Perspectives in clinical gastroenterology and hepatologyTherapeutic Drug Monitoring of Tumor Necrosis Factor Antagonists in Inflammatory Bowel Disease
Section snippets
Determinants of the Pharmacokinetics of Tumor Necrosis Factor Antagonists
A growing body of evidence suggests that both short- and long-term treatment outcomes are improved by achieving and maintaining adequate serum drug concentrations.10, 11, 12, 13, 14, 15, 16 One dominant factor that adversely affects the PK of TNF antagonists is the formation of antidrug antibodies (ADAs). These antibodies directly neutralize the biological activity of TNF antagonists by either binding specific drug idiotypes and/or accelerating drug clearance by the reticuloendothelial system
The Potential of Therapeutic Drug Monitoring
Historically, in clinical practice when a responding patient becomes refractory to a TNF antagonist, the following approach is used. First, the presence of active inflammation is evaluated by objective tools, either endoscopy or imaging and surrogate biomarkers of disease activity (CRP and fecal calprotectin). If inflammation is not confirmed, then other disease processes should be excluded by appropriate investigations (eg, bacterial overgrowth; bile salt deficiency; steatorrhea; infection,
Future Research Needs
To establish whether therapeutic monitoring is superior to the empiric dose-adjustment approach, randomized controlled trials are needed comparing both strategies. The TAXIT trial is one such study that will begin to provide evidence-based answers to this question.
On the other hand, the use of clinical pharmacology to define the PK profile of TNF antagonist agents, together with clinical, endoscopic, and imaging data, may be useful for the development of single predictive models based on
Conclusions
Available evidence suggests that adjustment of drug based only on clinical symptoms is frequently inaccurate and may lead to suboptimal outcomes. Observational data regarding therapeutic monitoring of drug and ADA concentrations suggests that incorporation of this strategy into clinical practice may allow clinicians to optimize treatment by maintaining effective drug concentrations over time.
Because of the high interpatient variability leading to heterogeneous responses to TNF antagonist
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Cited by (0)
This article has an accompanying continuing medical education activity on page e86. Learning Objective—At the end of this activity, the successful learner will be able to recognize the factors related to an increased clearance of TNF antagonist agents and to select the most appropriate strategy for treatment optimization in case of loss of response based on the assessment of drug and antidrug antibodies concentrations.
Conflicts of interest The authors disclose the following: Ingrid Ordás has received lecture fees from MSD (previously Schering-Plough), Abbott Laboratories, and Shire Pharmaceuticals. Brian G. Feagan has received research support, consulting, and lecture fees from Janssen (previously Centocor), Merck (previously Schering Plough), Abbott Laboratories, and UCB Pharma. William J. 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, GSK, Human Genome Sciences, Ironwood Pharmaceuticals, 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 and 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; research grants from Abbott, Bristol-Myers Squibb, Genentech, GSK, Janssen, Milennium Pharmaceuticals, Novartis, Pfizer, Procter and Gamble, Shire Pharmaceuticals, and UCB Pharma; payments for lectures/speakers bureau from Abbott, Bristol-Myers Squibb, and Janssen; and holds stock/stock options in Enteromedics.