Original article
Alimentary tract
Pharmacokinetic Features and Presence of Antidrug Antibodies Associate With Response to Infliximab Induction Therapy in Patients With Moderate to Severe Ulcerative Colitis

Preliminary results of this study were presented in part at Digestive Diseases Week 2014, Chicago, IL.
https://doi.org/10.1016/j.cgh.2015.10.029Get rights and content

Background & Aims

The pharmacokinetics of infliximab during induction treatment for ulcerative colitis (UC) have not been studied. We investigated serum concentrations of infliximab and the early appearance of antibodies to infliximab (ATI) during induction treatment in patients with moderate-to-severe UC.

Methods

We performed a prospective analysis of 19 consecutive patients with moderate-severe UC (endoscopic Mayo ≥ 2) receiving induction therapy with infliximab (5 mg/kg at weeks 0, 2, and 6) at 2 centers in Amsterdam, The Netherlands, from July 2012 through March 2014. Serial serum and fecal samples were collected for 6 weeks and concentrations of infliximab, ATI, c-reactive protein (CRP), albumin, and fecal calprotectin were measured. Treatment success was defined as endoscopic response (≥1 point reduction in the endoscopic Mayo score) at week 8.

Results

Eleven patients (58%) had an endoscopic response. The median serum concentrations of infliximab at week 6 were 8.1 μg/mL in responders (interquartile range, 3.0–13.7 μg/mL) and 2.9 μg/mL in nonresponders (interquartile range, 0.01–5.8 μg/mL) (P = .03). ATIs were detected in 7 patients as early as day 18 (median, 28 d; interquartile range, 18–42 d). Six of the 8 nonresponders tested positive for ATIs vs 1 of 11 responders (P < .01; odds ratio, 30.0; 95% CI, 2.2–406.2). Patients with a baseline concentration of CRP greater than 50 mg/L had lower drug exposure from weeks 0 to 6 (587 mg/L/d in patients with high levels of CRP vs 1361 mg/L/day in patients with low CRP; P = .001). The median area under the curve for serum concentration of infliximab during induction therapy was 1230 mg/L/d in nonresponders vs 1352 mg/L/d in responders (P = .65).

Conclusions

There is a significant difference in serum concentration of infliximab at week 6 of treatment between responders and nonresponders. Early development of ATIs during induction therapy reduces the serum concentration of infliximab and is associated with nonresponse to treatment. Patients with high baseline serum levels of CRP had lower serum concentrations of infliximab. Clinical trial number: NL39626.018.12.

Section snippets

Methods

This prospective cohort study was performed at 2 centers in Amsterdam, The Netherlands (an academic referral center, the Academic Medical Center, and a regional teaching hospital, Onze Lieve Vrouwe Gasthuis), between 2012 and 2014. Consecutive anti-TNF–naive adults with moderate-to-severe UC (endoscopic Mayo score, 2 or 3) were included after providing informed consent. Infliximab was administered intravenously at a dose of 5 mg/kg, either during admission or at the outpatient infusion clinic.

Results

Twenty consecutive UC patients were included. All but 1 patient suffered from severe Mayo 3 colitis at baseline endoscopy and one third of patients were hospitalized at initiation of IFX therapy (Table 1). Eleven patients were on concomitant steroids (40 mg, 7 intravenous and 4 oral).

Discussion

In this intensive pharmacokinetic study we observed that antidrug antibodies already appear during induction treatment, impair IFX drug concentrations, and predict nonresponse in patients with moderate-severe UC. Furthermore, high baseline CRP levels had a strong negative impact on serum IFX concentrations in UC patients receiving conventional IFX induction therapy. In addition to baseline CRP, low serum albumin levels and extensive colitis correlated with lower serum IFX concentrations and a

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    Conflicts of interest These authors disclose the following: Johannan Brandse has received lecture fees from MSD and Takeda; Ron Mathôt has received consulting fees from Merck Sharp & Dohme and research grants from Bayer, UCB Pharma, and Hoffmann La Roche; Desiree van der Kleij is the Head of the Biologicals Laboratory of Sanquin Diagnostic Services, which performs assays for biological levels and antidrug antibodies for many pharmaceutical industries and hospitals; Theo Rispens has received honoraria for lectures from Pfizer and AbbVie; Jeroen Jansen has served as a speaker for Merck Sharp & Dohme and Abbvie and has served as a consultant for Ferring Pharmaceuticals, Schering Plough, AbbVie, and Pfizer; Mark Löwenberg has served as speaker and/or principal investigator for AbbVie, Covidien, Dr. Falk, Ferring Pharmaceuticals, Merck Sharp & Dohme, Receptos, Takeda, and Tramedico, and has received research grants from AbbVie, Merck Sharp & Dohme, and Achmea Healthcare; Cyriel Ponsioen has served as a speaker for Schering Plough, Falk Pharma, Tramedico, Abbott, Inc, and Glaxo Smith Kline, has served as a consultant for Schering Plough, Falk Pharma, Tramedico, Abbott, Inc, and Glaxo Smith Kline, and has received research funding from Schering Plough, Falk Pharma, Tramedico, Abbott, Inc, and Glaxo Smith Kline; Sharat Singh worked for Prometheus Laboratories; Gijs van den Brink has received consulting fees from Abbott Laboratories, and lecture fees from Abbott Laboratories, Merck Sharp & Dohme, and Ferring Pharmaceuticals, and has received research grants from Abbott Laboratories, Crucell, and Ferring Pharmaceuticals; and Geert D’Haens has served as a speaker for AbbVie, Ferring, Jansen Biologics, Merck Sharp Dome, Mundipharma, Norgine, Shire, Takeda, Tillotts, UCB, and Vifor, and has served as an advisor for AbbVie, Ablynx, Actogenix, Amakem, Amgen, AM Pharma, AstraZeneca, Avaxia, Bristol Meiers Squibb, Boerhinger Ingelheim, Celgene, Celltrion, Cosmo, Covidien, Elan, Ferring, Dr Falk Pharma, Centocor/Jansen Biologics, Engene, Ferring, Galapagos, Gilead, Glaxo Smith Kline, Hospira, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Novonordisk, Otsuka, Pfizer, Protein Design Laboratories, Prometheus Laboratories/Nestle, Receptos, Robarts Clinical Trials, Salix, Sandoz, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, UCB, Versant, and Vifor. The remaining authors disclose no conflicts.

    Funding This investigator-initiated study was self-funded. Antidrug antibody assessment was supported by Prometheus Laboratories.

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