Best Use of Biologics in 2014 Dig Dis 2014;32(suppl 1):88–91 DOI: 10.1159/000367834
Tailoring Treatment to the Individual Patient: Drug Monitoring William J. Sandborn Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, Calif., USA
Abstract Understanding why drug concentrations vary between patients and which drug concentrations are associated with efficacy allow the development of rational treatment algorithms. Factors that affect the clearance of monoclonal antibodies include: (1) the presence of antidrug antibodies (increased clearance), (2) concomitant immunosuppression (decreased clearance), (3) increased serum CRP concentration (increased clearance), (4) decreased serum albumin concentration (increased clearance), (5) decreased body weight (increased clearance), and (6) increased fecal infliximab concentration (increased clearance). These factors can result in marked variability in drug clearance. Higher serum infliximab and adalimumab concentrations are associated with increased rates of clinical response and mucosal healing, and lower rates of colectomy. Treatment algorithms incorporate the following principles: (1) patients who have symptoms of active disease and in whom high concentrations of antibodies to infliximab or adalimumab are present should switch to another TNF antagonist, (2) patients who have symptoms of active disease and in whom there are low concentrations of infliximab or adalimumab should have dose intensification, and (3) patients who are negative for antidrug antibody and
© 2014 S. Karger AG, Basel 0257–2753/14/0327–0088$39.50/0 E-Mail [email protected] www.karger.com/ddi
who have a therapeutic drug concentration should undergo evaluation to confirm the presence of active disease by endoscopy or radiology studies, and if active disease is confirmed, then these patients should discontinue anti-TNF therapy and switch to another class of medications or consider surgical options. © 2014 S. Karger AG, Basel
Introduction
There is increasing use of therapeutic drug monitoring to tailor treatment of the individual patients with IBD who are treated with biologics. This article reviews why drug concentrations vary between patients, which specific drug concentrations are associated with efficacy, and the application of this knowledge in the development of rational treatment algorithms.
Why Do Drug Concentrations Vary between Patients
There are a variety of factors that affect the clearance of monoclonal antibodies [1]. These include: (1) the presence of antidrug antibodies which increases drug clearance; (2) the use of concomitant immunosuppressive agents which decreases drug clearance; (3) the presence of high concentrations of TNF which increases drug William J. Sandborn, MD University of California San Diego 9500 Gilman Drive, MC 0956 La Jolla, CA 92093 (USA) E-Mail wsandborn @ ucsd.edu
Downloaded by: NYU Medical Center Library 128.122.253.228 - 4/22/2015 11:09:16 AM
Key Words Crohn’s disease · Ulcerative colitis · IBD · Infliximab · Adalimumab · Antibody · Concentration
clearance via an antigen sink phenomenon; (4) the presence of a serum albumen below the normal range, which is likely both a surrogate for high inflammatory burden as well as protein-losing enteropathy or colopathy, which can include fecal drug loss, both of which increase drug clearance; (5) elevated CRP concentration which is a surrogate for inflammatory burden and increases drug clearance; (6) body size which can result in increased clearance for high-body-weight patients who received fixed dosing of biologics and low-body-weight patients who receive mg/kg dosing, and (7) male gender which has been associated with increased clearance [1]. Baert et al. [2] demonstrated that the presence of high concentrations of antibodies to infliximab is associated with a reduction in the duration of response from 71 to 35 days in patients with Crohn’s disease receiving infliximab therapy. Similarly, Karmiris et al. [3] demonstrated that the majority of patients with Crohn’s disease and undetectable concentrations of adalimumab were positive for antibodies to adalimumab. Other studies have demonstrated that both systematic maintenance dosing (as opposed to intermittent or episodic dosing) and concomitant immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate is associated with lower rates of antibodies to infliximab, adalimumab, and certolizumab, and higher concentrations of serum infliximab, adalimumab, and certolizumab [4–7]. Colombel et al. [8] demonstrated that patients with Crohn’s disease who received combination therapy with azathioprine and infliximab 5 mg/kg had 1% antibody to infliximab and a 2% undetectable infliximab trough concentration at 6 months, as compared with infliximab monotherapy where there was 14% antibody to infliximab and a 15% undetectable infliximab concentration. The serum trough concentration was 3.5 ug/ml for combination therapy and 1.6 μg/ml for infliximab monotherapy. Similarly, Lichtenstein et al. [9] demonstrated considerably lower infliximab concentrations over time in patients with Crohn’s disease who were receiving infliximab monotherapy as compared to those receiving combination therapy. Maser et al. [10] demonstrated an inverse correlation between serum CRP concentrations and serum infliximab concentrations in patients with Crohn’s disease. Fasanmade et al. [11] demonstrated that a serum albumin concentration below the normal range is associated with a markedly increased clearance of infliximab, leading to a decreased rate of response. Finally, recent data from Brandse et al. [12] have demonstrated that infliximab is excreted in the stool in some patients with Crohn’s disease and ulcerative colitis following intrave-
Cornillie et al. [14] demonstrated that trough serum infliximab concentrations greater than 3.5 μg/ml at week 14 were associated with higher rates of sustained response in patients with Crohn’s disease. Similarly, Maser et al. [10] demonstrated that infliximab concentrations were directly correlated with both clinical remission and endoscopic healing in patients with Crohn’s disease. One recent study by Feagan et al. [15] suggested that both serum infliximab and antibody to infliximab concentrations are independently associated with disease activity as measured by CRP concentration in patients with Crohn’s disease. Karmiris et al. [3] demonstrated that detectable trough serum adalimumab concentrations were associated with higher rates of sustained complete response in patients with Crohn’s disease. Reinisch et al. [16] demonstrated that higher serum infliximab concentrations at week 8 (following induction therapy at weeks 0, 2, and 6) are associated with greater rates of clinical response and that higher trough serum infliximab concentrations at week 30 are associated with increased rates of clinical remission in patients with ulcerative colitis. Interestingly, the difference between clinical remission rates for the lowest quartile of infliximab concentration and the highest two quartiles (approx. 35–45%) was greater than the differences between placebo and infliximab in the clinical trial (approx. 20–25%) [16]. These findings suggest that much greater rates of efficacy could be achieved with greater rates of infliximab exposure. Finally, Seow et al. [17] demonstrated that detectable concentrations of infliximab at trough were associated with greater rates of mucosal healing, and lower rates of colectomy in patients with ulcerative colitis.
Tailoring Treatment to the Individual Patient
Dig Dis 2014;32(suppl 1):88–91 DOI: 10.1159/000367834
nous administration, increased fecal infliximab concentrations are associated with decreased serum infliximab concentrations, and increased fecal infliximab concentration is associated with treatment failure. Together these factors can result in wide variability in clearance between patients and markedly increased drug clearance in some patients, particularly in the setting of hospitalized patients with severely active ulcerative colitis who are failing intravenous steroids [13]. In this clinical setting, patients can sometimes completely clear a dose of infliximab in 5 days, and then develop antibodies to infliximab with the 2nd dose of infliximab, thus transitioning from high infliximab clearance due to disease factors to high infliximab clearance due to antidrug antibodies.
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How Do Drug Concentrations Affect Efficacy?
These observations can be incorporated into a treatment algorithm. Afif et al. [18] demonstrated that patients with subtherapeutic infliximab concentrations have a greater response to dose escalation than to switching to adalimumab, whereas patients with antidrug antibodies to infliximab have a greater response to switching to adalimumab than to dose escalation. These findings suggest that for patients with non-antidrug antibody-mediated increased drug clearance, dose escalation is preferred to switching to another anti-TNF biologic at the starting dose, where the same disease-related factors are likely to accelerate clearance of the second drug as well. Thus, patients who have symptoms of active disease and in whom high concentrations of antibodies to infliximab or adalimumab are present should switch to another TNF antagonist. Patients who have symptoms of active disease and in whom there are low concentrations of infliximab or adalimumab should have dose intensification. Patients who are negative for antidrug antibody and who have a therapeutic drug concentration should undergo evaluation to confirm the presence of active disease by endoscopy or radiology studies. If active disease is confirmed, then these patients should discontinue anti-TNF therapy and switch to another class of medications or consider surgical options. A recent study by Vande Casteele et al. [19] demonstrated that during maintenance therapy with infliximab, patients with Crohn’s disease can go through optimization of dosing, which can include dose increase, dose decrease, and drug discontinuation or switching. Following dose optimization, there was little benefit from repeated therapeutic drug monitoring over the following year, suggesting that dose optimization may not need to be done on an ongoing basis, once optimization is achieved. A randomized trial by Steenholdt et al. [20] demonstrated that therapeutic drug monitoring of infliximab in patients with Crohn’s disease and secondary loss of response can achieve similar clinical outcomes as empiric dose intensification, with a marked reduction in overall costs, due to a reduction in the frequency of dose intensification. The results of this trial confirm the findings of an earlier decision analysis by Velayos et al. [21] which showed similar findings.
Conclusions
serum CRP concentration, fecal loss of drug, and variable body weight in the short term, and the development of antidrug antibodies in the intermediate to longer term. Clinicians need to recognize these clinical factors that influence pharmacokinetics. When patients experience primary nonresponse or partial response, or respond and then lose response, clinicians should employ therapeutic drug monitoring (currently infliximab and adalimumab; in the future certolizumab and golimumab) to optimize treatment outcomes and to reduce overall drug costs.
Disclosure Statement Consulting fees from ActoGeniX NV, AGI Therapeutics Inc., Alba Therapeutics Corporation, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas Pharma, Athersys Inc., Atlantic Healthcare Limited, Axcan Pharma (now Aptalis), BioBalance Corporation, Boehringer-Ingelheim Inc., Bristol Meyers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, Eisai Medical Research Inc., Elan Pharmaceuticals, EnGene Inc., Eli Lilly, Enteromedics, Exagen Diagnostics Inc., Ferring Pharmaceuticals, Flexion Therapeutics Inc., Funxional Therapeutics Limited, Genzyme Corporation, Genentech (now Roche), Gilead Sciences, Given Imaging, Glaxo Smith Kline, Human Genome Sciences, Ironwood Pharmaceuticals (previously Microbia Inc.), Janssen (previously Centocor), KaloBios Pharmaceuticals Inc., Lexicon Pharmaceuticals, Lycera Corporation, Meda Pharmaceuticals (previously Alaven Pharmaceuticals), Merck Research Laboratories, MerckSerono, Millennium Pharmaceuticals (subsequently merged with Takeda), Nisshin Kyorin Pharmaceuticals Co. Ltd., Novo Nordisk A/S, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics Inc., PDL Biopharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb Limited, Purgenesis Technologies Inc., Receptos, Relypsa Inc., Salient Pharmaceuticals, Salix Pharmaceuticals Inc., Santarus, Schering Plough Corporation (acquired by Merck), Shire Pharmaceuticals, Sigmoid Pharma Limited, Sirtris Pharmaceuticals Inc. (a GSK company), S.L.A. Pharma (UK) Limited, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG (acquired by Zeria Pharmaceutical Co., Ltd), TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics Limited (VBL), Warner Chilcott UK Limited, Wyeth (now Pfizer), has received lecture fees from Bristol Meyers Squibb and Janssen (previously Centocor), and has received research support from Bristol Meyers Squibb, Genentech, Glaxo Smith Kline, Janssen (previously Centocor), Millennium Pharmaceuticals (now Takeda), Novartis, Pfizer, Procter and Gamble Pharmaceuticals, Shire Pharmaceuticals, and UCB Pharma.
Patients with IBD have widely variable rates of clearance of anti-TNF biologic drugs due to disease-related factors such as low serum albumin concentration, high 90
Dig Dis 2014;32(suppl 1):88–91 DOI: 10.1159/000367834
Sandborn
Downloaded by: NYU Medical Center Library 128.122.253.228 - 4/22/2015 11:09:16 AM
Treatment Algorithms
References
Tailoring Treatment to the Individual Patient
9 Lichtenstein GR, Diamond RH, Wagner CL, et al: Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD-subgroup analyses across four randomized trials. Aliment Pharmacol Ther 2009;30:210–226. 10 Maser EA, Villela R, Silverberg MS, et al: Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol 2006;4:1248–1254. 11 Fasanmade AA, Adedokun OJ, Olson A, et al: Serum albumin concentration: a predictive factor of infliximab pharmacokinetics and clinical response in patients with ulcerative colitis. Int J Clin Pharmacol Ther 2010; 48: 297–308. 12 Brandse JF, Wildenberg M, de Bruyn JR, et al: Fecal loss of infliximab as a cause of lack of response in severe inflammatory bowel disease. Gastroenterology 2013; 144(suppl 1):S36. 13 Kevans D, Murthy S, Iacono A, et al: Accelerated clearance of serum infliximab during induction therapy for acute ulcerative colitis is associated with treatment failure. Gastroenterology 2012;142(suppl 1):S384–S385. 14 Cornillie F, Hanauer SB, Diamond RH, et al: Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial. Gut 2014, Epub ahead of print.
15 Feagan BG, Singh S, Lockton S, et al: Novel infliximab (IFX) and antibody-to-infliximab (ATI) assays are predictive of disease activity in patients with Crohn’s disease (CD). Gastroenterology 2012;142(suppl 1):S114. 16 Reinisch W, Feagan BG, Rutgeerts PJ, et al: Infliximab concentration and clinical outcome in patients with ulcerative colitis. Gastroenterology 2012;142(suppl 1):S114. 17 Seow CH, Newman A, Irwin SP, et al: Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut 2010;59:49–54. 18 Afif W, Loftus EV Jr, Faubion WA, et al: Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol 2010;105:1133–1139. 19 Vande Casteele N, Compernolle G, Ballet V, et al: Individualised infliximab treatment using therapeutic drug monitoring: a prospective controlled trough level adapted infliximab treatment (TAXIT) trial. J Crohns Colitis 2012;6(suppl 1):S6. 20 Steenholdt C, Brynskov J, Thomsen OO, et al: Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to antiTNF treatment: a randomised, controlled trial. Gut 2014;63:919–927. 21 Velayos FS, Kahn JG, Sandborn WJ, et al: A test-based strategy is more cost effective than empiric dose escalation for patients with Crohn’s disease who lose responsiveness to infliximab. Clin Gastroenterol Hepatol 2013; 11:654–666.
Dig Dis 2014;32(suppl 1):88–91 DOI: 10.1159/000367834
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1 Ordas I, Mould DR, Feagan BG, et al: AntiTNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther 2012;91: 635–646. 2 Baert F, Noman M, Vermeire S, et al: Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 2003;348:601–608. 3 Karmiris K, Paintaud G, Noman M, et al: Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn’s disease. Gastroenterology 2009;137:1628–1640. 4 Hanauer SB, Wagner CL, Bala M, et al: Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease. Clin Gastroenterol Hepatol 2004;2:542–553. 5 Rutgeerts P, Sandborn WJ, Feagan BG, et al: Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–2476. 6 Sandborn WJ, Feagan BG, Stoinov S, et al: Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 2007;357:228– 238. 7 Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al: Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med 2007; 357:239–250. 8 Colombel JF, Sandborn WJ, Reinisch W, et al: Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010;362:1383–1395.
Tailoring Treatment to the Individual Patient: Drug Monitoring William J. Sandborn Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, Calif., USA
Abstract Understanding why drug concentrations vary between patients and which drug concentrations are associated with efficacy allow the development of rational treatment algorithms. Factors that affect the clearance of monoclonal antibodies include: (1) the presence of antidrug antibodies (increased clearance), (2) concomitant immunosuppression (decreased clearance), (3) increased serum CRP concentration (increased clearance), (4) decreased serum albumin concentration (increased clearance), (5) decreased body weight (increased clearance), and (6) increased fecal infliximab concentration (increased clearance). These factors can result in marked variability in drug clearance. Higher serum infliximab and adalimumab concentrations are associated with increased rates of clinical response and mucosal healing, and lower rates of colectomy. Treatment algorithms incorporate the following principles: (1) patients who have symptoms of active disease and in whom high concentrations of antibodies to infliximab or adalimumab are present should switch to another TNF antagonist, (2) patients who have symptoms of active disease and in whom there are low concentrations of infliximab or adalimumab should have dose intensification, and (3) patients who are negative for antidrug antibody and
© 2014 S. Karger AG, Basel 0257–2753/14/0327–0088$39.50/0 E-Mail [email protected] www.karger.com/ddi
who have a therapeutic drug concentration should undergo evaluation to confirm the presence of active disease by endoscopy or radiology studies, and if active disease is confirmed, then these patients should discontinue anti-TNF therapy and switch to another class of medications or consider surgical options. © 2014 S. Karger AG, Basel
Introduction
There is increasing use of therapeutic drug monitoring to tailor treatment of the individual patients with IBD who are treated with biologics. This article reviews why drug concentrations vary between patients, which specific drug concentrations are associated with efficacy, and the application of this knowledge in the development of rational treatment algorithms.
Why Do Drug Concentrations Vary between Patients
There are a variety of factors that affect the clearance of monoclonal antibodies [1]. These include: (1) the presence of antidrug antibodies which increases drug clearance; (2) the use of concomitant immunosuppressive agents which decreases drug clearance; (3) the presence of high concentrations of TNF which increases drug William J. Sandborn, MD University of California San Diego 9500 Gilman Drive, MC 0956 La Jolla, CA 92093 (USA) E-Mail wsandborn @ ucsd.edu
Downloaded by: NYU Medical Center Library 128.122.253.228 - 4/22/2015 11:09:16 AM
Key Words Crohn’s disease · Ulcerative colitis · IBD · Infliximab · Adalimumab · Antibody · Concentration
clearance via an antigen sink phenomenon; (4) the presence of a serum albumen below the normal range, which is likely both a surrogate for high inflammatory burden as well as protein-losing enteropathy or colopathy, which can include fecal drug loss, both of which increase drug clearance; (5) elevated CRP concentration which is a surrogate for inflammatory burden and increases drug clearance; (6) body size which can result in increased clearance for high-body-weight patients who received fixed dosing of biologics and low-body-weight patients who receive mg/kg dosing, and (7) male gender which has been associated with increased clearance [1]. Baert et al. [2] demonstrated that the presence of high concentrations of antibodies to infliximab is associated with a reduction in the duration of response from 71 to 35 days in patients with Crohn’s disease receiving infliximab therapy. Similarly, Karmiris et al. [3] demonstrated that the majority of patients with Crohn’s disease and undetectable concentrations of adalimumab were positive for antibodies to adalimumab. Other studies have demonstrated that both systematic maintenance dosing (as opposed to intermittent or episodic dosing) and concomitant immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate is associated with lower rates of antibodies to infliximab, adalimumab, and certolizumab, and higher concentrations of serum infliximab, adalimumab, and certolizumab [4–7]. Colombel et al. [8] demonstrated that patients with Crohn’s disease who received combination therapy with azathioprine and infliximab 5 mg/kg had 1% antibody to infliximab and a 2% undetectable infliximab trough concentration at 6 months, as compared with infliximab monotherapy where there was 14% antibody to infliximab and a 15% undetectable infliximab concentration. The serum trough concentration was 3.5 ug/ml for combination therapy and 1.6 μg/ml for infliximab monotherapy. Similarly, Lichtenstein et al. [9] demonstrated considerably lower infliximab concentrations over time in patients with Crohn’s disease who were receiving infliximab monotherapy as compared to those receiving combination therapy. Maser et al. [10] demonstrated an inverse correlation between serum CRP concentrations and serum infliximab concentrations in patients with Crohn’s disease. Fasanmade et al. [11] demonstrated that a serum albumin concentration below the normal range is associated with a markedly increased clearance of infliximab, leading to a decreased rate of response. Finally, recent data from Brandse et al. [12] have demonstrated that infliximab is excreted in the stool in some patients with Crohn’s disease and ulcerative colitis following intrave-
Cornillie et al. [14] demonstrated that trough serum infliximab concentrations greater than 3.5 μg/ml at week 14 were associated with higher rates of sustained response in patients with Crohn’s disease. Similarly, Maser et al. [10] demonstrated that infliximab concentrations were directly correlated with both clinical remission and endoscopic healing in patients with Crohn’s disease. One recent study by Feagan et al. [15] suggested that both serum infliximab and antibody to infliximab concentrations are independently associated with disease activity as measured by CRP concentration in patients with Crohn’s disease. Karmiris et al. [3] demonstrated that detectable trough serum adalimumab concentrations were associated with higher rates of sustained complete response in patients with Crohn’s disease. Reinisch et al. [16] demonstrated that higher serum infliximab concentrations at week 8 (following induction therapy at weeks 0, 2, and 6) are associated with greater rates of clinical response and that higher trough serum infliximab concentrations at week 30 are associated with increased rates of clinical remission in patients with ulcerative colitis. Interestingly, the difference between clinical remission rates for the lowest quartile of infliximab concentration and the highest two quartiles (approx. 35–45%) was greater than the differences between placebo and infliximab in the clinical trial (approx. 20–25%) [16]. These findings suggest that much greater rates of efficacy could be achieved with greater rates of infliximab exposure. Finally, Seow et al. [17] demonstrated that detectable concentrations of infliximab at trough were associated with greater rates of mucosal healing, and lower rates of colectomy in patients with ulcerative colitis.
Tailoring Treatment to the Individual Patient
Dig Dis 2014;32(suppl 1):88–91 DOI: 10.1159/000367834
nous administration, increased fecal infliximab concentrations are associated with decreased serum infliximab concentrations, and increased fecal infliximab concentration is associated with treatment failure. Together these factors can result in wide variability in clearance between patients and markedly increased drug clearance in some patients, particularly in the setting of hospitalized patients with severely active ulcerative colitis who are failing intravenous steroids [13]. In this clinical setting, patients can sometimes completely clear a dose of infliximab in 5 days, and then develop antibodies to infliximab with the 2nd dose of infliximab, thus transitioning from high infliximab clearance due to disease factors to high infliximab clearance due to antidrug antibodies.
89
Downloaded by: NYU Medical Center Library 128.122.253.228 - 4/22/2015 11:09:16 AM
How Do Drug Concentrations Affect Efficacy?
These observations can be incorporated into a treatment algorithm. Afif et al. [18] demonstrated that patients with subtherapeutic infliximab concentrations have a greater response to dose escalation than to switching to adalimumab, whereas patients with antidrug antibodies to infliximab have a greater response to switching to adalimumab than to dose escalation. These findings suggest that for patients with non-antidrug antibody-mediated increased drug clearance, dose escalation is preferred to switching to another anti-TNF biologic at the starting dose, where the same disease-related factors are likely to accelerate clearance of the second drug as well. Thus, patients who have symptoms of active disease and in whom high concentrations of antibodies to infliximab or adalimumab are present should switch to another TNF antagonist. Patients who have symptoms of active disease and in whom there are low concentrations of infliximab or adalimumab should have dose intensification. Patients who are negative for antidrug antibody and who have a therapeutic drug concentration should undergo evaluation to confirm the presence of active disease by endoscopy or radiology studies. If active disease is confirmed, then these patients should discontinue anti-TNF therapy and switch to another class of medications or consider surgical options. A recent study by Vande Casteele et al. [19] demonstrated that during maintenance therapy with infliximab, patients with Crohn’s disease can go through optimization of dosing, which can include dose increase, dose decrease, and drug discontinuation or switching. Following dose optimization, there was little benefit from repeated therapeutic drug monitoring over the following year, suggesting that dose optimization may not need to be done on an ongoing basis, once optimization is achieved. A randomized trial by Steenholdt et al. [20] demonstrated that therapeutic drug monitoring of infliximab in patients with Crohn’s disease and secondary loss of response can achieve similar clinical outcomes as empiric dose intensification, with a marked reduction in overall costs, due to a reduction in the frequency of dose intensification. The results of this trial confirm the findings of an earlier decision analysis by Velayos et al. [21] which showed similar findings.
Conclusions
serum CRP concentration, fecal loss of drug, and variable body weight in the short term, and the development of antidrug antibodies in the intermediate to longer term. Clinicians need to recognize these clinical factors that influence pharmacokinetics. When patients experience primary nonresponse or partial response, or respond and then lose response, clinicians should employ therapeutic drug monitoring (currently infliximab and adalimumab; in the future certolizumab and golimumab) to optimize treatment outcomes and to reduce overall drug costs.
Disclosure Statement Consulting fees from ActoGeniX NV, AGI Therapeutics Inc., Alba Therapeutics Corporation, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas Pharma, Athersys Inc., Atlantic Healthcare Limited, Axcan Pharma (now Aptalis), BioBalance Corporation, Boehringer-Ingelheim Inc., Bristol Meyers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, Eisai Medical Research Inc., Elan Pharmaceuticals, EnGene Inc., Eli Lilly, Enteromedics, Exagen Diagnostics Inc., Ferring Pharmaceuticals, Flexion Therapeutics Inc., Funxional Therapeutics Limited, Genzyme Corporation, Genentech (now Roche), Gilead Sciences, Given Imaging, Glaxo Smith Kline, Human Genome Sciences, Ironwood Pharmaceuticals (previously Microbia Inc.), Janssen (previously Centocor), KaloBios Pharmaceuticals Inc., Lexicon Pharmaceuticals, Lycera Corporation, Meda Pharmaceuticals (previously Alaven Pharmaceuticals), Merck Research Laboratories, MerckSerono, Millennium Pharmaceuticals (subsequently merged with Takeda), Nisshin Kyorin Pharmaceuticals Co. Ltd., Novo Nordisk A/S, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics Inc., PDL Biopharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb Limited, Purgenesis Technologies Inc., Receptos, Relypsa Inc., Salient Pharmaceuticals, Salix Pharmaceuticals Inc., Santarus, Schering Plough Corporation (acquired by Merck), Shire Pharmaceuticals, Sigmoid Pharma Limited, Sirtris Pharmaceuticals Inc. (a GSK company), S.L.A. Pharma (UK) Limited, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG (acquired by Zeria Pharmaceutical Co., Ltd), TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics Limited (VBL), Warner Chilcott UK Limited, Wyeth (now Pfizer), has received lecture fees from Bristol Meyers Squibb and Janssen (previously Centocor), and has received research support from Bristol Meyers Squibb, Genentech, Glaxo Smith Kline, Janssen (previously Centocor), Millennium Pharmaceuticals (now Takeda), Novartis, Pfizer, Procter and Gamble Pharmaceuticals, Shire Pharmaceuticals, and UCB Pharma.
Patients with IBD have widely variable rates of clearance of anti-TNF biologic drugs due to disease-related factors such as low serum albumin concentration, high 90
Dig Dis 2014;32(suppl 1):88–91 DOI: 10.1159/000367834
Sandborn
Downloaded by: NYU Medical Center Library 128.122.253.228 - 4/22/2015 11:09:16 AM
Treatment Algorithms
References
Tailoring Treatment to the Individual Patient
9 Lichtenstein GR, Diamond RH, Wagner CL, et al: Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD-subgroup analyses across four randomized trials. Aliment Pharmacol Ther 2009;30:210–226. 10 Maser EA, Villela R, Silverberg MS, et al: Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol 2006;4:1248–1254. 11 Fasanmade AA, Adedokun OJ, Olson A, et al: Serum albumin concentration: a predictive factor of infliximab pharmacokinetics and clinical response in patients with ulcerative colitis. Int J Clin Pharmacol Ther 2010; 48: 297–308. 12 Brandse JF, Wildenberg M, de Bruyn JR, et al: Fecal loss of infliximab as a cause of lack of response in severe inflammatory bowel disease. Gastroenterology 2013; 144(suppl 1):S36. 13 Kevans D, Murthy S, Iacono A, et al: Accelerated clearance of serum infliximab during induction therapy for acute ulcerative colitis is associated with treatment failure. Gastroenterology 2012;142(suppl 1):S384–S385. 14 Cornillie F, Hanauer SB, Diamond RH, et al: Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial. Gut 2014, Epub ahead of print.
15 Feagan BG, Singh S, Lockton S, et al: Novel infliximab (IFX) and antibody-to-infliximab (ATI) assays are predictive of disease activity in patients with Crohn’s disease (CD). Gastroenterology 2012;142(suppl 1):S114. 16 Reinisch W, Feagan BG, Rutgeerts PJ, et al: Infliximab concentration and clinical outcome in patients with ulcerative colitis. Gastroenterology 2012;142(suppl 1):S114. 17 Seow CH, Newman A, Irwin SP, et al: Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut 2010;59:49–54. 18 Afif W, Loftus EV Jr, Faubion WA, et al: Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol 2010;105:1133–1139. 19 Vande Casteele N, Compernolle G, Ballet V, et al: Individualised infliximab treatment using therapeutic drug monitoring: a prospective controlled trough level adapted infliximab treatment (TAXIT) trial. J Crohns Colitis 2012;6(suppl 1):S6. 20 Steenholdt C, Brynskov J, Thomsen OO, et al: Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to antiTNF treatment: a randomised, controlled trial. Gut 2014;63:919–927. 21 Velayos FS, Kahn JG, Sandborn WJ, et al: A test-based strategy is more cost effective than empiric dose escalation for patients with Crohn’s disease who lose responsiveness to infliximab. Clin Gastroenterol Hepatol 2013; 11:654–666.
Dig Dis 2014;32(suppl 1):88–91 DOI: 10.1159/000367834
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