Curr Treat Options Gastro DOI 10.1007/s11938-016-0085-z
Inflammatory Bowel Disease (G Lichtenstein, Section Editor)
Advances in Therapeutic Drug Monitoring of Biologic Therapies in Inflammatory Bowel Disease: 2015 in Review Frank I. Scott, MD MSCE1,* Gary R. Lichtenstein, MD2 Address *,1 Crohn’s and Colitis Center, Division of Gastroenterology, University of Colorado School of Medicine, 12605 E. 16th Ave., Aurora, CO, 80045, USA Email: [email protected] 2 Center for IBD, Perelman Center for Advanced Medicine, Perelman School of Medicine of the University of Pennsylvania, One Convention Avenue, 7- South, Room 753, Philadelphia, PA, 19104, USA
* Springer Science+Business Media, LLC 2016
This article is part of the Topical Collection on Inflammatory Bowel Disease Keywords Inflammatory bowel disease I Crohn’s disease I Ulcerative colitis I Therapeutic drug monitoring I Anti-TNF antibodies I Anti-TNF drug levels
Opinion statement Monoclonal antibody therapy directed against tumor necrosis factor-alpha (anti-TNFs) has revolutionized the care of patients with Crohn’s disease and ulcerative colitis. These large proteins are potentially immunogenic. Early clinical trials demonstrated an association with both serum concentrations of these agents as well as the presence of antidrug antibodies generated by the host with loss of response. More recent research has provided further evidence to confirm the impact of low drug trough concentrations and antidrug antibodies on subsequent clinical course in CD and UC. Given these clinical implications, treatment algorithms have been developed to aid clinicians in interpreting trough drug levels and antibody concentrations in those with confirmed active disease. Several studies have demonstrated the utility of these approaches. Furthermore, there are growing data supporting the use of therapeutic drug monitoring in a prospective fashion in those patients who are clinically stable on anti-TNF therapies to ensure they are receiving appropriate dosing and have not yet developed antibodies. In addition, for those who have developed low-level antibodies, increasing the dose of an anti-TNF or adding an immunomodulator may help to overcome this immunologic response. Further research is required to assess these proposed strategies, as well as to determine the role of trough drug level assessment and antibody testing for new anti-TNFs and biologic medication with alternative mechanisms of action.
Inflammatory Bowel Disease (G Lichtenstein, Section Editor)
Introduction Inflammatory bowel disease (IBD), which is primarily comprised of Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic idiopathic inflammation involving the alimentary tract of unknown etiology. These diseases manifest as a response to microbes residing within the lumen of the gastrointestinal tract, with subsequent destruction of the mucosa and endoscopic manifestations such as erythema, friability, and ulceration of the mucosa lining the bowel. In UC, this inflammation is confined primarily to the mucosa and involves only the colon, though the extent of colonic involvement can vary between patients and over time. In CD, this inflammatory process is transmural, can affect any portion of the gastrointestinal tract from the mouth to the anus, and can be associated with penetrating phenomena such as intraperitoneal abscesses or fistula. Pharmacologic therapy for IBD has focused on dampening this chronic inflammatory response [1]. Initially available therapies included the 5-aminosalicylate derivatives such as sulfasalazine and mesalamine, as well as systemic glucocorticoids. Growing recognition of the deleterious effects of long-term steroid use prompted the search for steroid-sparing immunosuppressive therapies. The first agents assessed were the immunomodulators (IM), including azathioprine and 6-mercaptopirine. These agents are useful in the maintenance of remission in both CD and UC [2, 3] and continue to play a role in management of IBD today. Further research has demonstrated a similar role for methotrexate in CD, though clinical trials supporting the use of this medication in UC are still ongoing [4]. A major breakthrough in pharmacotherapy for IBD was the development of monoclonal antibodies directed against one of the primary inflammatory cytokines implicated in IBD, tumor necrosis factor-α (TNF-α). Infliximab was the first of this class of medications to
be FDA approved for the induction and maintenance of remission in CD and, subsequently, UC [5, 6]. This “biologic” medication consists of a chimeric IgG1 molecule, with a murine Fc fragment and a human Fab’ fragment, and is administered intravenously. Since the approval of infliximab, several additional anti-TNF agents have demonstrated efficacy in the treatment of IBD. Adalimumab, a humanized IgG1 molecule, administered subcutaneously, is FDA approved for both CD and UC [7–10]. Certolizumab pegol, a pegylated Fab’ fragment, administered subcutaneously, has been FDA approved for use in CD and is being actively studied in UC [11]. Golimumab, a humanized IgG1 molecule, is the most recently FDA approved anti-TNF agent and has demonstrated efficacy in UC [12]. Several additional biologic agents targeting other components of the inflammatory cascade have been FDA-approved for the treatment of IBD. Natalizumab, a monoclonal antibody targeting the alpha-4 integrin subunit of leukocyte trafficking, was initially FDAapproved for CD [13]. This agent inhibits leukocyte adhesion and tracking in both the gut and the brain. Natalizumab was subsequently removed from market after an increase in the risk of progressive multifocal leukoencephalopathy was appreciated in both MS and CD clinical trials [14]. It has subsequently been reintroduced to the market with an intensive monitoring program. Vedolizumab, which specifically targets the alpha-4 beta-7 integrin of the GI tract, has demonstrated efficacy in both CD and UC, and has not been associated with PML risk [15, 16]. Ustekinumab, an antibody against the p40 subunit of IL-12 and 23, was initially approved for the therapy of psoriatic arthritis and is currently undergoing phase 3 clinical trials in both CD and UC after promising phase 2 results [17].
Assays employed in measuring anti-TNF drug levels Several assays have been developed to monitor trough anti-TNF levels as well as antibodies against these drugs. The most commonly used assays currently on the market consist of the ANSER assays, available through Prometheus, and an electrochemiluminescence assay via Labcorp. The Prometheus assays currently in use are liquid-phase mobility shift assays, capable of measuring drug concentrations and antibodies against the drug in the same serum sample for both infliximab and adalimumab. This assay has been used in several studies thus far
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to assess the impact of clinical decision-making based on its’ results. The assay available via Labcorp is an eletrochemiluminescence assay [18]. This solidphase assay can measure antibody in the presence of drug concentrations, though it can only measure unbound infliximab. This assay has not yet been validated in clinical or observational trials. The Mayo clinic is also developing an assay for infliximab drug levels using liquid chromatography combined with mass spectrometry [19]. This is a two-step assay, and antibody measurement is performed when initial drug level measurements are below 5.1 mcg/mL. Heterogeneity in assay results and interpretation of their findings has caused some confusion, with limited data comparing these assays head-to-head. Recently published European data demonstrated strong correlation between three separate assays within France, Germany, and Turkey; however, it is important to note that all three of these assays were ELISA-based, as opposed to using different techniques such as the commercially available assays in the USA [20]. The limitations of any ELISA assays are that in the presence of drug in the serum, antidrug antibodies cannot be accurately measured.
Anti-TNF drug levels, antibodies, and loss of response in initial clinical trials It was recognized early on in clinical trials of anti-TNF drugs that maintenance of response to these medications is dependent on both serum drug levels and antibody formation. The pharmacokinetics of anti-TNF drug levels are dependent on several factors, and result in peak and trough serum concentrations due to multiple metabolic pathways, including endocytosis with proteolytic catabolism in the reticuloendothelial system (RES) and internalization after binding cell wall bound antigens with lysosomal degradation [21]. Plasma concentrations of anti-TNFs are thought to correlate in a linear fashion with the delivered dose, though there is some agent-dependent variation in half-life, with infliximab having a median half-life of 7.7 to 9.5 days while adalimumab’s halflife is thought to be twice that [22]. Several clinical trials have examined the impact of drug levels on clinical efficacy. Maser and colleagues demonstrated that lower endoscopic scores and CRP levels were correlated with higher drug concentrations, while Baert and colleagues appreciated that the duration of response with episodic dosing was improved with infliximab levels 912 μg/mL at 4 weeks [23, 24•]. Similarly, Van Assche and colleagues appreciated an inverse correlation between Crohn’s disease activity index (CDAI) and inflammatory markers with infliximab drug levels in an open-label trial of immunomodulator withdrawal [25]. In the landmark SONIC trial, trough levels of 91.0 μg/ml were associated with higher rates of remission at week 30 as well (72.8 vs 58.2 %) [26••] and similar results were appreciated in the SUCCESS trial [27••]. In UC, detectable infliximab levels have also been associated with higher rates of mucosa healing (OR 7.3, 95 % CI 2.9– 18.4), while undetectable levels have been associated with an increased probability of colectomy (OR 9.3, 95 % CI 2.9–29.9) [6, 28]. Interestingly, the association of drug levels with clinical remission and response rates with adalimumab and certolizumab in early clinical trials was less convincing [29, 30]. However, more recent data, particularly with regard to adalimumab, has noted similar trends with these agents. Higher clinical response and remission
Inflammatory Bowel Disease (G Lichtenstein, Section Editor) rates were appreciated in those with higher drug concentrations with golimumab, though the authors did not comment on statistical significance [31]. Antibody formation also plays a significant role in reduced serum drug concentrations. Antibodies directed against anti-TNF agents can consist of several different immunoglobulin subtypes and can bind multiple different sites on each anti-TNF molecule [32, 33]. These epitopes can exist within the Fab’ region or Fc’ region, though the prior is preferred. Once such complexes form, the TNF binding capability of the monoclonal antibodies can be reduced and drug clearance rates are increased [34, 35]. As with anti-TNF drug levels, the clinical impact of antibodies directed against anti-TNF agents was appreciated in several early clinical trials, though results have been conflicting. In trials of episodic dosing, three studies appreciated a reduced duration of response in those who had developed antibodies to infliximab [24•, 36, 37]. Vermeire and colleagues also appreciated significantly lower response rates in those who had developed antibodies to infliximab (14 vs 52 %, p = 0.0005) [37]. Conflicting results have been reported in scheduled dosing studies, however, where antibody levels are significantly reduced. Neither the initial ACCENT 1 trial nor a subsequent open-label cohort study employing scheduled dosing noted an association between anti-TNF antibodies and clinical outcomes [23, 38]. The landmark SONIC trial, which compared infliximab monotherapy to azathioprine to combination therapy, appreciated improved response rates specifically in those with inconclusive ELISA results, potentially signifying continued circulating infliximab [26••]. Similarly, in UC, the ACT trials actually demonstrated an improved response rate in those with positive or inconclusive ATIs. In a subsequent study by Seow and colleagues, antibodies appeared to have no impact on rates of clinical response, though those with inconclusive ELISA results had lower rates of colectomy, as well as improved endoscopic scores and remission rates [39]. Similarly, conflicting results were appreciated with initial studies examining the impact of antidrug antibodies with adalimumab and certolizumab. Karmiris and colleagues appreciated no correlation between antibodies against adalimumab and induction or maintenance of remission in a cohort of 130 patients receiving the drug [30]. However, in a smaller cross-sectional Japanese study of 40 patients with Crohn’s disease using an HMSA assay, patients with antibodies against adalimumab had significantly higher ESRs, CRPs, and clinical indices [40]. Antibodies against certolizumab were associated with a nonsignificant reduction in remission through week 26 in the PRECISE-2 trial (71 vs 62 %), though the rate of antibody positivity was low [41]. Similar findings were appreciated in the WELCOME trial [42]. Despite these conflicting results, most experts agree at this juncture that antibody formation contributes significantly to loss of response with anti-TNF agents. Several prior studies had retrospectively assessed the clinical impact of anti-TNF drug level monitoring in patients with IBD, further demonstrating their utility in clinical practice. A commonly used algorithm incorporates both drug level information as well as the presence of antibodies in reactive fashion, when patients are flaring (Fig. 1). In this algorithm, if drug levels are adequate and antibodies negative, one should consider switching to another class of biologic agents after confirming active inflammation via serum markers and then subsequently via colonoscopy or cross sectional imaging (CT enterography or MRI enterography) [43, 44]. If high levels of antibodies are present, then one could consider using another anti-TNF drug. If low-level antibodies are present,
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Fig. 1. Algorithm for interpreting therapeutic drug monitoring. A proposed algorithm for the interpretation of anti-TNF drug levels and antibodies against these agents.
one could consider the addition of an immunomodulator such as azathioprine or methotrexate as opposed to switching to another anti-TNF or anti-integrin. While one small case series of patients has demonstrated the ability to reduce or eliminate antibody concentrations in this patient population while regaining clinical response, further research is needed in this field [45]. Several recent studies have demonstrated the utility of similar algorithms. Afif and colleagues examined 155 patients with IBD with therapeutic drug monitoring results at the time of active disease. Of those with subtherapeutic infliximab levels, 83 % responded to dose escalation, whereas only 33 % responded to switching to an alternative anti-TNF. In those who were found to have antibodies to infliximab, 92 % responded to switching to another anti-TNF, while only 17 % of these patients responded to dose escalation [46•]. However, in another retrospective cohort study by Pariente and colleagues examining 16 patients who had lost response with positive antibodies, 60 % were able to recapture response using dose escalation [47]. The efficacy of this algorithm may also be dependent on the assay employed and time of testing. In a retrospective study by Vande Casteele published in 2013, 53 patients were found to have anti-infliximab antibodies, of which 15 had transient antibodies [35]. The clinical response to dose intensification was significantly higher in those with transient antibodies than in those with persistent antibodies (69 vs 16 %, p = 0.0028). Further studies to assess this phenomenon and develop predictive models for who may respond to dose intensification strategies is required. In addition, a recent retrospective study demonstrated that therapeutic drug monitoring serves to reduce overall costs of irrespective of clinical benefit [48].
Updates in therapeutic drug monitoring with biologics in 2015 Several recent studies have added further support to the use of therapeutic drug monitoring in clinical practice over the past year, including the use of harder
Inflammatory Bowel Disease (G Lichtenstein, Section Editor) endpoints such as serologic and endoscopic remission. Ungar and colleagues performed a cross-sectional analysis examining the impact of therapeutic drug levels on rates of mucosal healing in a cohort of 145 patients receiving either infliximab or adalimumab. Those with mucosal healing had drug levels 92× those without for both infliximab and adalimumab. Furthermore, infliximab levels 95 μg/mL and adalimumab levels 97.1 μg/mL were strongly predictive of mucosal healing on endoscopic evaluation. The authors were also able to demonstrate a plateau effect, where infliximab levels 98 μg/mL and adalimumab levels 912 μg/mL did not provide significant benefit. These data support the concept of a therapeutic window for both of these agents and also highlight that target levels may need to be higher when using adalimumab (7– 12 μg/mL) than infliximab (3–8 μg/mL) [49]. Yarur and colleagues also examined the impact of infliximab and adalimumab levels in both the serum and inflamed mucosal biopsies in 30 patients with IBD, with several important findings. For most individuals in this study, anti-TNF drug concentrations were similarly elevated in the serum and in areas of active inflammation, where the inflammation may serve as a “sink” for the drug. However, a subset of 11 of 15 patients with active disease were noted to have an elevated serum drug level while demonstrating much lower levels of tissue anti-TNF. These unique data may identify a subgroup of individuals with increased local drug clearance, possibly secondary to luminal protein losses. These intriguing findings warrant further study [50]. Yanai and colleagues examined the clinical outcomes of 247 patients with IBD who had lost response to either infliximab or adalimumab and had also undergone therapeutic drug monitoring [51]. The authors demonstrated that adalimumab trough levels greater than 4.5 had an 85 % positive predictive value (PPV) for failure to respond to dose intensification with adalimumab, and also had a 100 % PPV of response for those that switched to an alternative class of therapy. These results demonstrate that for those with adequate drug levels and loss of response to adalimumab, there is a little benefit from dose intensification. Interestingly, the test characteristics for infliximab levels, using a cutoff of 3.8 μg/mL, did not perform as well (PPV of 56 % for failure to respond to dose intensification, PPV 72 % for probability of response to switching out of class). When combining both cohorts and examining the efficacy of dose titration in those with no or low-level antidrug antibodies, significantly higher response rates were appreciated in those who underwent dose intensification in the setting of no or low-level drug antibodies (p = 0.001). The authors were able to appreciate a significant increase in serum drug concentrations in those with low level or negative antibody tests after dose escalation (p G 0.001), compared to no significant changes in those with high level antibodies. These data support the potential therapeutic strategy of dose-titration alone in the setting of lowlevel antibodies, in contrast to the previously published approach of adding an antimetabolite such as azathioprine, 6-MP, or methotrexate. The landmark “Trough level Adapted infliXImab Treatment (TAXIT)” trial is one of the first published studies to demonstrate the utility of prospective therapeutic drug monitoring, assessing a unique proactive monitoring design. Whereas previous retrospective studies had focused on examining the benefit of assessing drug levels in those who had lost response to an anti-TNF, this study assessed the utility of assessing drug levels and antibodies shortly after induction to ensure adequate levels were attained. After assuring that all individuals
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were within the target range of 3–7 μg/mL via infliximab level monitoring and dose optimization, individuals were randomized to either undergo symptom based trough level assessment and subsequent dose modification or to undergo repeat infliximab trough concentration testing with each medication infusion, with subsequent extension of the dosing interval if levels exceeded 7 μg/mL or reduction of the dosing interval by 2 weeks or up titration of the dose if the trough was below 3 μg/ml. Interestingly, remission rates were similar between the therapeutic monitoring and clinically dosed groups (69 vs 66 %), though rates of relapse were significantly higher in the clinically monitored group (17 vs 7 %, p = 0.018), and overall costs were significantly reduced in the monitored arm [52••]. It is possible that the primary endpoint of increased rates of clinical remission at 1 year was not achieved due to the use of therapeutic drug monitoring by both groups to ensure adequate concentrations of infliximab after initiation: 76 patients were subtherapeutic at the end of standard induction, and 91 % were able to achieve therapeutic levels with subsequent dose optimization. However, this study is a unique demonstration not only of the ability to reduce rates of clinical flares and costs for individuals on maintenance therapy but also as a clear example of the utility of early therapeutic drug monitoring in maximizing clinical response for a significant proportion of patients undergoing standard induction with infliximab [53].
Anti-TNF antibodies, drug levels, and safety The deleterious impact of antidrug antibodies has been appreciated since early clinical trials. Antibodies against infliximab were associated with an increased risk of infusion reactions by Baert and colleagues, particularly if the concentration of antibodies was 98 μg/ml [24•]. Rates of infusion reactions were also higher in those who had developed antibodies in the ACCENT-1 trial in CD as well as the ACT-1, ACT-2 and other prospective cohorts [6, 23, 32, 38, 39]. It is not clear that increased anti-TNF drug levels are associated with adverse events with therapy. While there was initial concern that dermatologic manifestations such as psoriaform lesions or rheumatologic manifestations were associated with higher trough levels, more recent studies have cast doubt on this association. A case-control study published in 2015 by Coutzac and colleagues examining 121 patients with Crohn’s disease appreciated no significant difference in anti-TNF drug levels between those who had dermatologic or rheumatologic reactions to the drug when compared to those who had not [54]. Similar results were appreciated for dermatologic complications in a large cohort of 917 patients receiving anti-TNFs, with no association between infliximab levels and dermatologic complications [55]. Based on the findings of these two large retrospective studies, it does not appear that drug levels can be used to predict future complications of therapy.
Therapeutic drug monitoring with other biologic agents in IBD There are little data on the utilization of therapeutic drug monitoring with biologic agents with alternative mechanisms of action at this time.
Inflammatory Bowel Disease (G Lichtenstein, Section Editor) Vedolizumab is the only other monoclonal antibody currently FDA approved for use in both CD and UC. This antibody is directed against the α4β7 integrin complex, preventing leukocyte honing to areas of active inflammation. There was not a significant difference in clinical remission rates in clinical trials in UC for those receiving the medication every 4 weeks versus every 8 weeks, despite the increased dosing interval resulting in increased mean drug levels (11.2 ± 7.2 vs 38.3 ± 24.4 μg/ml) [15]. Approximately 1.0 % of individuals developed persistent antibodies against the drug, although the clinical significance of this was not assessed. Interestingly, at both dosing regimens, approximately 95 % of α4β7 heterodimers were bound to drug upon assessment, potentially explaining the disparity between drug levels and clinical efficacy. Similar results were appreciated in CD [16]. Additional data presented at Digestive Diseases Week in 2015 also demonstrated similar findings, with similar rates of response and remission at 52 weeks among those individuals with UC who received vedolizumab every 8 weeks compared to every 4 weeks after temporarily holding their initial therapy. It is important to note that these cohorts were small and not specifically powered to assess these outcomes [56]. Further research is required for this and future biologic therapies to determine the role of therapeutic drug monitoring for each medication.
Future directions Research in utilizing therapeutic drug monitoring in IBD is ongoing. One area of particular interest is the use of nontrough levels. One of the main disadvantages of measuring infliximab troughs is that that the prescribing gastroenterologist must then wait until the next dose of medication before making an adjustment. While this does not result in a significant delay in regimen modification for those agents given on a more frequent dosing schedule, for agents that are infused less frequently, in particular, infliximab, this delay can be as long as 8 weeks. Therefore, assessing infliximab levels 1 week before dosing, and then making a modification to that subsequent dose, may improve clinical care. Recently presented data at Digestive Diseases Week in 2015 demonstrated the potential application of such an approach in a cohort of 20 patients receiving infliximab maintenance therapy at 5 mg/kg every 8 weeks, demonstrating that serum IFX levels ≥15 μg/ml at week 4 and ≥7.5 μg/ml at week 6 predicted IFX trough levels ≥3 μg/ml at week 8 [57]. Further research is required to explore this approach and to determine appropriate drug concentrations, while ensuring that interpatient heterogeneity in drug metabolism in larger patient populations does not make testing at alternative time points less efficacious. Further research is also required in the utilization of drug level and antibody measurement for new biologic agents coming to market. As noted previously, there are limited data on the impact of serum drug level concentrations and the efficacy of vedolizumab. Further research on both the effect of drug levels for this agent and the impact of antibody formation is required. Similar research is required for newer biologics with alternative mechanisms of action, such as ustekinumab. In addition, while there is ample and growing evidence at this juncture demonstrating the role of anti-TNF drug level and antibody monitoring with
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infliximab and adalimumab, there are no commercially available assays for assessing the impact of drug levels with newer anti-TNFs such as certolizumab or golimumab. One could envision there being similar utility for therapeutic drug monitoring with biosimilar agents as well.
Summary In summary, there is currently evidence to suggest there is utility in measuring anti-TNF drug and antibody levels when employing biologic therapies in IBD. More recent research has demonstrated a role not only for reactive therapeutic monitoring in those who have not responded to or lost response to therapy, but also with early evidence suggesting a role for prospective monitoring of drug levels and antibodies in those on maintenance therapy to ensure that the potential of current treatments is maximized. Further research is required with new biologic agents as they come to market to further elucidate the role of therapeutic drug monitoring for each medication.
Acknowledgments A special thank you to Dr. Gary Falk for taking the time to review this manuscript.
Compliance With Ethical Standards Conflict of Interest Frank I. Scott has received research grant funding from Takeda Pharmaceuticals and a Career Development award from the NIH (NIDDK Grant K08-DK095951). Gary R. Lichtenstein has received consultancy fees from Abbott Corporation/Abbvie, Actavis, Alaven, Ferring, Hospira, Janssen Orthobiotech, Luitpold/American Regent, Pfizer Pharmaceuticals, Prometheus Laboratories, Inc., Romark, Salix Pharmaceuticals/Valeant, Santarus, Shire Pharmaceuticals, Takeda, UCB, and Warner Chilcotte. Dr. Lichtenstein also has received honorarium payments from Ironwood and Luitpold/American Regent. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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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(5):1628–40. Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146D1]:96–109. e101. Scott FI, Lichtenstein GR. Therapeutic drug monitoring of anti-TNF therapy in inflammatory bowel disease. Curr Treat Options Gastroenterol. 2014;12(1):59–75. Ben-Horin S, Yavzori M, Katz L, et al. The immunogenic part of infliximab is the F(ab’)2, but measuring antibodies to the intact infliximab molecule is more clinically useful. Gut. 2011;60(1):41–8. Ordas I, Mould DR, Feagan BG, Sandborn WJ. AntiTNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther. 2012;91(4):635–46. Vande Casteele N, Gils A, Singh S, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol. 2013;108(6):962–71. Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology. 2003;124(4):917–24. Vermeire S, Noman M, Van Assche G, Baert F, D’Haens G, Rutgeerts P. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut. 2007;56(9):1226–31. 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: Off Clin Pract J Am Gastroenterol Assoc. 2004;2(7):542–53. Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2010;59(1):49–54. Imaeda H, Takahashi K, Fujimoto T, et al. Clinical utility of newly developed immunoassays for serum concentrations of adalimumab and anti-adalimumab antibodies in patients with Crohn’s disease. J Gastroenterol. 2013. Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med. 2007;357(3):239–50. Sandborn WJ, Abreu MT, D’Haens G, et al. Certolizumab pegol in patients with moderate to severe Crohn’s disease and secondary failure to infliximab. Clin Gastroenterol Hepatol: Off Clin Pract J Am Gastroenterol Assoc. 2010;8D8]:688–95. e682. Khanna R, Sattin BD, Afif W, et al. Review article: a clinician’s guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease. Aliment Pharmacol Ther. 2013;38(5):447–59.
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Colombel JF, Feagan BG, Sandborn WJ, Van Assche G, Robinson AM. Therapeutic drug monitoring of biologics for inflammatory bowel disease. Inflamm Bowel Dis. 2012;18(2):349–58. 45. Ben-Horin S, Waterman M, Kopylov U, et al. Addition of an immunomodulator to infliximab therapy eliminates antidrug antibodies in serum and restores clinical response of patients with inflammatory bowel disease. Clin Gastroenterol Hepatol: Off Clin Pract J Am Gastroenterol Assoc. 2013;11(4):444–7. 46.• 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(5):1133– 1139. This retrospective study provided important early clinical evidence of the importance of considering the presence of antibodies and drug concentrations when modifying medical regimens in those who have had a clinical relapse in IBD. 47. Pariente B, Pineton de Chambrun G, Krzysiek R, et al. Trough levels and antibodies to infliximab may not predict response to intensification of infliximab therapy in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2012;18(7):1199–206. 48. 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 anti-TNF treatment: a randomised, controlled trial. Gut. 2013. 49. Ungar B, Levy I, Yavne Y, et al. optimizing antiTNFalpha therapy: serum levels of infliximab and adalimumab associate with mucosal healing in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol: Off Clin Pract J Am Gastroenterol Assoc. 2015. 50. Yarur AJ, Jain A, Sussman DA, et al. The association of tissue anti-TNF drug levels with serological and endoscopic disease activity in inflammatory bowel disease: the ATLAS study. Gut. 2015. 51. Yanai H, Lichtenstein L, Assa A, et al. Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol Hepatol: Off Clin Pract J Am Gastroenterol Assoc. 2015;13D3]:522–30. e522. 52.•• Vande Casteele N, Ferrante M, Van Assche G, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;148(7):1320–1329 e1323. This study is the first prospective study demonstrating the utility of anti-TNF optimisation during induction and drug level monitoring during maintenance therapy. 53. Ben-Horin S. Drug level-based anti-tumor necrosis factor therapy: ready for prime time? Gastroenterology. 2015;148(7):1268–1271. 54. Coutzac C, Chapuis J, Poullenot F, et al. Association between Infliximab trough levels and the occurrence of paradoxical manifestations in patients with
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inflammatory bowel disease: a case–control study. J Crohn’s Colitis. 2015;9(11):982–7. Cleynen I, Moerkercke WV, Billiet T, et al. characteristics of skin lesions associated with anti-tumor necrosis factor therapy in patients with inflammatory bowel disease: a cohort study. Ann Intern Med. 2015;10–22.
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Advances in Therapeutic Drug Monitoring of Biologic Therapies in Inflammatory Bowel Disease: 2015 in Review Frank I. Scott, MD MSCE1,* Gary R. Lichtenstein, MD2 Address *,1 Crohn’s and Colitis Center, Division of Gastroenterology, University of Colorado School of Medicine, 12605 E. 16th Ave., Aurora, CO, 80045, USA Email: [email protected] 2 Center for IBD, Perelman Center for Advanced Medicine, Perelman School of Medicine of the University of Pennsylvania, One Convention Avenue, 7- South, Room 753, Philadelphia, PA, 19104, USA
* Springer Science+Business Media, LLC 2016
This article is part of the Topical Collection on Inflammatory Bowel Disease Keywords Inflammatory bowel disease I Crohn’s disease I Ulcerative colitis I Therapeutic drug monitoring I Anti-TNF antibodies I Anti-TNF drug levels
Opinion statement Monoclonal antibody therapy directed against tumor necrosis factor-alpha (anti-TNFs) has revolutionized the care of patients with Crohn’s disease and ulcerative colitis. These large proteins are potentially immunogenic. Early clinical trials demonstrated an association with both serum concentrations of these agents as well as the presence of antidrug antibodies generated by the host with loss of response. More recent research has provided further evidence to confirm the impact of low drug trough concentrations and antidrug antibodies on subsequent clinical course in CD and UC. Given these clinical implications, treatment algorithms have been developed to aid clinicians in interpreting trough drug levels and antibody concentrations in those with confirmed active disease. Several studies have demonstrated the utility of these approaches. Furthermore, there are growing data supporting the use of therapeutic drug monitoring in a prospective fashion in those patients who are clinically stable on anti-TNF therapies to ensure they are receiving appropriate dosing and have not yet developed antibodies. In addition, for those who have developed low-level antibodies, increasing the dose of an anti-TNF or adding an immunomodulator may help to overcome this immunologic response. Further research is required to assess these proposed strategies, as well as to determine the role of trough drug level assessment and antibody testing for new anti-TNFs and biologic medication with alternative mechanisms of action.
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Introduction Inflammatory bowel disease (IBD), which is primarily comprised of Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic idiopathic inflammation involving the alimentary tract of unknown etiology. These diseases manifest as a response to microbes residing within the lumen of the gastrointestinal tract, with subsequent destruction of the mucosa and endoscopic manifestations such as erythema, friability, and ulceration of the mucosa lining the bowel. In UC, this inflammation is confined primarily to the mucosa and involves only the colon, though the extent of colonic involvement can vary between patients and over time. In CD, this inflammatory process is transmural, can affect any portion of the gastrointestinal tract from the mouth to the anus, and can be associated with penetrating phenomena such as intraperitoneal abscesses or fistula. Pharmacologic therapy for IBD has focused on dampening this chronic inflammatory response [1]. Initially available therapies included the 5-aminosalicylate derivatives such as sulfasalazine and mesalamine, as well as systemic glucocorticoids. Growing recognition of the deleterious effects of long-term steroid use prompted the search for steroid-sparing immunosuppressive therapies. The first agents assessed were the immunomodulators (IM), including azathioprine and 6-mercaptopirine. These agents are useful in the maintenance of remission in both CD and UC [2, 3] and continue to play a role in management of IBD today. Further research has demonstrated a similar role for methotrexate in CD, though clinical trials supporting the use of this medication in UC are still ongoing [4]. A major breakthrough in pharmacotherapy for IBD was the development of monoclonal antibodies directed against one of the primary inflammatory cytokines implicated in IBD, tumor necrosis factor-α (TNF-α). Infliximab was the first of this class of medications to
be FDA approved for the induction and maintenance of remission in CD and, subsequently, UC [5, 6]. This “biologic” medication consists of a chimeric IgG1 molecule, with a murine Fc fragment and a human Fab’ fragment, and is administered intravenously. Since the approval of infliximab, several additional anti-TNF agents have demonstrated efficacy in the treatment of IBD. Adalimumab, a humanized IgG1 molecule, administered subcutaneously, is FDA approved for both CD and UC [7–10]. Certolizumab pegol, a pegylated Fab’ fragment, administered subcutaneously, has been FDA approved for use in CD and is being actively studied in UC [11]. Golimumab, a humanized IgG1 molecule, is the most recently FDA approved anti-TNF agent and has demonstrated efficacy in UC [12]. Several additional biologic agents targeting other components of the inflammatory cascade have been FDA-approved for the treatment of IBD. Natalizumab, a monoclonal antibody targeting the alpha-4 integrin subunit of leukocyte trafficking, was initially FDAapproved for CD [13]. This agent inhibits leukocyte adhesion and tracking in both the gut and the brain. Natalizumab was subsequently removed from market after an increase in the risk of progressive multifocal leukoencephalopathy was appreciated in both MS and CD clinical trials [14]. It has subsequently been reintroduced to the market with an intensive monitoring program. Vedolizumab, which specifically targets the alpha-4 beta-7 integrin of the GI tract, has demonstrated efficacy in both CD and UC, and has not been associated with PML risk [15, 16]. Ustekinumab, an antibody against the p40 subunit of IL-12 and 23, was initially approved for the therapy of psoriatic arthritis and is currently undergoing phase 3 clinical trials in both CD and UC after promising phase 2 results [17].
Assays employed in measuring anti-TNF drug levels Several assays have been developed to monitor trough anti-TNF levels as well as antibodies against these drugs. The most commonly used assays currently on the market consist of the ANSER assays, available through Prometheus, and an electrochemiluminescence assay via Labcorp. The Prometheus assays currently in use are liquid-phase mobility shift assays, capable of measuring drug concentrations and antibodies against the drug in the same serum sample for both infliximab and adalimumab. This assay has been used in several studies thus far
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to assess the impact of clinical decision-making based on its’ results. The assay available via Labcorp is an eletrochemiluminescence assay [18]. This solidphase assay can measure antibody in the presence of drug concentrations, though it can only measure unbound infliximab. This assay has not yet been validated in clinical or observational trials. The Mayo clinic is also developing an assay for infliximab drug levels using liquid chromatography combined with mass spectrometry [19]. This is a two-step assay, and antibody measurement is performed when initial drug level measurements are below 5.1 mcg/mL. Heterogeneity in assay results and interpretation of their findings has caused some confusion, with limited data comparing these assays head-to-head. Recently published European data demonstrated strong correlation between three separate assays within France, Germany, and Turkey; however, it is important to note that all three of these assays were ELISA-based, as opposed to using different techniques such as the commercially available assays in the USA [20]. The limitations of any ELISA assays are that in the presence of drug in the serum, antidrug antibodies cannot be accurately measured.
Anti-TNF drug levels, antibodies, and loss of response in initial clinical trials It was recognized early on in clinical trials of anti-TNF drugs that maintenance of response to these medications is dependent on both serum drug levels and antibody formation. The pharmacokinetics of anti-TNF drug levels are dependent on several factors, and result in peak and trough serum concentrations due to multiple metabolic pathways, including endocytosis with proteolytic catabolism in the reticuloendothelial system (RES) and internalization after binding cell wall bound antigens with lysosomal degradation [21]. Plasma concentrations of anti-TNFs are thought to correlate in a linear fashion with the delivered dose, though there is some agent-dependent variation in half-life, with infliximab having a median half-life of 7.7 to 9.5 days while adalimumab’s halflife is thought to be twice that [22]. Several clinical trials have examined the impact of drug levels on clinical efficacy. Maser and colleagues demonstrated that lower endoscopic scores and CRP levels were correlated with higher drug concentrations, while Baert and colleagues appreciated that the duration of response with episodic dosing was improved with infliximab levels 912 μg/mL at 4 weeks [23, 24•]. Similarly, Van Assche and colleagues appreciated an inverse correlation between Crohn’s disease activity index (CDAI) and inflammatory markers with infliximab drug levels in an open-label trial of immunomodulator withdrawal [25]. In the landmark SONIC trial, trough levels of 91.0 μg/ml were associated with higher rates of remission at week 30 as well (72.8 vs 58.2 %) [26••] and similar results were appreciated in the SUCCESS trial [27••]. In UC, detectable infliximab levels have also been associated with higher rates of mucosa healing (OR 7.3, 95 % CI 2.9– 18.4), while undetectable levels have been associated with an increased probability of colectomy (OR 9.3, 95 % CI 2.9–29.9) [6, 28]. Interestingly, the association of drug levels with clinical remission and response rates with adalimumab and certolizumab in early clinical trials was less convincing [29, 30]. However, more recent data, particularly with regard to adalimumab, has noted similar trends with these agents. Higher clinical response and remission
Inflammatory Bowel Disease (G Lichtenstein, Section Editor) rates were appreciated in those with higher drug concentrations with golimumab, though the authors did not comment on statistical significance [31]. Antibody formation also plays a significant role in reduced serum drug concentrations. Antibodies directed against anti-TNF agents can consist of several different immunoglobulin subtypes and can bind multiple different sites on each anti-TNF molecule [32, 33]. These epitopes can exist within the Fab’ region or Fc’ region, though the prior is preferred. Once such complexes form, the TNF binding capability of the monoclonal antibodies can be reduced and drug clearance rates are increased [34, 35]. As with anti-TNF drug levels, the clinical impact of antibodies directed against anti-TNF agents was appreciated in several early clinical trials, though results have been conflicting. In trials of episodic dosing, three studies appreciated a reduced duration of response in those who had developed antibodies to infliximab [24•, 36, 37]. Vermeire and colleagues also appreciated significantly lower response rates in those who had developed antibodies to infliximab (14 vs 52 %, p = 0.0005) [37]. Conflicting results have been reported in scheduled dosing studies, however, where antibody levels are significantly reduced. Neither the initial ACCENT 1 trial nor a subsequent open-label cohort study employing scheduled dosing noted an association between anti-TNF antibodies and clinical outcomes [23, 38]. The landmark SONIC trial, which compared infliximab monotherapy to azathioprine to combination therapy, appreciated improved response rates specifically in those with inconclusive ELISA results, potentially signifying continued circulating infliximab [26••]. Similarly, in UC, the ACT trials actually demonstrated an improved response rate in those with positive or inconclusive ATIs. In a subsequent study by Seow and colleagues, antibodies appeared to have no impact on rates of clinical response, though those with inconclusive ELISA results had lower rates of colectomy, as well as improved endoscopic scores and remission rates [39]. Similarly, conflicting results were appreciated with initial studies examining the impact of antidrug antibodies with adalimumab and certolizumab. Karmiris and colleagues appreciated no correlation between antibodies against adalimumab and induction or maintenance of remission in a cohort of 130 patients receiving the drug [30]. However, in a smaller cross-sectional Japanese study of 40 patients with Crohn’s disease using an HMSA assay, patients with antibodies against adalimumab had significantly higher ESRs, CRPs, and clinical indices [40]. Antibodies against certolizumab were associated with a nonsignificant reduction in remission through week 26 in the PRECISE-2 trial (71 vs 62 %), though the rate of antibody positivity was low [41]. Similar findings were appreciated in the WELCOME trial [42]. Despite these conflicting results, most experts agree at this juncture that antibody formation contributes significantly to loss of response with anti-TNF agents. Several prior studies had retrospectively assessed the clinical impact of anti-TNF drug level monitoring in patients with IBD, further demonstrating their utility in clinical practice. A commonly used algorithm incorporates both drug level information as well as the presence of antibodies in reactive fashion, when patients are flaring (Fig. 1). In this algorithm, if drug levels are adequate and antibodies negative, one should consider switching to another class of biologic agents after confirming active inflammation via serum markers and then subsequently via colonoscopy or cross sectional imaging (CT enterography or MRI enterography) [43, 44]. If high levels of antibodies are present, then one could consider using another anti-TNF drug. If low-level antibodies are present,
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Fig. 1. Algorithm for interpreting therapeutic drug monitoring. A proposed algorithm for the interpretation of anti-TNF drug levels and antibodies against these agents.
one could consider the addition of an immunomodulator such as azathioprine or methotrexate as opposed to switching to another anti-TNF or anti-integrin. While one small case series of patients has demonstrated the ability to reduce or eliminate antibody concentrations in this patient population while regaining clinical response, further research is needed in this field [45]. Several recent studies have demonstrated the utility of similar algorithms. Afif and colleagues examined 155 patients with IBD with therapeutic drug monitoring results at the time of active disease. Of those with subtherapeutic infliximab levels, 83 % responded to dose escalation, whereas only 33 % responded to switching to an alternative anti-TNF. In those who were found to have antibodies to infliximab, 92 % responded to switching to another anti-TNF, while only 17 % of these patients responded to dose escalation [46•]. However, in another retrospective cohort study by Pariente and colleagues examining 16 patients who had lost response with positive antibodies, 60 % were able to recapture response using dose escalation [47]. The efficacy of this algorithm may also be dependent on the assay employed and time of testing. In a retrospective study by Vande Casteele published in 2013, 53 patients were found to have anti-infliximab antibodies, of which 15 had transient antibodies [35]. The clinical response to dose intensification was significantly higher in those with transient antibodies than in those with persistent antibodies (69 vs 16 %, p = 0.0028). Further studies to assess this phenomenon and develop predictive models for who may respond to dose intensification strategies is required. In addition, a recent retrospective study demonstrated that therapeutic drug monitoring serves to reduce overall costs of irrespective of clinical benefit [48].
Updates in therapeutic drug monitoring with biologics in 2015 Several recent studies have added further support to the use of therapeutic drug monitoring in clinical practice over the past year, including the use of harder
Inflammatory Bowel Disease (G Lichtenstein, Section Editor) endpoints such as serologic and endoscopic remission. Ungar and colleagues performed a cross-sectional analysis examining the impact of therapeutic drug levels on rates of mucosal healing in a cohort of 145 patients receiving either infliximab or adalimumab. Those with mucosal healing had drug levels 92× those without for both infliximab and adalimumab. Furthermore, infliximab levels 95 μg/mL and adalimumab levels 97.1 μg/mL were strongly predictive of mucosal healing on endoscopic evaluation. The authors were also able to demonstrate a plateau effect, where infliximab levels 98 μg/mL and adalimumab levels 912 μg/mL did not provide significant benefit. These data support the concept of a therapeutic window for both of these agents and also highlight that target levels may need to be higher when using adalimumab (7– 12 μg/mL) than infliximab (3–8 μg/mL) [49]. Yarur and colleagues also examined the impact of infliximab and adalimumab levels in both the serum and inflamed mucosal biopsies in 30 patients with IBD, with several important findings. For most individuals in this study, anti-TNF drug concentrations were similarly elevated in the serum and in areas of active inflammation, where the inflammation may serve as a “sink” for the drug. However, a subset of 11 of 15 patients with active disease were noted to have an elevated serum drug level while demonstrating much lower levels of tissue anti-TNF. These unique data may identify a subgroup of individuals with increased local drug clearance, possibly secondary to luminal protein losses. These intriguing findings warrant further study [50]. Yanai and colleagues examined the clinical outcomes of 247 patients with IBD who had lost response to either infliximab or adalimumab and had also undergone therapeutic drug monitoring [51]. The authors demonstrated that adalimumab trough levels greater than 4.5 had an 85 % positive predictive value (PPV) for failure to respond to dose intensification with adalimumab, and also had a 100 % PPV of response for those that switched to an alternative class of therapy. These results demonstrate that for those with adequate drug levels and loss of response to adalimumab, there is a little benefit from dose intensification. Interestingly, the test characteristics for infliximab levels, using a cutoff of 3.8 μg/mL, did not perform as well (PPV of 56 % for failure to respond to dose intensification, PPV 72 % for probability of response to switching out of class). When combining both cohorts and examining the efficacy of dose titration in those with no or low-level antidrug antibodies, significantly higher response rates were appreciated in those who underwent dose intensification in the setting of no or low-level drug antibodies (p = 0.001). The authors were able to appreciate a significant increase in serum drug concentrations in those with low level or negative antibody tests after dose escalation (p G 0.001), compared to no significant changes in those with high level antibodies. These data support the potential therapeutic strategy of dose-titration alone in the setting of lowlevel antibodies, in contrast to the previously published approach of adding an antimetabolite such as azathioprine, 6-MP, or methotrexate. The landmark “Trough level Adapted infliXImab Treatment (TAXIT)” trial is one of the first published studies to demonstrate the utility of prospective therapeutic drug monitoring, assessing a unique proactive monitoring design. Whereas previous retrospective studies had focused on examining the benefit of assessing drug levels in those who had lost response to an anti-TNF, this study assessed the utility of assessing drug levels and antibodies shortly after induction to ensure adequate levels were attained. After assuring that all individuals
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were within the target range of 3–7 μg/mL via infliximab level monitoring and dose optimization, individuals were randomized to either undergo symptom based trough level assessment and subsequent dose modification or to undergo repeat infliximab trough concentration testing with each medication infusion, with subsequent extension of the dosing interval if levels exceeded 7 μg/mL or reduction of the dosing interval by 2 weeks or up titration of the dose if the trough was below 3 μg/ml. Interestingly, remission rates were similar between the therapeutic monitoring and clinically dosed groups (69 vs 66 %), though rates of relapse were significantly higher in the clinically monitored group (17 vs 7 %, p = 0.018), and overall costs were significantly reduced in the monitored arm [52••]. It is possible that the primary endpoint of increased rates of clinical remission at 1 year was not achieved due to the use of therapeutic drug monitoring by both groups to ensure adequate concentrations of infliximab after initiation: 76 patients were subtherapeutic at the end of standard induction, and 91 % were able to achieve therapeutic levels with subsequent dose optimization. However, this study is a unique demonstration not only of the ability to reduce rates of clinical flares and costs for individuals on maintenance therapy but also as a clear example of the utility of early therapeutic drug monitoring in maximizing clinical response for a significant proportion of patients undergoing standard induction with infliximab [53].
Anti-TNF antibodies, drug levels, and safety The deleterious impact of antidrug antibodies has been appreciated since early clinical trials. Antibodies against infliximab were associated with an increased risk of infusion reactions by Baert and colleagues, particularly if the concentration of antibodies was 98 μg/ml [24•]. Rates of infusion reactions were also higher in those who had developed antibodies in the ACCENT-1 trial in CD as well as the ACT-1, ACT-2 and other prospective cohorts [6, 23, 32, 38, 39]. It is not clear that increased anti-TNF drug levels are associated with adverse events with therapy. While there was initial concern that dermatologic manifestations such as psoriaform lesions or rheumatologic manifestations were associated with higher trough levels, more recent studies have cast doubt on this association. A case-control study published in 2015 by Coutzac and colleagues examining 121 patients with Crohn’s disease appreciated no significant difference in anti-TNF drug levels between those who had dermatologic or rheumatologic reactions to the drug when compared to those who had not [54]. Similar results were appreciated for dermatologic complications in a large cohort of 917 patients receiving anti-TNFs, with no association between infliximab levels and dermatologic complications [55]. Based on the findings of these two large retrospective studies, it does not appear that drug levels can be used to predict future complications of therapy.
Therapeutic drug monitoring with other biologic agents in IBD There are little data on the utilization of therapeutic drug monitoring with biologic agents with alternative mechanisms of action at this time.
Inflammatory Bowel Disease (G Lichtenstein, Section Editor) Vedolizumab is the only other monoclonal antibody currently FDA approved for use in both CD and UC. This antibody is directed against the α4β7 integrin complex, preventing leukocyte honing to areas of active inflammation. There was not a significant difference in clinical remission rates in clinical trials in UC for those receiving the medication every 4 weeks versus every 8 weeks, despite the increased dosing interval resulting in increased mean drug levels (11.2 ± 7.2 vs 38.3 ± 24.4 μg/ml) [15]. Approximately 1.0 % of individuals developed persistent antibodies against the drug, although the clinical significance of this was not assessed. Interestingly, at both dosing regimens, approximately 95 % of α4β7 heterodimers were bound to drug upon assessment, potentially explaining the disparity between drug levels and clinical efficacy. Similar results were appreciated in CD [16]. Additional data presented at Digestive Diseases Week in 2015 also demonstrated similar findings, with similar rates of response and remission at 52 weeks among those individuals with UC who received vedolizumab every 8 weeks compared to every 4 weeks after temporarily holding their initial therapy. It is important to note that these cohorts were small and not specifically powered to assess these outcomes [56]. Further research is required for this and future biologic therapies to determine the role of therapeutic drug monitoring for each medication.
Future directions Research in utilizing therapeutic drug monitoring in IBD is ongoing. One area of particular interest is the use of nontrough levels. One of the main disadvantages of measuring infliximab troughs is that that the prescribing gastroenterologist must then wait until the next dose of medication before making an adjustment. While this does not result in a significant delay in regimen modification for those agents given on a more frequent dosing schedule, for agents that are infused less frequently, in particular, infliximab, this delay can be as long as 8 weeks. Therefore, assessing infliximab levels 1 week before dosing, and then making a modification to that subsequent dose, may improve clinical care. Recently presented data at Digestive Diseases Week in 2015 demonstrated the potential application of such an approach in a cohort of 20 patients receiving infliximab maintenance therapy at 5 mg/kg every 8 weeks, demonstrating that serum IFX levels ≥15 μg/ml at week 4 and ≥7.5 μg/ml at week 6 predicted IFX trough levels ≥3 μg/ml at week 8 [57]. Further research is required to explore this approach and to determine appropriate drug concentrations, while ensuring that interpatient heterogeneity in drug metabolism in larger patient populations does not make testing at alternative time points less efficacious. Further research is also required in the utilization of drug level and antibody measurement for new biologic agents coming to market. As noted previously, there are limited data on the impact of serum drug level concentrations and the efficacy of vedolizumab. Further research on both the effect of drug levels for this agent and the impact of antibody formation is required. Similar research is required for newer biologics with alternative mechanisms of action, such as ustekinumab. In addition, while there is ample and growing evidence at this juncture demonstrating the role of anti-TNF drug level and antibody monitoring with
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infliximab and adalimumab, there are no commercially available assays for assessing the impact of drug levels with newer anti-TNFs such as certolizumab or golimumab. One could envision there being similar utility for therapeutic drug monitoring with biosimilar agents as well.
Summary In summary, there is currently evidence to suggest there is utility in measuring anti-TNF drug and antibody levels when employing biologic therapies in IBD. More recent research has demonstrated a role not only for reactive therapeutic monitoring in those who have not responded to or lost response to therapy, but also with early evidence suggesting a role for prospective monitoring of drug levels and antibodies in those on maintenance therapy to ensure that the potential of current treatments is maximized. Further research is required with new biologic agents as they come to market to further elucidate the role of therapeutic drug monitoring for each medication.
Acknowledgments A special thank you to Dr. Gary Falk for taking the time to review this manuscript.
Compliance With Ethical Standards Conflict of Interest Frank I. Scott has received research grant funding from Takeda Pharmaceuticals and a Career Development award from the NIH (NIDDK Grant K08-DK095951). Gary R. Lichtenstein has received consultancy fees from Abbott Corporation/Abbvie, Actavis, Alaven, Ferring, Hospira, Janssen Orthobiotech, Luitpold/American Regent, Pfizer Pharmaceuticals, Prometheus Laboratories, Inc., Romark, Salix Pharmaceuticals/Valeant, Santarus, Shire Pharmaceuticals, Takeda, UCB, and Warner Chilcotte. Dr. Lichtenstein also has received honorarium payments from Ironwood and Luitpold/American Regent. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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