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A Real-life Population Pharmacokinetic Study Reveals Factors Associated with Clearance and Immunogenicity of Infliximab in Inflammatory Bowel Disease

Brandse, Johannan F. MD, PhD; Mould, Diane PhD; Smeekes, Oscar MD; Ashruf, Yaël BS; Kuin, Sabine BS; Strik, Anne MD; van den Brink, Gijs R. MD, PhD; D'Haens, Geert R. MD, PhD

doi: 10.1097/MIB.0000000000001043
Original Clinical Articles

Background: Several factors influencing the pharmacokinetics of infliximab (IFX) in inflammatory bowel disease (IBD) have been identified. We studied the impact of patient, disease, and treatment characteristics on clearance and immunogenicity of IFX in a real-world patient-with-IBD cohort.

Methods: Serum concentrations of IFX and antibodies to IFX (ATIs) were measured in patients with IBD at a single center using an enzyme-linked immunosorbent assay and radioimmunoassay. Patient, disease, and treatment characteristics were retrospectively collected along with laboratory values. Pharmacokinetics and ATI titer were analyzed simultaneously by nonlinear mixed-effects modeling.

Results: Nine hundred ninety-seven IFX concentrations and 756 ATI measurements from 332 patients with IBD (253 Crohn's disease and 79 ulcerative colitis) were included. Mean (SD) IFX dose was 5.47 ± 1.33 mg/kg. ATIs were detected in 75/332 (23%) patients; insufficient exposure below an IFX trough level of 3 μg/mL was the most predictive factor of developing ATI and resulted in a 4-fold increased risk of ATI development. ATI titer was a better predictor of IFX clearance than ATI as a dichotomous parameter. ATI titers >30 AU/mL were consistently associated with undetectable IFX concentrations. IFX clearance was affected by body weight (40–149 kg) ranging from 0.27 to 0.53 L/d, serum albumin (2–5.4 g/dL) from 0.93 to 0.24 L/d, and titers of ATIs (0–53,000 AU/mL) from 0.36 L/d to 15.93 L/d (P < 0.001). Previously biologic-treated patients exhibited a higher clearance of IFX.

Conclusions: IFX exposure below 3 μg/mL increases risk of ATIs. Identification of influential pharmacokinetics and ATI factors improves prediction of IFX levels, potentially allowing individualized dosing and cost reduction.

Published online 10 February 2017

*Department of Gastroenterology, Academic Medical Center, Amsterdam, the Netherlands; and

Projections Research Inc., Phoenixville, Pennsylvania.

Address correspondence to: Geert R. D'Haens, MD, PhD, Department of Gastroenterology, Academic Medical Centre, room C2-208, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands (e-mail: g.dhaens@amc.uva.nl).

Presented at DDW, May 23, 2016, San Diego, CA.

J. F. Brandse has received speakers' fees from Takeda, MSD, and AbbVie. D. Mould is the president of Projections Research Inc., a consulting company to the pharmaceutical industry. G. R. van den Brink has received consulting fees from AbbVie and lecture fees from AbbVie, Takeda, Merck Sharp & Dohme, and Ferring Pharmaceuticals. He has received research grants from AbbVie, Crucell, the Janssen Prevention Center, Tillotts, and Ferring Pharmaceuticals. G. R. D'Haens has served as an advisor for AbbVie, Ablynx, ActoGeniX, Amakem, Amgen, AM-Pharma, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Cosmo, Covidien, Elan, Ferring, Dr FALK Pharma, Centocor/Janssen Biologics, Engene, Ferring, Galapagos, Gilead, GlaxoSmithKline, Hospira, Medimetrics, Millennium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Novo Nordisk, Otsuka, Pfizer, Protein Design Laboratories, Prometheus laboratories/Nestle, Receptos, Robarts Clinical Trials, Salix, Sandoz, Setpoint, Shire, Teva, TiGenix, Tillotts, TopiVert, UCB, Versant, and Vifor and received speaker fees from AbbVie, Ferring, Jansen Biologics, Merck Sharp Dome, Mundipharma, Norgine, Shire, Takeda, Tillotts, UCB, and Vifor. The remaining authors have no conflict of interest to disclose.

Received October 25, 2016

Accepted December 31, 2016

© Crohn's & Colitis Foundation of America, Inc.
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