Association Between Serum Concentration of Infliximab and Efficacy in Adult Patients With Ulcerative Colitis

doi:10.1053/j.gastro.2014.08.035

Gastroenterology

Volume 147, Issue 6, December 2014, Pages 1296-1307.e5

https://doi.org/10.1053/j.gastro.2014.08.035 Get rights and content

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Background & Aims

We analyzed data collected during the Active Ulcerative Colitis Trials (ACT-1 and ACT-2) to assess relationships between serum concentrations of infliximab and outcomes of adults with moderate-to-severe ulcerative colitis.

Methods

We compared serum concentrations of infliximab with outcomes of 728 patients with moderately-to-severely active ulcerative colitis who participated in ACT-1 or ACT-2; efficacy data were collected at weeks 8, 30, and 54 (for ACT-1 only). Relationships between serum concentration of infliximab and efficacy outcomes were assessed using trend, logistic regression, and receiver operating characteristic curve analyses. We also evaluated factors that affected the relationship between exposure and response.

Results

Median serum concentrations of infliximab at weeks 8, 30, and/or 54 were significantly higher in patients with clinical response, mucosal healing, and/or clinical remission than in patients who did not meet these response criteria. There were statistically significant relationships between quartile of infliximab serum concentration and efficacy at these time points (P < .01). Infliximab therapy was effective for a smaller proportion of patients in the lowest quartile, and these patients had lower serum levels of albumin and a higher incidence of antibodies to infliximab than patients in other quartiles. Although the relationship between exposure to infliximab and response varied among patients, approximate serum concentrations of 41 μg/mL infliximab at week 8 of induction therapy and 3.7 μg/mL at steady-state during maintenance therapy produced optimal outcomes in patients.

Conclusions

Serum concentrations of infliximab are associated with efficacy in patients with moderate-to-severe ulcerative colitis; however, complex factors determine the relationship between exposure to this drug and response. A prospective evaluation of the value of measuring serum concentrations of infliximab should be performed before these data can be included in patient management strategies. Clinicaltrials.gov numbers: NCT00036439 and NCT00096655.

Keywords

Anti–Tumor Necrosis Factor

Monoclonal Antibody

Pharmacokinetics

Inflammatory Bowel Disease

Abbreviations used in this paper

ACT-1

Active Ulcerative Colitis Trial 1

ACT-2

Active Ulcerative Colitis Trial 2

ATI

antibodies to infliximab

AUC

area under the curve

confidence interval

CPW2/6/14/30/54

preinfusion concentration at weeks 2/6/14/30/54

CW8

concentration at week 8

IBD

inflammatory bowel disease

NPV

negative predictive value

pharmacokinetic

PPV

positive predictive value

ROC

receiver operator characteristic

TNF

tumor necrosis factor

ulcerative colitis

Cited by (0)

: Conflicts of interest These authors disclose the following: Omoniyi Adedokun is an employee of Janssen Research & Development, LLC; William Sandborn has received consulting fees from Abbott, ActoGeniX NV, AGI Therapeutics, Inc, Alba Therapeutics Corp, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas, Athersys, Inc, Atlantic Healthcare, Ltd, Aptalis, BioBalance Corp, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, EnGene, Inc, Eli Lilly, Enteromedics, Exagen Diagnostics, Inc, Ferring Pharmaceuticals, Flexio Therapeutics, Inc, Funxional Therapeutics, Ltd, Genzyme Corp, Gilead Sciences, Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood Pharmaceuticals, Janssen Pharmaceutical Research & Development, LLC, KaloBios Pharmaceuticals, Lexicon Pharmaceuticals, Lycera Corp, Meda Pharmaceuticals, Merck Research Laboratories, Merck/Serono, Millenium Pharmaceuticals, Nisshin Kyorin Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics, Inc, PDL Biopharma, Pfizer, Procter & Gamble, Prometheus Laboratories, ProtAb, Ltd, Purgenesis Technologies, Inc, Relypsa, Inc, Roche, Salient Pharmaceuticals, Salix Pharmaceuticals, Santarus, Schering Plough, Shire Pharmaceuticals, Sigmoid Pharma, Ltd, Sirtris Pharmaceuticals, SLA Pharma UK Ltd, Targacept, Teva Pharmaceuticals, Therakos, Tilliotts Pharma AG, TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics, Ltd, Warner Chilcott UK, Ltd, and Wyeth, has received research grants from Abbott, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen Pharmaceutical Research & Development, LLC, Millennium Pharmaceuticals, Novartis, Pfizer, Procter & Gamble, Shire Pharmaceuticals, and UCB Pharma, has received payments for lectures/speakers bureau from Abbott, Bristol-Myers Squibb, and Janssen Pharmaceutical Research & Development, LLC, and holds stock/stock options in Enteromedics; Brian Feagan has received research/grant support from Abbott/AbbVie, Amgen, Astra Zeneca, Bristol-Myers Squibb, Janssen Biotech (Centocor), Johnson & Johnson/Janssen, Millennium, Pfizer, Receptos, Roche/Genentech, Santarus, Sanofi, Tillotts, and UCB Pharma, serves as a consultant/speaker for Abbott/AbbVie, Actogenix, Albireo Pharma, Amgen, Astra Zeneca, Avaxia Biologics, Inc, Axcan, Baxter Healthcare Corp, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, GiCare Pharma, Gilead, Given Imaging, Inc, GlaxoSmithKline, Ironwood Pharma, Janssen Biotech (Centocor), Johnson & Johnson/Janssen, Kyowa Kakko Kirin Co, Ltd, Lexicon, Lilly, Merck/Schering-Plough, Millennium, Nektar, Novo Nordisk, Prometheus Therapeutics and Diagnostics, Pfizer, Receptos, Roche/Genentech, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma, Inc, Takeda, Teva Pharma, Tillotts Pharma AG, UCB Pharma, Vertex Pharma, Warner-Chilcott, Wyeth, Zealand, and Zyngenia, and is a Steering Committee member for Abbott/AbbVie, Amgen, Astra Zeneca, Avaxia Biologics, Inc, Bristol-Myers Squibb, Celgene, Elan/Biogen, Ferring, Janssen Biotech (Centocor), Johnson & Johnson/Janssen, Merck/Schering-Plough, Novartis, Novo Nordisk, Pfizer, Prometheus Laboratories, Salix Pharma, Takeda, Teva, Tillotts Pharma AG, and UCB Pharma; Paul Rutgeerts has received research support from Abbott, Janssen, Merck/Schering-Plough, and UCB, consulting fees from Abbott, Bristol-Meyers Squibb, Falk Pharma, Genentech/Hoffman Janssen, Merck/Serono, Merck/Schering-Plough, Millenium/Takeda, Neovacs, Pfizer, Robarts, Tillots, and UCB, and has served as a speaker for Abbott, Janssen, and Merck/Schering-Plough; Zhenhua Xu, Colleen Marano, Jewel Johanns, Honghui Zhou, and Hugh Davis are employees of Janssen Research & Development, LLC; Freddy Cornillie was an employee of Janssen Biologics BV at the time the manuscript was drafted and submitted; and Walter Reinisch has served as a consultant and/or an advisory board member for Abbott Laboratories, Abbvie, Amgen, AM Pharma, Aptalis, Astellas, Astra Zeneca, Biogen IDEC, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Grünenthal, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Robarts Clinical Trials, Schering-Plough, Setpointmedical, Shire, Takeda, Therakos, Tigenix, UCB, Vifor, Yakult, Zyngenia, and 4SC and has served as a speaker for Abbott, Abbvie, Aptalis, Ferring, Mitsubishsi Tanabe, Celltrion, MSD, Otsuka, Pharmacosmos, Shire, and Therakos.

: Funding The ACT-1 and ACT-2 trials were sponsored by Janssen Research & Development, LLC (formerly Centocor Research and Development).

: Author names in bold designate shared co-first authors.