The Value of Therapeutic Drug Monitoring in IBD
While tumor necrosis factor-alpha (TNF-alpha) antagonists have revolutionized therapy for irritable bowel disease (IBD), challenges still remain. As many as 40% of patients who initially respond to anti-TNF-alpha biotherapeutics, such as TNF-alpha blockers, ultimately lose response. Therapeutic drug monitoring in IBD cases can provide a significant advantage not only in determining the appropriate dose or agent for a better clinical outcome, but also in cost savings.
Targeting Tumor Necrosis Factor in IBD
IBD is characterized by chronic, uncontrolled inflammation of the intestinal mucosa. Several inflammatory mediators including cytokines have been shown to be involved in the pathogenesis of IBD.1 Elevated levels of certain pro-inflammatory cytokines including TNF-alpha, IL-1, IL-6 and IL-8 have been shown upon analysis of inflamed mucosa from patients with both ulcerative colitis and Crohn’s disease.2 TNF-alpha has been shown to play a pivotal role in the development and progression of IBD in the following animal and human studies:
- Mice overexpressing TNF-alpha developed a Crohn’s-like phenotype.3
- In a clinical study Remicade was given via single infusion to CD patients and roughly 2/3 of patients responded.4
Tumor necrosis factor has been shown to play a key role in the pathogenesis of IBD and anti-TNF-alpha biotherapeutics have revolutionized the treatment paradigm for those afflicted with IBD. Many of these drugs are TNF-alpha blockers designed to prevent TNF-alpha activity in order to reduce inflammation.
In 1998, Remicade® was the first monoclonal TNF-alpha antibody approved for the acute treatment of moderate to severe Crohn’s disease in patients displaying an inadequate response to conventional therapy and who also have fistulizing disease. It is a purified, recombinant DNA-derived chimeric human-mouse IgG monoclonal antibody.3 Remicade® is administered intravenously and has been proven to be a highly efficacious induction and maintenance agent in patients with refractory luminal and fistulizing Crohn’s disease.3,5,6,7,8, 9 One of the primary concerns with infliximab is the development of antibodies to infliximab (ATI). These antibodies predispose the patient to acute infusion reactions and delayed serum sickness-like reactions and secondary loss of response.10, 11,12 In response to this ATI-linked reaction, new anti-TNF-alpha agents were developed.
In 2007, Humira® (adalimumab) was approved to treat adult patients with moderately to severely active Crohn’s disease. Humira® is a complete human IgG1 anti-TNF-alpha monoclonal antibody.13 Adalimumab is given subcutaneously and can be self-administered by patients at home. Four pivotal trials demonstrated adalimumab to lead to remission at week 4 in up to 35% of patients. It was also found that patients were able to maintain remission in ≥23% at week 56.14,15,16 Since many patients who were given its predecessor developed antibodies, a key question was whether adalimumab would be able to overcome this lost response. At week 4, only 21% of patients who had previously been treated with another anti-TNF-alpha (such as infliximab) achieved remission. These findings suggest that a proportion of patients could be developing a resistance to anti-TNF-alpha strategies overall rather than to one single agent.17
Cimzia® (certolizumab pegol)
Cimzia® was approved to treat adults with moderate to severe Crohn’s disease who had not responded to conventional therapies in 2008. Certolizumab is a pegylated humanized fragment antigen binding (Fab) that binds to TNF-alpha.18 It is subcutaneously administered. Two large placebo-controlled phase III studies were performed to evaluate the efficacy in inducing and maintaining a response in patients with Crohn’s disease. Using clinical response as a primary endpoint in the first study, it was concluded that 22% of patients had a clinical response at week 26. The second study utilized maintenance of clinical response at week 26 and found that 61.6% of those patients with a clinical response at week 6 maintained a response. 19,20
Simponi® was approved for the treatment of adults with moderate to severe ulcerative colitis in 2013. Golimumab is a fully human IgG1 monoclonal antibody targeting TNF-alpha.21 Simponi® is subcutaneously administered and has been shown to maintain remission with signs of mucosal healing in 42.4% of patients at week 54. 22,23
Understanding the Value of Therapeutic Drug Monitoring: Infliximab
While TNF-alpha antagonists have revolutionized therapy for IBD, challenges still remain. As many as 40% of patients who initially respond to anti-TNF-alpha biotherapeutics ultimately lose response.24 A number of factors could be related to this loss of response, such as subtherapeutic levels with or without development antibodies. The typical next steps in instances like this include dose escalation followed by switching agents. However, without evidence, it is difficult to determine the root cause of lost response and, therefore, it can be difficult to overcome this resistance. In 2003, a key study demonstrated the importance of maintaining optimal infliximab (IFX) concentrations in order to achieve greater efficacy in patients.10 These results initiated the demand for a better understanding of the relationship between PK and clinical efficacy of anti-TNF-alpha biotherapeutics.
Therapeutic drug monitoring (TDM) is one approach offering a significant advantage to the patient in terms of saving money and finding the right dose or agent for a better clinical outcome. Therapeutic drug monitoring in IBD provides insight into the lost response and arms physicians with confidence in the decision-making process in order to outline the appropriate next steps for patients.
The Process of Therapeutic Drug Monitoring in IBD
The following chart represents the steps that can be taken when utilizing therapeutic drug monitoring in IBD cases to guide the decision-making process.
Additionally, this video from the Gastrointestinal Society further outlines details around the concept of using therapeutic drug monitoring in IBD, as well as how it can be used to guide therapeutic decisions in IBD patients.
Therapeutic Drug Monitoring Assays*
Drug levels are measured to ensure therapeutic concentrations are achieved and maintained so as to avoid doses that are either too low (ineffective) or too high (toxic). The Adalimumab Drug Level ELISA and the Infliximab Drug Level ELISA can be used to quantify levels of two commonly used TNF-alpha blockers: adalimumab and infliximab.
The measurement of free and bound antibodies allows for the semi-quantitative determination of free and bound antibodies in circulation. The Adalimumab Total Anti-Drug Antibody ELISA and Infliximab Total Anti-Drug ELISA can be used to semi-quantitatively determine the total anti-drug antibody levels of two commonly used TNF-alpha blockers: adalimumab and infliximab.
The measurement of free anti-drug antibodies allows for the semi-quantitative determination of unbound antibodies against a given therapeutic. The Adalimumab Free Anti-Drug Antibody ELISA and Infliximab Free Anti-Drug Antibody ELISA can be used to semi-quantitatively determine the unbound anti-drug antibodies against two commonly used TNF-alpha blockers: adalimumab and infliximab.
The Value of Therapeutic Drug Monitoring in IBD
Many anti-TNF-alpha biotherapeutics have been developed as TNF-alpha blockers to treat inflammation associated with IBD. At the same time, TDM ELISAs allow for the easy measurement of drug levels as well as free or total anti-drug antibodies in order to monitor patient IBD treatments. Therapeutic drug monitoring in IBD cases can provide a significant advantage not only in determining the appropriate dose or agent for a better clinical outcome, but also in cost savings.
*These assays are Health Canada Licensed and for Research Use Only in the U.S.
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- Targan et al. (1997). A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn’s disease. N. Engl. J. Med., 337, 1029-35.
- Kontoyiannis et al. (1999). Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity, 10, 387-98.
- Present et al. (1999). Infliximab for the treatment of fistulas in patients with Crohn’s disease. N. Engl. J. Med., 340, 1398-1405.
- Rutgeerts et al. (1999). Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology, 117, 761-769.
- Hanauer et al. (2002). Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet, 359, 1541-1549.
- Sands et al. (2004). Infliximab maintenance therapy for fistulizing Crohn’s disease. N. Engl J. Med., 350, 876-885.
- Rutgeerts et al. (2004). Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology, 126, 402-413.
- Baert et al. (2003). Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N. Engl. J. Med., 348, 601-608.
- Maser et al. (2006). Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin. Gastroenterol. Hepatol., 4, 1248-1254.
- Vermeire et al. (2007). Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut, 56, 1226-1231.
- Salfeld et al. (1998). Generation of fully human anti-TNF antibody D2E7. Arthritis Rheum., 41(9), S57.
- Hanauer et al. (2006). Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology, 130, 323-333.
- Sandborn et al. (2007). Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut, 56, 1232-1239.
- Colombel et al. (2007). Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology, 132, 52-65.
- Sandborn et al. (2007). Adalimumab induction therapy for Crohn’s disease previously treated with infliximab: a randomized trial. Ann. Intern. Med., 146, 829-38.
- Nesbitt et al. (2007). Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor α. Inflamm. Bowel Dis., 13(11), 1323-1332.
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- Sandborn et al. (2014). Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology, 146, 96-109.
- Sandborn et al. (2014). Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology, 146, 85-95.
- Gisbert et al. (2009). Loss of response and requirement of infliximab dose intensification in Crohn’s disease: a review. Am. J. Gastroenterol., 104, 760-7.