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Development of Infliximab Target Concentrations During Induction in Pediatric Crohn Disease Patients

Clarkston, Kathryn; Tsai, Yi-Ting; Jackson, Kimberly; Rosen, Michael J.; Denson, Lee A.; Minar, Phillip

Journal of Pediatric Gastroenterology and Nutrition: July 2019 - Volume 69 - Issue 1 - p 68–74
doi: 10.1097/MPG.0000000000002304
Original Articles: Gastroenterology: Inflammatory Bowel Disease
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Objectives: Subtherapeutic drug concentrations contribute to both primary and secondary nonresponse to infliximab in children with Crohn disease (CD). The aim of this study was to evaluate treatment outcomes and infliximab concentrations at infusions 2 and 3 with an objective to establish infliximab targets during induction for primary responders.

Methods: Single-center, prospective cohort of anti- tumor necrosis factor-alpha naïve CD patients younger than 22 years starting infliximab. Clinical response was defined with the weighted pediatric CD activity index at the fourth infusion. Rates of biological response (>50% improvement in fecal calprotectin) and maintenance concentrations ≥5 μg/mL were secondary outcomes.

Results: We enrolled 72 patients with CD with 70 of 72 receiving infliximab monotherapy. Clinical response, biological response, and start of maintenance concentrations ≥5 μg/mL were achieved in 64%, 54%, and 22%, respectively. The median (interquartile range) infliximab concentrations at infusion 2 and 3 in clinical responders were 27.8 μg/mL (19.5–40) and 14 μg/mL (8.3–24) compared to 18.8 μg/mL (9.1–23, P < 0.001) and 7.8 μg/mL (4–13.2, P < 0.01) in nonresponders. Receiver operating characteristic analysis determined that an infliximab concentration ≥15.9 μg/mL at infusion 3 was associated with clinical response (area under the curve [AUC] 0.73), whereas an infusion 3 level ≥18 μg/mL was associated with a start of maintenance concentration >5 μg/mL (AUC 0.85). Independent predictors for infusion 3 levels <18 μg/mL included pretreatment prednisone, low body mass index, elevated erythrocyte sedimentation rate and C-reactive protein, hypoalbuminemia, and an infusion 2 infliximab level <29 μg/mL.

Conclusions: We found that infusion 2 (≥29 μg/mL) and infusion 3 (≥18 μg/mL) infliximab concentrations were strongly associated with improved early outcomes and higher first maintenance dose levels.

Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

Address correspondence and reprint requests to Phillip Minar, MD, MS, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, MLC 2010, 3333 Burnet Ave, Cincinnati, OH 45229 (e-mail: phillip.minar@cchmc.org).

Received 27 June, 2018

Accepted 16 January, 2019

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org).

We have presented the abstract from this study at the 2017 North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) Annual Meeting in Las Vegas, Nevada.

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health (K23 DK105229 to P.M., K23 DK094832 to M.J.R.) and by the Cincinnati Children's Research Foundation Trustee Award Program (P.M.).

The authors report no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.jpgn.org).

© 2019 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,