Pediatric Discovery published by John Wiley & Sons Australia, Ltd on behalf of Children’s Hospital of Chongqing Medical University.