Proactive versus Reactive Therapeutic Drug Monitoring: Why, When, and How? Open Access

Despite the expanding therapeutic armamentarium for patients with inflammatory bowel disease (IBD), many patients continue to struggle with primary nonresponse (PNR) and secondary loss of response (LOR) to the different available biological agents. As a result, therapeutic drug monitoring (TDM) remains a very important tool in optimizing the management of patients with IBD and subsequently improving their outcomes [1]. In the past, TDM was only used for thiopurines, but more recently, it has become readily available for all the different biological agents approved for the management of IBD. The question that is yet to be answered is whether TDM should be ordered when patients are unwell, regardless of the biological they are receiving, as a reactive measurement, or if proactive monitoring should be implemented as well.

In reactive TDM, serum drug level and presence of anti-drug antibodies (ADA) are measured in patients receiving a biological agent, in response to evidence of active disease that is confirmed with objective evidence via endoscopy, biochemically, or radiographically [2]. Reactive TDM allows physicians to determine whether a patient has developed ADA to the biological they are receiving, if the drug level is suboptimal, or if the patient has adequate drug levels. Interpretation of these results guide managements which could be to increase the dose of the biologic, narrow the interval, add an immunomodulator, or switch to a different biological, of the same or different class. In the recent years, some experts have encouraged the practice of proactive TDM in patients receiving antitumor necrosis factor (anti-TNF) agents, where drug levels are measured in an empirical manner to ensure optimal drug levels and potentially decrease the risk of ADA development and subsequent LOR. Proactive TDM can be performed either during the induction or post-induction periods or during the maintenance phase in asymptomatic patients who have no objective/endoscopic evidence of active disease. This review will cover the updated guidelines on TDM and will discuss the available data supporting proactive and reactive TDM in patients with Crohn’s disease (CD) and those with ulcerative colitis (UC) using the different biological agents.

Different commercial assays exist to measure serum drug and ADA levels. The 3 most commonly utilized assay formats are the enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and homogenous mobility shift assay (HMSA). Measurement of trough concentrations is comparable between the assays, with acceptable accuracy, specificity, and reproducibility. However, the reporting of ADA is variable between these commercial assays and there is no standardized reporting for these values. There are known advantages for measuring ADA in a fluid phase system (RIA and HMSA) over the solid phase system (ELISA) since fluid phase techniques can detect low-affinity ADA, in contrast to the solid phase assays [3]. One of the major limitations in using ELISA is the inability to detect ADA in the presence of drug, as ADA is bound in ADA-drug complexes that evade detection, even if the amount of drug is 1 µg/mL. However using HMSA, the ability to measure ADA is preserved up to serum drug titer of 60 µg/mL [4]. Therefore, differences in sensitivity are mainly attributed to the interference of drug in the detection of ADA. It is advised to utilize the same assay per patient when checking for trough concentrations and ADA.

Four scenarios can exist when TDM is checked [5-9]. Approximately half of the patients (50%) undergoing reactive TDM have undetectable/subtherapeutic drug trough level and undetectable ADAs. This situation is referred to as nonimmune-mediated pharmacokinetic failure and likely represents rapid drug clearance in the setting of high inflammatory burden or suboptimal weight-based dosing. This is the most favorable TDM result since administration of more drugs should fix the problem; either by increasing the dose or narrowing the frequency of drug administration. Around 20% of patients undergoing reactive TDM will have undetectable/subtherapeutic drug trough level but detectable ADAs that are referred to as “neutralizing” ADAs [5]. In this scenario of immune-mediated pharmacokinetic failure, if the ADA titers are low, then trial to overcome these neutralizing drug antibodies by adding an immunomodulator agent and giving more of that same biological agent may be considered. In case the ADA titers are high, then a switch of biological needs to be performed; and the decision of in-class or out-of-class switch depends on the patient’s initial response to the drug. In cases where the trough level is therapeutic, regardless of presence or absence of ADAs, mechanistic failure exists and patients should be switched to a different biological out of class. A quarter of patients (25%) undergoing reactive TDM will have mechanistic failure with therapeutic drug trough levels and absent/undetectable ADAs, while 5% of patients undergoing reactive TDM, will have a therapeutic drug level and detectable ADAs. In the latter situation, in addition to switching out of class, it is recommended to add an immunomodulator agent [5].

The American Gastroenterological Association recently published suggested target drug trough concentrations based on cross-sectional studies of IBD patients receiving maintenance therapy to be used as a guide when applying reactive TDM [5]. For infliximab, the suggested trough concentration was ≥5 µg/mL, while for adalimumab, it was ≥7.5 µg/mL, and for certolizumab pegol, it was ≥20 µg/mL. It is important to interpret these results with caution since the studies used to extract these data were variable utilizing different assays, heterogeneous patient sample, and were not designed to evaluate patients who had secondary LOR. To date, optimal trough concentrations for induction are lacking.

Different societies have set a number of recommendations regarding TDM use, despite the absence of high quality of evidence on this topic. In a conditional recommendation supported by very low quality of evidence, the AGA suggests reactive TDM in adults with active IBD on anti-TNF therapy to guide treatment changes. No recommendation was made regarding the use of proactive TDM in quiescent IBD patients on anti-TNF treatment, based on a knowledge gap on this subject [10]. No TDM recommendations were made by the AGA with regards to nonanti-TNF biologicals. However, in an expert opinion, a recommendation was made for reactive TDM for vedolizumab and ustekinumab in patients showing signs of primary or secondary nonresponse [2]. The American College of Gastroenterology (ACG) suggests the use of reactive TDM in moderately severe UC patients who are experiencing signs of disease relapse. There are no available recommendations regarding proactive TDM [11]. Regarding CD, the ACG makes no clear recommendations, but make a comment to consider reactive TDM in patients displaying evidence of active CD. The European Crohn’s and Colitis Organization (ECCO) do not make any recommendations for or against reactive or proactive TDM in CD patients on anti-TNF due to insufficient evidence [12]. The IBD Sydney Organization and the Australian Inflammatory Bowel Diseases Consensus Working Groups, however, recommended reactive TDM in any IBD patient with secondary LOR to guide clinical decision-making, and they advised that proactive TDM should be performed for patients in stable remission only if results are likely to impact clinical management [13]. The British Society of Gastroenterology suggests that patients with LOR have to undergo TDM to guide treatment with an agreement of 97.6% [14]. For patients who recently start an anti-TNF, assessment 2–4 weeks after completing the loading dose should be performed. This assessment is based on clinical response and blood measures, such as serum drug and ADA concentrations, serum inflammatory markers, fecal biomarkers, or endoscopy [14]. As for the BRIDGe group, this group makes recommendations for anti-TNF and vedolizumab-treated patients who are experiencing PNR or secondary LOR, specifically to exclude presence of ADAs, and provide no guidance on therapeutic drug concentrations [2]. The BRIDGe group also supports proactive TDM at least once during maintenance for patients on all anti-TNFs [2]. The same groups also support proactive TDM in responders after induction of anti-TNF therapy [2].

Up to one-third of patients with IBD show PNR to anti-TNF biological therapy and of the responders, 25–40% of patients develop secondary LOR after 12 months, and 20% annually thereafter [15-18]. TDM explains why negative therapeutic outcomes are occurring and allow for the identification of patients who will benefit from dose adjustment or those who should switch to a different biological agent. There are more data available on the use of TDM for the anti-TNF agents than the nonanti-TNF biologicals.

Over 50% of patients receiving infliximab will eventually lose response to the drug, with an estimated LOR rate of 13% per year [19]. In patients who display signs and symptoms of secondary LOR, reactive TDM has been shown to be more cost effective than empirical dose escalation in the management of these patients. Additionally, in the same study by Papamichael et al. [20], reactive TDM was associated with better endoscopic outcomes than clinical decision-making alone. In a different multicenter prospective randomized double-blinded controlled study of 122 biological naive adult CD patients, the TAILORIX study demonstrated that increasing the infliximab dose based on a combination of symptoms, biomarkers, and/or TDM did not lead to corticosteroid-free clinical remission at week 54 compared to patients who underwent infliximab dose escalation based on symptoms alone [21].

The post hoc analysis of the TAILORIX study found that infliximab trough concentrations >23.1 mg/L at week 2 and >10.0 mg/L at week 6 were associated with endoscopic remission at week 12 [22]. It was also shown that the use of fecal calprotectin and proactive TDM can guide dose adjustment and increase the rates of endoscopic response and remission during the maintenance period [22]. The post hoc analysis of ACCENT 1, a multicenter, randomized, placebo-controlled study on CD patients showed that serum infliximab concentration of >3.5 µg/mL at week 14 was a predictor of durable sustained response during maintenance therapy at a dose of 5 mg/kg [23].

A retrospective observational study on perianal CD patients receiving infliximab revealed that infliximab drug levels of 9.25 µg/mL at week 2 and 7.25 µg/mL at week 6 were the best predictors of fistula response [24]. Additionally, high-induction infliximab levels at weeks 2 and 6 were found to be independently associated with fistula response at both weeks 14 and 30 [24]. The PRECISION study was the first prospective randomized trial evaluating clinical benefit from personalized infliximab dosing in IBD patients. In the majority of patients with trough levels >3 µg/mL dose reduction did not lead to clinical LOR except in CD patients with perianal fistulas suggesting that a trough level of 3 µg/mL is probably insufficient for fistula control [25]. In a pilot observational study, optimization of infliximab (“optimized monotherapy”) to a trough concentration of ≥5 µg/mL using TDM was reported as an alternative strategy to combination therapy with concomitant immunomodulators in a subset of patients [26].

Reactive TDM was compared with proactive TDM in a simulated cohort study among CD patients receiving maintenance infliximab monotherapy [19]. Patients who underwent proactive TDM every 6 months were found to have higher infliximab concentrations and much lower ADA levels with subsequent less CD flares and a marginally cost-effective strategy than patients undergoing reactive TDM [19]. In a meta-analysis by Shah et al. [27] that compared proactive TDM with reactive TDM, results favored proactive TDM in order to prevent drug failure, while possibly being a more cost-saving method particularly that de-escalation of drug could be implemented depending on trough levels in the adequate clinical scenario. The evidence supporting these conclusions, however, was deemed to be of very low quality because of significant heterogeneity between the included studies [27].

In a study that included both CD and UC patients, the Trough Concentration Adapted Infliximab Treatment (TAXIT) trial, IBD patients on infliximab maintenance therapy were adjusted, either increased or decreased, to a trough concentration between 3 and 7 µg/mL. Among CD patients, significant improvements in clinical remission rates and median C-reactive protein measurements were noted when pre- and post-dose adjustments were compared. These improvements were not noted among UC patients. Patients were then randomized to 2 groups; 1 with drug dose adjustment based on clinical and biological biomarkers and another with concentration based dosing (aiming for trough level between 3 and 7 µg/mL). After 1-year follow-up, although no further improvement occurred in clinical remission rates, more relapses and higher ADAs were detected in the clinically based group [28].

In a comparative study that also included CD and UC patients, treatment was proactively escalated aiming at a trough level between 3 and 7 µg/mL for CD patients or between 5 and 10 µg/mL for UC patients. Further escalation/de-escalation of treatment based on clinician’s discretion was performed. The results showed that proactive TDM is associated with increased rates of mucosal healing and lower rates of surgery and endoscopic inflammation, than a cohort managed without TDM [29]. A new prospective study involving 34 CD and 29 UC patients revealed that intermediate infliximab levels in addition to infliximab peak (week 2) and infliximab trough (week 6) levels were associated with remission at week 30 [30].

In the past, adalimumab was presumed to be less immunogenic than the chimeric infliximab because of its fully human structure and subcutaneous administration [31]. However, data showed that immunogenicity significantly affects the outcome of adalimumab therapy in CD patients and that ADA were identified in patients who have no response to adalimumab (odds ratio [OR]: 13.1, confidence interval [CI]: 1.7–99.2; p = 0.006) [31]. In the POETIC study, a prospective observational study including 98 CD patients who were initiated on adalimumab, 32% developed ADA, at least half of whom (55%) developed antibodies as early as week 2, while almost 80% had ADA by week 14. Compared to ADA to infliximab, rates of ADA to adalimumab over time was significantly lower (p = 0.01) [32].

In a meta-analysis enrolling 459 CD patients, it was found that patients with adalimumab trough levels over 4.85–5.9 mg/mL were twice more likely to be in remission than patients with a trough level below this cutoff (OR: 2.6, 95% CI: 1.79–3.77; p < 0.0001) [33]. In a retrospective cohort study including 116 biological naive CD patients who were started on adalimumab, patients with low-serum levels at week 4 (<8.3 µg/mL) were at significantly higher risk of having ADA by week 12 (46.7 vs. 13.0%, p = 0.009) [34]. This supports that early monitoring of adalimumab serum levels guides dose optimization, may prevent immunogenicity, and influence long-term outcomes.

The relationship between serum adalimumab concentrations and clinical outcomes was assessed in 275 CD patients using data from CLinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in CD (CLASSIC) I/II. Among patients who achieved clinical remission, the median adalimumab concentrations were significantly higher than in those who did not achieve clinical remission at week 4 of CLASSIC I (8.10 vs. 5.05 mg/mL, p < 0.05) [35]. In a retrospective study of 43 patients with moderate to severe UC who were initiated on adalimumab, it was found that patients with short-term mucosal healing had higher adalimumab concentrations at week 4 than those without (10.6 vs. 7.4 µg/mL, p = 0.014) [36]. In a retrospective multicenter study, including 98 IBD patients on adalimumab therapy, higher adalimumab concentrations during maintenance therapy were associated with objective therapeutic outcomes in IBD, including endoscopic, histologic, and composite remission [37]. Achieving adalimumab concentrations ≥12 µg/mL (OR: 8; 95% CI: 2–31.9; p = 0.003) and ≥12.2 µg/mL (OR: 9.6; 95% CI: 1.7–56.1; p = 0.012) were independently associated with endoscopic and histologic remission in CD, respectively [37].

In a retrospective cohort study of 382 IBD patients (311 CD and 71 UC) on adalimumab, proactive TDM was compared to standard of care which consists of empirical dose escalation or reactive TDM. This study revealed that having at least one proactive TDM was independently associated with a reduced risk for treatment failure (hazard ratio: 0.4; p = 0.022) [38].

Data supporting the use of TDM with vedolizumab is not as robust as that with anti-TNF therapies. Increased vedolizumab drug clearance was found in patients with hypoalbuminemia and in those with an increased body weight [39]. Additionally, immunogenicity rates are low and the addition of immunomodulator agents does not affect vedolizumab clearance. It has been shown that high receptor saturation is achieved even with low-serum trough levels of vedolizumab [40]. Studies in UC (GEMINI 1) and CD patients (GEMINI-2 and GEMINI- 3) have demonstrated that high-serum vedolizumab levels are associated with improved outcomes during both induction and maintenance phases [41-50]. These results were more significant with quartile analyses and absolute increases in remission were stronger for UC rather than CD [42, 51]. In GEMINI-I, patients in the highest quartile of vedolizumab levels at week 6 had higher remission rates than patients in the lowest quartile of vedolizumab levels [52]. Similarly, in GEMINI-2, patients in the highest quartile of vedolizumab levels at week 6 had higher clinical remission rates compared to patients in the lowest quartile of vedolizumab levels [53]. Specifically, higher vedolizumab trough levels, >20 µg/mL at 6 weeks during the induction phase, showed an association with improved clinical outcomes [44, 48, 52-54]. As for maintenance concentrations, in a post hoc analysis of the GEMINI 1 study, UC patients who had higher vedolizumab level quartiles had greater deep remission rates at week 52 than patients who were in the lowest quartile [49, 55]. Guidi et al. [56] recently demonstrated in a prospective study of 101 patients with IBD (42 CD and 59 UC) that a vedolizumab level >16.55 µg/mL at week 14 predicted treatment persistence during the first year of treatment.

Despite the available data supporting a correlation between high vedolizumab levels and improved clinical outcomes, using TDM for vedolizumab remains unclear, since immunogenicity with this drug is very low, and since therapeutic/target trough concentrations are still undetermined [51, 57, 58]. Based on a systemic review and meta-analysis, Singh et al. [55] proposed that if TDM is utilized, then a therapeutic target range for achieving clinical and/or endoscopic remission at week 6 would be between 20 and 30 µg/mL, and a level between 12 and 20 µg/mL for maintenance therapy. In a recently published article, experts agreed that target vedolizumab level at week 6 should be 33–37 µg/mL, while levels between 15 and 20 µg/mL should be achieved at week 14, after the induction period, and levels 10–15 µg/mL during maintenance in order to have improved clinical outcomes [59].

Similar to vedolizumab, there are limited data to guide TDM utilization, whether in the reactive or proactive setting, for patients receiving ustekinumab. In the initial trials of UC (UNIFI) and CD (UNITI-1, UNITI-2, and IM-UNITI), when different doses of ustekinumab for induction and maintenance were compared, median drug concentrations were higher for patients achieving clinical response and remission [58, 60-62]. In the ustekinumab induction trials (UNITI-1 and UNITI-2), patients who were in the higher trough level quartiles at week 8 had higher rates of clinical remission than patients who had ustekinumab levels in the lower quartiles [58, 60]. Also, during maintenance, more of the patients in with high quartile levels than low quartile levels were in clinical remission [61]. A recent prospective study on 86 CD patients demonstrated that patients who had an ustekinumab trough level ≥4.2 µg/mL at week 8 had a 50% decrease in fecal calprotectin level [63]. In a recently published article, experts agreed that target ustekinumab level at week 8 should be 3–7 µg/mL while levels between 1 and 32 µg/mL should be targeted during maintenance for both UC and CD patients [59].

Prospective studies are needed to define therapeutic trough levels for ustekinumab. Shukula et al. [40] suggest that ustekinumab level of >4 µg/mL at week 8 and a level >1–2 µg/mL during maintenance could be important to optimize IBD outcomes.

Table 1 summarizes the abovementioned studies and their outcomes. Table 2 displays the target.

TDM-based therapeutic guidance is becoming widely used in routine practice, particularly in patients with LOR or those who develop infusion reactions. A survey study of 403 gastroenterologists in the United States regarding the use and the barriers toward TDM showed that the majority use reactive TDM for secondary and primary LOR, while only 36.6% use TDM proactively [64]. The greatest barriers to TDM implementation were uncertainty about insurance coverage (77.9%), high out-of-pocket patient costs (76.4%), and time lag from serum sample to result (38.5%) [64].

TDM is a valuable tool used by gastroenterologists to aid in optimizing IBD therapies. Reactive TDM is widely accepted in IBD patients with suspected LOR, especially in those receiving anti-TNF agents. Reactive TDM for the newer biologicals (ustekinumab and vedolizumab) is also acceptable, although the immunogenicity rates of these drugs are very low and the therapeutic drug levels have not been clearly defined. Proactive TDM is emerging as a reasonable approach to patients initiated on anti-TNF therapy, specifically infliximab and, to some extent, adalimumab. For example, post-induction TDM for infliximab and adalimumab in patients with severe UC and fistulizing CD may improve outcomes and optimize therapeutic levels of drug. Similarly, TDM may play a role in patients considering de-escalation from combination with a thiopurine. In this scenario, checking levels of anti-TNF prior to and after stopping the concomitant immunomodulator is a reasonable strategy. To date, proactive TDM is not widely applied to ustekinumab and vedolizumab and more data are required before this becomes part of clinical practice.

The presented work is a review article and has not directly dealt with human or animal research; therefore, no informed consent was obtained.

The authors have no conflicts of interest to declare.

The authors received no funding.

M. Shmais contributed to the data collection and drafting of the manuscript. M. Regueiro contributed to critical review of the manuscript for important intellectual content and final approval of the version to be published. J.G. Hashash contributed to the data collection, drafting of the manuscript, critical review of the manuscript, and final approval of the version to be published.