Gastroenterology

Gastroenterology

Volume 148, Issue 7, June 2015, Pages 1320-1329.e3
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Trough Concentrations of Infliximab Guide Dosing for Patients With Inflammatory Bowel Disease

https://doi.org/10.1053/j.gastro.2015.02.031Get rights and content

Background & Aims

Infliximab, a tumor necrosis factor antagonist, is effective for treating patients with Crohn’s disease (CD) and ulcerative colitis (UC). We aimed to determine whether dosing based on therapeutic drug monitoring increases rate of remission and whether continued concentration-based dosing is superior to clinically based dosing of infliximab for maintaining remission in patients with CD and UC.

Methods

We performed a 1-year randomized controlled trial at a tertiary referral center, including 263 adults (178 with CD and 85 with UC) with stable responses to maintenance infliximab therapy. Doses were escalated or reduced using an algorithm to reach a target trough concentration (TC) of 3–7 μg/mL in all patients (optimization phase). Patients were randomly assigned (1:1) to groups that received infliximab dosing based on their clinical features (n = 123) or continued dosing based on TCs (n = 128) (maintenance phase). The primary end point was clinical and biochemical remission at 1 year after the optimization phase.

Results

At screening, 115 of 263 patients had a TC of infliximab of 3–7 μg/mL (43.7%). Of 76 patients with TCs <3 μg/mL, 69 patients (91%) achieved TCs of 3–7 μg/mL after dose escalation. This resulted in a higher proportion of CD patients in remission than before dose escalation (88% vs 65%; P = .020) and a decrease in the median concentration of C-reactive protein, compared with before the dose increase (3.2 vs 4.3 mg/L; P < .001); these changes were not observed in patients with UC. Of 72 patients with TCs >7 μg/mL, 67 patients (93%) achieved TCs of 3–7 μg/mL after dose reduction. This resulted in a 28% reduction in drug cost from before dose reduction (P < .001). Sixty-six percent of patients whose dosing was based on clinical features and 69% whose dosing was based on TC achieved remission, the primary end point (P = .686). Disease relapsed in 21 patients who received clinically based dosing (17%) and 9 patients who received concentration-based dosing (7%) (P = .018).

Conclusions

Targeting patients’ infliximab TCs to 3–7 μg/mL results in a more efficient use of the drug. After dose optimization, continued concentration-based dosing was not superior to clinically based dosing for achieving remission after 1 year, but was associated with fewer flares during the course of treatment. ClinicalTrialsRegister.eu number: 2011-002061-38.

Section snippets

Design Overview

This randomized controlled trial was conducted at the University Hospitals Leuven, an academic and tertiary referral center from August 2011 to April 2013. The protocol was approved by the Institutional Review Board (ClinicalTrialsRegister.eu number, 2011-002061-38). All patients provided written informed consent.

Setting and Participants

Eligibility criteria included age of at least 18 years and a diagnosis of moderate-to-severe CD or UC confirmed by endoscopy and histology. Patients needed to be treated with

Screening

A consecutive cohort of 275 IBD patients (186 CD and 89 UC) receiving maintenance infliximab were screened from August through October 2011. Overall median CRP was 1.8 mg/L (IQR, 0.7–4.8 mg/L) and median infliximab TC was 4.6 μg/mL (IQR, 2.4–7.3 μg/mL). Of 275 patients, the infliximab TC was >7 μg/mL in 72 patients (26.2%); between 3 and 7 μg/mL in 121 patients (44.0%); detectable but <3 μg/mL in 58 patients (21.1%); and undetectable in 24 patients (8.7%). Of the 24 patients with an

Discussion

Fewer than half of the patients treated with maintenance infliximab had optimal infliximab TCs. Dose escalation in CD patients with a suboptimal infliximab TC led to a significant increase in patients in clinical remission and a concomitant significant drop in CRP concentrations. A similar effect was not seen for UC patients, most likely because the majority had a PMS of 0 and a normal CRP at baseline. Dose reduction in CD and UC patients with a supra-optimal infliximab TC did not lead to

Acknowledgments

The authors are grateful to the patients who were willing to participate in this study and for their support in the research on IBD. The authors are indebted to the IBD nurses at the infusion unit: Ingrid De Wolf, Marie-Josee Vermeyen, Anita Vleminckx, and Ellen Weyts for their professionalism, help, and involvement. Karolien Claes for her help with serum sample collection, Sophie Tops and Miet Peeters for their help with analyzing serum drug and anti-drug antibody concentrations, and Sarah

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    This article has an accompanying continuing medical education activity on page e13. Learning Objective: Upon completion of this exam, successful learners will be able to discuss the impact of dose escalation of infliximab in Crohn's disease patients with low troughs; identify patients where dose reduction is appropriate based on symptoms, trough concentrations, and inflammatory markers; and review timing and frequency of testing for anti-infliximab antibody testing.

    Conflicts of interest These authors disclose the following: Niels Vande Casteele reports consultancy fees from MSD, Janssen Biologics, UCB, and speaker’s fees from Abbvie, outside the submitted work. Marc Ferrante reports consultancy fees from Abbvie, Merck, Janssen Biologics, grants from Janssen Biologics, and speaker’s fees from Merck, Tillots, Ferring, Abbvie, outside the submitted work. Gert Van Assche reports consultancy fees from Zealand Pharma, Shire, Abbott/Abbvie, Novartis, MSD, Janssen, BMS, Ferring, Chiesi, Takeda, grants from MSD, Abbott/Abbvie, Zealand Pharma, and speaker’s fees from Janssen, Abbott/Abbvie, Ferring, Aptalis, Ferring, MSD, outside the submitted work; Vera Ballet has nothing to disclose; Griet Compernolle has nothing to disclose. Paul Rutgeerts reports consultancy fees from Amgen, Merck, UCB Pharma, Genentech, BMS, Abbvie, Janssen Biologics, Millennium, Neovacs, Actogenics, Prometheus Laboratories, Inc., grants from UCB Pharma, Abbvie, Janssen Biologics, Merck, Prometheus Laboratories, Inc., and speaker’s fees from Abbvie, Merck, outside the submitted work. Ann Gils reports grants from Pfizer, and speaker’s fees from MSD, Janssen Biologicals, Pfizer, outside the submitted work. Séverine Vermeire reports consultancy fees from Takeda, Roche/Genentech, Merck, Centocor, Abbvie, UCB, Pfizer, Ferring, grants from Centocor, Abbvie, Merck, and speaker’s fees from Merck, Abbvie, Takeda, Pfizer, Ferring, Falk, Centocor, outside the submitted work. The remaining authors disclose no conflicts.

    Funding This study was funded in part by the Research Foundation–Flanders (FWO), Belgium; grant number G061712 and Niels Vande Casteele is a Postdoctoral Fellow of the Research Foundation–Flanders (FWO), Belgium; grant number 1260714N. There was no external funding source that had an involvement on any aspect pertinent to the study.

    Author names in bold designate shared co-first authorship.

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    Authors share co-senior authorship.

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