Curr Treat Options Gastro

DOI 10.1007/s11938-019-00222-9

Inflammatory Bowel Disease (G Lichtenstein, Section Editor)

Advances in Therapeutic Drug

Monitoring for Small-Molecule
and Biologic Therapies
in Inflammatory Bowel Disease
Christopher Ma, MD1,2
Robert Battat, MD2,3
Vipul Jairath, MD, PhD2,4,5
Niels Vande Casteele, PharmD, PhD2,6,*
Address
1
Division of Gastroenterology and Hepatology, University of Calgary, 3280 Hos-
pital Drive NW, Calgary, Alberta, T2N 4Z6, Canada
2
Robarts Clinical Trials, Inc., #200, 100 Dundas Street, London, Ontario, N6A 5B6,
Canada
3
Division of Gastroenterology, University of California San Diego, 9500 Gilman
Drive, #0956, La Jolla, CA, 92093, USA
4
Department of Medicine, Division of Gastroenterology, Western University, #200,
100 Dundas Street, London, Ontario, N6A 5B6, Canada
5
Department of Epidemiology and Biostatistics, Western University, #200, 100
Dundas Street, London, Ontario, N6A 5B6, Canada
*,6
Department of Medicine, University of California San Diego, 9500 Gilman Drive,
#0956, La Jolla, CA, 92093, USA
Email: nvandecasteele@ucsd.edu

* Springer Science+Business Media, LLC, part of Springer Nature 2019

This article is part of the Topical Collection on Inflammatory Bowel Disease

Keywords Biologics I Crohn’s disease I Inflammatory bowel disease I Therapeutic drug monitoring I Thiopurines I
Ulcerative colitis

Abstract
Purpose of review Therapeutic drug monitoring (TDM) is increasingly utilized as a strategy
to optimize inflammatory bowel disease (IBD) therapeutics. As management paradigms
have evolved towards treat-to-target strategies, there has been growing interest in
expanding the role of TDM to guide drug optimization for achieving objective endpoints.
This review summarizes the evidence for using TDM with biologic and oral small-molecule
therapies, evaluates the role of reactive versus proactive TDM in treatment algorithms, and
identifies potential future applications for TDM.
Recent findings Achieving therapeutic drug concentrations has been associated with
 Inflammatory Bowel Disease (G Lichtenstein, Section Editor)

important clinical, endoscopic, and histologic outcomes in IBD. However, the optimal
drug concentration varies by therapeutic agent, disease phenotype, inflammatory burden,
phase of treatment, and target outcome. Traditionally, TDM has been used reactively to
define pharmacokinetic versus mechanistic failures after loss of response to a tumor
necrosis factor-α (TNF) antagonist and while observational data suggests a benefit to
proactive TDM, this has not been definitively confirmed in prospective randomized
controlled trials. The role of TDM in optimizing vedolizumab, ustekinumab, and tofacitinib
remains unclear, given differences in pharmacokinetics and immunogenicity compared to
TNF antagonists. Measuring drug action at the site of inflamed tissue may provide
additional insights into treatment optimization.
Summary The use of TDM offers the possibility of a more personalized treatment approach
for patients with IBD. High-quality studies are needed to delineate the role of proactive
TDM for maintaining remission, for optimizing induction regimens, and for novel agents.

Introduction
The medical management of inflammatory bowel metabolite and anti-drug antibody (ADAb) concentra-
disease (IBD) has been revolutionized over the past tions to guide therapy is based on the premise that (1)
few decades by an expanding therapeutic armamen- there is an exposure-response relationship wherein
tarium that now features several effective biologic higher drug concentrations are positively associated with
agents and oral small molecules targeting different the magnitude of therapeutic efficacy [5]; (2) non-
components of the immune response, including response can be mediated by pharmacokinetic failure,
antagonists to cytokines such as tumor necrosis defined by inadequate drug exposure secondary to im-
factor-α (TNF) and the p40 common subunit of mune (i.e., ADAb formation) or non-immune causes
interleukin (IL)-12 and IL-23, the α4β7 integrin (i.e., body mass index (BMI), gender, disease phenotype,
on leukocytes, and the Janus kinase (JAK) intracel- concomitant immunosuppression, degree of systemic
lular signal transducers [1]. Although these ad- inflammation) leading to accelerated drug clearance [6,
vances have afforded patients with Crohn’s disease 7]; or (3) non-response can be mediated by mechanistic
(CD) and ulcerative colitis (UC) more treatment failure due to alternative pathways of inflammation in
options than ever before, the role of optimizing disease pathogenesis [8].
drug therapy has also become increasingly impor- TDM has been increasingly adopted in clinical prac-
tant [2]. A substantial proportion of patients will tice [9] and recent American Gastroenterological Associ-
experience either primary non-response or second- ation (AGA) Institute guidelines suggest the use of reac-
ary loss of response to biologic therapy [3]. The tive TDM in the context of secondary loss of response to
mechanisms of treatment failure in IBD are com- thiopurines or biologic therapy [10••]. However, many
plex, including disease-related, drug-related, and questions remain unanswered. First, it is unclear if TDM
patient-related factors [4]. Given this complexity, performed during induction or proactive TDM for pa-
treatment decisions directed by symptom assess- tients in symptomatic remission improves long-term
ment alone are unlikely to achieve optimal outcomes. Second, the role of TDM for small-molecule
outcomes. therapies and biologic agents with a non-anti-TNF-
Therapeutic drug monitoring (TDM) has emerged as driven mechanism of action is unclear. Third, thresholds
a promising strategy to maximize treatment response in for therapeutic drug concentrations above which further
IBD. Using measurements of serum drug or active dose escalation would likely prove futile have not been
 Advances in TDM for IBD Ma et al.

fully validated. In this review, we summarize the most algorithms and propose potential future applications
current evidence for incorporating TDM in treatment of TDM in clinical practice.

Therapeutic drug monitoring for small molecules

Therapeutic drug monitoring has routinely been used for small molecules in the
treatment of IBD, to detect nonadherence to therapy or to guide dose adjust-
ments because of lack of efficacy or adverse events. Azathioprine is a prodrug
that is converted into 6-mercaptopurine, which in turn is converted into 6-
methylmercaptopurine (through thiopurine methyltransferase [TPMT]), 6-
thiouric acid (through xanthine oxidase), or active 6-thioguanine nucleotides
[6-TGN] (through hypoxanthine-guanine phosphoribosyl-transferase). Clinical
response is highly correlated with levels of 6-TGN [11], whereas patients with
low or absent TPMT enzyme activity are at risk for excess production of drug-
derived TGN metabolites potentially leading to life-threatening
myelosuppression [12]. Current guidelines recommend routine TPMT testing
(enzymatic activity or genotype) in patients starting thiopurine therapy to guide
thiopurine dosing and in those patients who are treated with thiopurine ther-
apy and who have active disease and/or adverse events thought to be due to
thiopurine toxicity, to do reactive thiopurine metabolite monitoring to guide
treatment changes [10••].
Tofacitinib, a recently approved oral small-molecule pan-JAK inhibitor, has
shown to be effective for induction and maintenance therapy in patients with
moderately-to-severely active ulcerative colitis. In the OCTAVE studies, a nu-
merical higher proportion of patients randomized to 10 mg twice daily during
maintenance therapy reached the primary endpoint of remission at week 52,
compared to those randomized to 5 mg twice daily [13]. This is in line with an
earlier phase 2 trial in patients with ulcerative colitis where a dose-dependent
effect was observed during induction therapy [14]. These results indicate that
some patients may benefit from higher doses of tofacitinib. Interestingly, data
on the pharmacokinetics of tofacitinib in patients with psoriasis showed that
heavier subjects and those with prior exposure to biologic therapies were
predicted to require a higher dose to achieve benefit compared to lighter
subjects [15]. A population pharmacokinetic analysis of tofacitinib was per-
formed in patients with moderately-to-severely active UC showing that plasma
tofacitinib concentrations increased proportionately with dose and estimated
oral clearance, and the average steady-state concentrations were not signifi-
cantly different between baseline and week 8 [16]. The estimated between-
patient variability (% coefficient of variation) was 31.4% for clearance, which is
similar to what has been observed for biologics. Clearance of tofacitinib did not
significantly correlate with any of the covariates tested including baseline
measurements of fecal calprotectin, C-reactive protein (CRP), albumin, and
total Mayo Clinic score. Although these results indicate that baseline disease
activity is likely not a determinant of tofacitinib clearance, a more extensive
 Inflammatory Bowel Disease (G Lichtenstein, Section Editor)

covariate analysis is warranted to determine factors that can explain part of the
observed interindividual variability for clearance in patients with UC. An
exposure-response analysis was also conducted to evaluate the association
between different measures of exposure (dose, average steady-state concentra-
tion, and steady-state trough concentration) and important clinical outcomes. It
was found that the baseline Mayo Clinic score was an important determinant of
efficacy at week 8 and that plasma concentrations in individual patients did not
provide additional predictive value for efficacy beyond that provided by
tofacitinib dose [16].

Therapeutic drug monitoring for biologics

Advances in drug and anti-drug antibody detection assays
Several assays are commercially available for measuring biologic drug and
ADAb concentrations. Drug-sensitive solid-phase enzyme-linked immunosor-
bent assays (ELISAs) are widely available and less expensive compared to drug-
tolerant tests such as the homogeneous mobility shift assay (HMSA) and
electrochemiluminescence immunoassay (ECLIA). However, drug-sensitive as-
says are unable to detect ADAbs in the presence of drug [17]. Van Stappen et al.
[18] have recently shown that an acid-based pre-treatment protocol can be used
to convert the traditional solid-phase bridging ELISA to a drug-tolerant assay,
improving the detection of ADAbs. Fluid-phase drug-tolerant assays have a
greater sensitivity for detecting low-level, low-affinity ADAbs compared to
ELISA, though neither can determine ADAb functionality. In contrast, a reporter
gene assay (RGA) allows differentiation of neutralizing antibodies using an
erythrocyte cell-based test [19].
Serum concentrations of TNF antagonists are generally well correlated when
comparing across different assays. Marini et al. [20] evaluated infliximab levels
measured using four commercial ELISAs and demonstrated that the intraclass
correlation coefficient exceeded 0.89 for all tests. Similarly, golimumab levels as
measured by two different ELISAs are closely correlated (Spearman’s r = 0.98,
p G 0.0001) [21]. When comparing different assay types, Steenholdt et al. [22]
showed that ELISA, HMSA, radioimmunoassay, and functional RGA all accu-
rately detected serum infliximab (Pearson’s r = 0.91–0.97, p G 0.0001), but all
assays except radioimmunoassay and RGA significantly disagreed on sample
IFX concentrations and with a mean difference from 0.64 (0.15–1.12) μg/mL in
ELISA and HMSA to up to 3.44 (2.49–4.39) μg/mL in RGA and ELISA. A
previous study demonstrated that while correlated (r = 0.69–0.82),
adalimumab concentrations measured by HMSA were consistently higher
compared to ELISA, highlighting potential limitations of cross-assay extrapo-
lation of absolute concentrations [23]. There is emerging data for ustekinumab
on the comparison of the KU Leuven ELISAs for measuring ustekinumab and
ADAb concentrations with ECLIAs developed at Janssen R&D and used in
clinical studies of IBD patients showing a strong agreement [24], although
comparative studies with a wider range of assays are urgently needed. For
vedolizumab, a comparison between an ELISA and ultra-performance liquid
chromatography tandem mass spectrometry system showed a moderate-to-
good correlation [25], but comparative studies including assays used commer-
cially in the EU and US are also urgently needed.
 Advances in TDM for IBD Ma et al.

Measurements of ADAb concentrations across assays are poorly correlated.

ADAb titers are frequently reported in different units (μg/mL, μg/mL equiva-
lents, U/mL, arbitrary units/mL) and quantitative results are variable depending
on methodology [12]. Therefore, comparison across assays should be avoided.
For TNF antagonists, the presence of ADAbs is associated with accelerated drug
clearance and loss of response, although drug-tolerant assays may over-detect
very-low-titer, clinically irrelevant ADAbs that have limited effects on drug
pharmacokinetics. Over half of ADAbs detected by drug-tolerant HMSA may
not have neutralizing potential when assessed by functional RGA [22] and
approximately 30% of antibodies to infliximab may be transient [26].
Effective implementation of TDM into clinical practice requires timely and
efficient drug level and ADAb quantification. Historically, the slow turnaround
time for results has precluded using drug and ADAb concentrations measured at
trough for adjusting the next biologic dose, or timely decision to switch treat-
ments if antibodies are present. A point-of-care assay has been developed for
infliximab and when compared to two ELISA-based methods, the accuracy of
the rapid test was high with intraclass correlation coefficients of 0.889 and
0.939 [27]. Similarly, a lateral flow-based assay with a time to result of 20 min
has also shown excellent agreement with ELISA for quantification of infliximab
(Pearson r = 0.95 during induction and r = 0.93 during maintenance) [28].
Adoption of rapid assays may permit the use of TDM to make “on-demand”
adjustments to therapy and improve uptake for optimizing induction regimens
with TNF antagonists or facilitate decision to switch out of class.

Defining therapeutic trough concentrations for TNF antagonists

The concept of defining a therapeutic target range for serum TNF antagonist
trough concentrations stems from several observations. First, there is an
exposure-response relationship between serum drug concentrations and clinical
efficacy, wherein higher levels of infliximab [29, 30•], adalimumab [31, 32],
certolizumab pegol [33], and golimumab [34] are associated with higher rates
of clinical remission. Second, low drug concentrations are associated with loss
of response to both infliximab and adalimumab and increase the risk of
developing ADAbs [35, 36]. Third, the therapeutic drug concentration can be
defined based on correlation with efficacy rather than safety outcomes as higher
TNF antagonist concentrations have not been shown to correlate with the risk of
adverse events [37]. Trough drug concentration thresholds in the literature have
been primarily derived from retrospective cross-sectional studies that validate a
chosen cutoff, maximize the area under the receiver operating characteristic
(ROC) curve, analyze incremental gains with higher drug levels, or evaluate
differences in the proportion of patients achieving treatment endpoints by
quartile of exposure [12]. The optimal therapeutic trough level is dependent on
the clinical context in which TDM is applied and varies by treatment target
(clinical versus objective outcomes, response versus remission), disease state
(reactive versus proactive testing), and phase of therapy (induction versus
maintenance). Suggested trough concentrations according to the AGA guide-
lines as well as the Australian Inflammatory Bowel Diseases Consensus Work-
ing Group are summarized in Table 1.
Treatment targets in both CD and UC have shifted from achieving symp-
tomatic remission towards targeting objective endoscopic, biomarker, and
 Inflammatory Bowel Disease (G Lichtenstein, Section Editor)

Table 1. Suggested target trough concentrations for therapeutic drug monitoring of TNF antagonists

Drug 2017 American Gastroenterological 2017 Australian Inflammatory Bowel Diseases

Association Guideline Suggestions Consensus Working Group Suggestions
Infliximab ≥ 5 μg/mL 3–8 μg/mL
Adalimumab ≥ 7.5 μg/mL 5–12 μg/mL
Certolizumab ≥ 20 μg/mL Not stated
Golimumab Unknown Not stated

histologic endpoints [38]. Higher drug concentrations may be required to

achieve these more robust, objective outcomes [32, 39–41]. For example, Ungar
et al. [39] have recently described that a therapeutic window of 6–10 μg/mL for
infliximab and 8–12 μg/mL for adalimumab is associated with mucosal
healing in 80–90% of patients with IBD. Juncadella et al. [42] found that
threshold adalimumab concentrations of 11.8, 12.0, and 12.2 μg/mL in CD
and 10.5, 16.2, and 16.2 μg/mL in UC stratified patients with and without
biochemical (CRP ≤ 5 mg/L), endoscopic (absence of ulcerations/erosions,
Rutgeerts score ≤ i1, or Mayo endoscopic subscore ≤ 1), and histologic remis-
sion (absence of active inflammation). Similarly, higher infliximab concentra-
tions are associated with endoscopic (9.7 μg/mL) and histologic (9.8 μg/mL)
healing in CD [43]. Infliximab serum concentrations ≥ 5.1 μg/mL at week 14
and ≥ 2.3 μg/mL at week 30 were associated with week 30 Mayo Clinic endo-
scopic subscore ≤ 1, whereas higher concentrations of ≥ 6.7 μg/mL and ≥
3.8 μg/mL, respectively, were associated with a subscore of 0 [44]. Cumula-
tively, these results suggest that better outcomes can be achieved with higher
drug trough concentrations, although determination of causality in cross-
sectional studies is challenging because better disease control may result in
higher trough levels secondary to reduced drug clearance.
Disease phenotype also influences the optimal therapeutic trough level
associated with remission. Patients with highly aggressive fistulizing CD may
require higher drug levels to achieve response. Yarur et al. [45] evaluated 117
CD patients with perianal fistulizing disease treated with infliximab for a
minimum of 24 weeks; those achieving fistula healing had significantly higher
median serum drug concentrations compared to those with persistently active
disease (15.8 vs. 4.4 μg/mL, p G 0.0001). In quartile analysis, the highest rate of
fistula healing (86%) was achieved by patients in the top quartile of infliximab
exposure (trough level 20.2–50 μg/mL) and levels associated with fistula
healing and closure were higher than those previously correlated with luminal
mucosal healing.
Less is known about the optimal drug concentration during induction
therapy prior to achievement of steady state. There is great interest in using
early optimization to distinguish patients who are primary non-responders to
TNF antagonists (due to mechanistic failure) from those patients who require
more aggressive dosing (due to pharmacokinetic failure) [46]. Patients at risk
for accelerated drug clearance could be identified before initiating therapy by
using a population pharmacokinetic approach, as a linear relationship was
found between baseline infliximab clearance and week 8 Mayo Clinic
 Advances in TDM for IBD Ma et al.

endoscopic subscore (p G 0.001) [44]. A threshold infliximab clearance of G

0.397 L/day was associated with week 8 Mayo Clinic endoscopic subscore ≤ 1
with a sensitivity, specificity, positive predictive value, and an area under ROC
curve of 75%, 48%, 68%, and 0.64 (95% CI, 0.59–0.69) (p G 0.0001), respec-
tively. Observational studies demonstrate that higher infliximab and
adalimumab serum concentrations as early as 2 to 6 weeks after the first TNF
antagonist dose are associated with improved rates of clinical response and
remission [30•, 47], mucosal healing [28, 48], and long-term drug retention
and surgery-free survival [49]. Infliximab concentration ≥ 15 μg/mL at week 6 is
associated with a 4.6-fold increase in likelihood of achieving weeks 10–14
endoscopic mucosal healing [48]. Conversely, infliximab levels below 6.8 μg/
mL or early antibodies to infliximab (9 4.3 μg/mL) before the second infusion
are associated with primary non-response [50]. During the induction phase, the
high rate of drug clearance, early development of ADAbs, and heavy inflam-
matory burden are important mediators of serum drug levels. Patients with
moderate-to-severe UC for example have highly accelerated infliximab drug
clearance from demonstrable infliximab fecal losses [51]. Furthermore, high
inflammatory burden (defined by CRP 9 50 mg/L) predicts those UC patients
with lower total infliximab exposure (587 vs. 1361 mg/L/day, p = 0.001) [52].
Using an incremental gain analysis, therapeutic windows of 30–36 μg/mL at
week 2 and 24–30 μg/mL at week 6 for infliximab have been proposed to
maximize likelihood of early mucosal healing although these thresholds re-
quire prospective validation [46].
In maintenance treatment with TNF antagonists, based on a meta-analysis,
the AGA guidelines suggest trough concentrations of infliximab ≥ 5 μg/mL,
adalimumab ≥ 7.5 μg/mL, and certolizumab pegol ≥ 20 μg/mL to be associat-
ed with clinical remission [10]. Insufficient evidence was available to establish a
target trough for golimumab. These cutoffs were chosen based on the propor-
tion of patients not in remission for incremental increases in drug trough
concentration: however, 8% of patients with an infliximab trough concentra-
tion ≥ 5 μg/mL, 10% of patients with an adalimumab trough concentration ≥
7.5 μg/mL, and 26% of patients with a certolizumab pegol trough concentra-
tion ≥ 20 μg/mL will not be in clinical remission, and a subset of these patients
may still respond by targeting higher concentrations.

Treatment algorithms incorporating reactive and/or proactive TDM

Prior to the adoption of TDM, patients experiencing secondary loss of response
to TNF antagonists were typically managed by empiric dose escalation. Al-
though this approach exhausts the therapeutic potential of each treatment and
is sensible when limited options are available, it may delay initiation of effective
therapy and increase potentially unnecessary drug exposure among patients
with immune-mediated pharmacokinetic treatment failure or mechanistic
treatment failure [53]. The use of reactive TDM can direct more personalized
and efficient treatment decisions by distinguishing patients with pharmacoki-
netic failure due to inadequate drug levels from those whose disease is not
driven by TNF-mediated pathways (Fig. 1). The use of reactive TDM is more
cost-effective compared to empiric dose escalation [54, 55] and allows earlier
implementation of effective treatment decisions. For example, in a retrospective
cohort study of 247 IBD patients developing 330 loss-of-response events to
 Inflammatory Bowel Disease (G Lichtenstein, Section Editor)

Fig. 1. Algorithm for use of reactive therapeutic drug monitoring in IBD patients with secondary loss of response to TNF
antagonists.

infliximab or adalimumab, Yanai et al. [56] identified that the presence of either
therapeutic trough levels (adalimumab 9 4.5 μg/mL, infliximab 93.8 μg/mL)
or high-titer ADAbs (anti-adalimumab 9 4 μg/mL equivalent, anti-infliximab 9
9 μg/mL equivalent) predicted failure to respond to dose escalation with 90%
specificity and had longer duration of response when switched to a different
class of treatment.
While reactive TDM has an established role for managing secondary loss of
response, integrating TDM into clinical practice proactively for patients in stable
remission remains controversial. In a multicenter retrospective study of 264
consecutive IBD patients receiving infliximab maintenance therapy,
Papamichael et al. [57] compared proactive versus reactive drug monitoring
based on measurements of first infliximab concentration and ADAb. In multi-
variable Cox regression, proactive drug monitoring was associated with a re-
duced risk for treatment failure (hazard ratio HR 0.16 [95% CI, 0.09–0.27]),
IBD-related surgery (HR 0.30 [95% CI, 0.11–0.80]), IBD-related hospitalization
(HR 0.16 [95% CI, 0.07–0.33]), and serious infusion reactions (HR 0.17 [95%
CI, 0.04–0.78]). However, this retrospective comparison is limited by potential
differences in patient characteristics wherein patients undergoing proactive
testing were asymptomatic compared to those patients potentially experiencing
a symptomatic disease flare in the reactive group.
A second purported benefit to proactive drug optimization is the potential
to circumvent the need for concomitant immunosuppression with azathioprine
or methotrexate. Combination therapy with infliximab and azathioprine is
superior to infliximab monotherapy in CD [58] and UC [59], mediated by a
reduction in ADAb formation and higher trough infliximab levels. However,
 Advances in TDM for IBD Ma et al.

concomitant immunosuppression is associated with an increased risk of ad-

verse events [60]. In a comparison of 16 patients managed with week 10
proactive infliximab TDM and 35 patients on combination infliximab and
immunosuppressant therapy, Lega et al. [61] demonstrated that proactive
“optimized monotherapy” achieved comparable endpoints to combination
therapy with respect to median infliximab trough concentration (9.1 vs. 7.7 μg/
mL, p = 0.24), probability of anti-infliximab antibody-free survival (p = 0.27),
and frequency of infliximab discontinuation (0% vs. 3%, p = 1.0). Corre-
spondingly, post hoc analysis of the SONIC (the Study of Biologic and Immu-
nomodulator Naïve Patients in Crohn’s Disease) trial showed comparable
outcomes are achieved regardless of concomitant azathioprine when patients
are stratified by infliximab trough quartiles [62].
Although observational evidence supports the use of proactive TDM, two
randomized controlled trials have been inconclusive. The TAXIT study (Trough
Level Adapted Infliximab Treatment study) was a 1-year trial that evaluated 178
CD patients and 85 UC patients with stable response to infliximab maintenance
therapy who were then randomized to receive infliximab dosing either based on
clinical features or based on proactive TDM [63••]. Importantly, all patients
initially underwent an optimization phase where infliximab dosing was esca-
lated or reduced to reach a trough level range of 3–7 μg/mL prior to random-
ization. At 12 months, the proportion of patients with combined clinical and
biochemical remission was similar between the clinically based and proactive
TDM-based dosing groups (66%vs. 69%, p = 0.686). At the end of the study,
similar rates of mucosal healing were observed in patients randomized to
clinically based compared to proactive TDM-based dosing (91% vs. 90%) [64].
During long-term follow-up after TAXIT (median 41 months), there were no
differences in IBD-related hospitalization (13% vs. 15%), abdominal surgery
(6% vs. 7%), or corticosteroid use (13% vs. 8%) in those patients previously
randomized to clinically based compared to proactive TDM-based dosing,
respectively, although proactive TDM was continued approximately once per
year in all patients. Interestingly, proactive TDM-based dose optimization in all
patients before randomization, to achieve trough concentrations in the 3–7-μg/
mL range, was associated with significant reductions in CRP and an increase in
the proportion of CD patients in remission—potentially negating some of the
benefits associated with TDM—and a 28% reduction in drug costs among
patients with a trough level 9 7 μg/mL who were able to undergo dose reduc-
tion. Although the trial did not meet its primary endpoint, important differ-
ences in secondary outcomes were achieved between the proactive TDM-based
and clinically based dosing groups including a lower proportion of patients
who required rescue therapy due to loss of response (7% vs. 17%, p = 0.018)
and a higher proportion of patients who stayed within the target trough level
range (74% vs. 57%, p = 0.001).
Treatment with infliximab incorporating proactive TDM was also evalu-
ated in the TAILORIX (A Randomized Controlled Trial Investigating Tai-
lored Treatment With Infliximab for Active Luminal Crohn’s Disease) ran-
domized controlled trial [65••] that evaluated a treatment algorithm based
on clinical symptoms, biomarkers, and infliximab TDM compared to
symptom-based management alone. In the two dose intensification strategy
(DIS) groups, dose escalation was prompted by the following criteria: (1)
Crohn’s Disease Activity Index (CDAI) 9 220 with a CRP 9 5 mg/L and/or
Inflammatory Bowel Disease (G Lichtenstein, Section Editor)

fecal calprotectin (FC) 9 250 μg/g; (2) CDAI 150–220 for two consecutive
weeks with an elevated CRP and/or FC; (3) infliximab serum concentration
at trough G 1 μg/mL; (4) infliximab trough level 1–3 μg/mL; and (5)
infliximab trough level 3–10 μg/mL with a drop by 9 50% compared with
the week 14 infliximab concentration. The control group received
infliximab dose escalation based on clinical symptoms (CDAI 9 220 or a
CDAI 150–220 in the two prior visits) alone. A stringent primary endpoint
of corticosteroid-free clinical remission without ulcers, need for surgery, or
the development of fistulas between weeks 22 to 54 was used.
The primary endpoint was achieved in 33% (15/45), 27% (10/37), and 40%
(16/40) of patients in the DIS1, DIS2, and the control groups, respectively (p =
0.50). Furthermore, no significant differences were observed in the proportion
of patients achieving secondary endpoints of absence of ulcers, endoscopic
remission, or endoscopic improvement at both weeks 12 and 54. Although
outcomes did not differ between the DIS and control groups, dose escalation
algorithms in TAILORIX were complex and incorporated symptoms, bio-
markers, and TDM: separating the independent effects of each of these com-
ponents is not possible. Second, only 47% (21/45) and 46% (17/37) of
patients in the DIS1 and DIS2 groups sustained therapeutic infliximab trough
concentrations 9 3 mg/mL between weeks 12 and 54, respectively. Also, only 5
(25%) and 7 (30%) patients in DIS1 and DIS2 groups, respectively, underwent
dose escalation because of TDM.
The AGA guidelines conditionally recommend the use of reactive TDM to
guide therapeutic decisions in patients with active IBD treated with TNF an-
tagonists, recognizing that the quality of evidence is very low [10]. However, no
recommendation is made regarding the use of routine proactive TDM for
patients with quiescent disease. Rather, this area is characterized as a knowledge
gap. Additional concerns regarding proactive TDM were also raised, including
(1) the potential for inappropriate treatment changes in the context of low-titer
ADAbs that are of uncertain clinical significance, (2) the unclear frequency with
which TDM should be repeated, and (3) the cost associated with both testing
and downstream treatment changes.
These guidelines have come under scrutiny [66] and are contrasted
with recent expert consensus statements that support using TDM reac-
tively in secondary loss of response, in patients with primary induction
non-response, and periodically in patients in clinical remission, with the
caveat that proactive testing should only be performed if the results are
likely to impact management [67••]. Furthermore, it is suggested that
patients with supra-therapeutic drug trough levels be considered for dose
reduction whereas high-risk patients with sub-therapeutic trough levels
and undetectable or low ADAbs should have immunomodulators added/
optimized and/or dose escalation. Eighty-six percent of panelists agreed
that patients in clinical remission with high-risk features, undetectable
trough drug levels, and persistently high titers of ADAbs be considered
for switching within or out-of-class.
Differences in the AGA guidelines and expert consensus recommendations
may in part reflect differences in methodology. The AGA guidelines were
developed using standards set by the Institute of Medicine and the Grading of
Recommendations Assessment, Development and Evaluation framework,
whereas Mitrev et al. developed the consensus statements using a modified 3-
 Advances in TDM for IBD Ma et al.

iteriation Delphi to achieve agreement. Nevertheless, both groups reiterated the

need for high-quality, controlled, prospective long-term studies to better clarify
the role TDM in clinical practice.

Using TDM for non-TNF-antagonist biologics

The role of measuring drug and ADAb levels for novel biologic agents such
as vedolizumab, an α4β7 integrin antagonist, and ustekinumab, a mono-
clonal antibody targeting the common p40 subunit of IL-12/-23, is less
clear. Interindividual variability in drug clearance for both treatments has
been demonstrated, with differences in serum albumin, body weight, and
inflammatory burden affecting drug pharmacokinetics [68, 69]. Persistent
antibody presence also increases drug clearance although, interestingly,
immunogenicity to ustekinumab and vedolizumab appears attenuated
compared to therapy with TNF antagonists. In CD, the incidence of
ustekinumab antibody formation after 1 year of treatment in the IM-UNITI
phase III trial program was only 2.3% using a purportedly drug-tolerant
assay [70]. Approximately 12% of patients randomized to placebo in the
maintenance arm of the GEMINI trials developed ADAb to vedolizumab
after exposure in induction, and 10% developed antibodies in the active
treatment arm at week 66 (14 weeks after the last dose of vedolizumab)
[68].
An exposure-response relationship for vedolizumab has been demon-
strated in both UC and CD. In the GEMINI-1 trial, UC patients with
vedolizumab trough levels in the lowest quartile (G 17 μg/mL) had clinical
remission rates of only 6% compared to 37% of patients in the highest
quartile (9 35.7 μg/mL) [71]. A similar exposure-response relationship was
demonstrated in GEMINI-2 among CD patients although this was less
robust (difference in clinical remission rates of 22% vs. 6% comparing the
highest quartile 9 33.7 μg/mL and the lowest quartile G 16 μg/mL) [72]. In
maintenance treatment, a dose-response relationship was evident in both
CD and UC patients on every 8-week dosing; however, this response was less
evident in patients on every 4-week dosing where the lowest trough con-
centration quartile overlapped with the highest quartile of the 8-week group
in terms of serum concentrations.
Interpreting the exposure-response relationship for vedolizumab is further
confounded by the fact that there is complete saturation of the α4β7 receptors
on peripheral lymphocytes even at every 8-week maintenance dosing and at
drug concentrations as low as 1 μg/mL [73]. This suggests that higher serum
concentrations would not be associated with improved efficacy but are
contrasted by the clinical observation that a substantial proportion of patients
recapture response with vedolizumab dose escalation [74]. Therefore, receptor
saturation may not be the only mechanism mediating vedolizumab efficacy.
Furthermore, given that vedolizumab purportedly affects gut-specific leukocyte
trafficking, it is unclear if serum levels are an accurate approximation of drug
efficacy.
Exposure-response relationships have also been described with
ustekinumab [75]. Clinical remission at week 8 after induction in the UNITI-1
and UNITI-2 trial programs was positively associated with serum drug concen-
trations [70]. Ustekinumab concentrations of 0.9–1.2 μg/mL in quartile
 Inflammatory Bowel Disease (G Lichtenstein, Section Editor)

analysis were associated with higher rates of clinical remission and the optimal
cutoff determined in ROC analysis was a trough concentration of 1 μg/mL (area
under the curve 0.64, p G 0.003). Higher trough concentrations were associated
with increased rates of CRP normalization (52% vs. 25%, p G 0.0001 for trough
concentration of above 1.1 μg/mL) and endoscopic response (40% vs. 8%,
p G 0.003 for trough concentration of above 0.5 μg/mL) [75]. A higher serum
trough concentration of 9 4.5 μg/mL measured using a drug-tolerant HMSA
after 26 weeks of treatment was reported to be associated with improved
biomarker and endoscopic response in a real-world cohort, although this study
did not incorporate intravenous induction and timing of assessment was not
standardized [76].
In summary, although exposure-response relationships have been demon-
strated with both ustekinumab and vedolizumab, the utility of TDM for opti-
mizing treatment with these agents is still to be delineated, particularly given
important differences in mode of action, immunogenicity, and drug pharma-
cokinetics of these novel agents compared to TNF antagonists.

Measuring drug at the site of action

Little is known about colonic mucosal concentrations of infliximab and
TNF in IBD patients and whether this correlates with either (1) serum or
stool drug concentrations or (2) clinically important outcomes. The recent
proof of concept ATLAS (Anti-TNF Tissue Level and Antibodies in Serum)
study demonstrated that serum TNF antagonist concentrations correlated
with tissue concentrations in uninflamed, but not inflamed tissue [77].
Furthermore, TNF antagonist concentrations in tissue correlated with the
degree of endoscopic inflammation, except for tissue with severe inflam-
mation. Patients with active mucosal disease had high rates of serum-to-
tissue drug concentration mismatch. This study demonstrated that in pa-
tients with active disease, serum concentrations may not accurately guide
clinical management of IBD.
A recent study by Yoshihara et al. [78] confirmed the correlation of
serum TNF antagonist with tissue TNF concentration in non-inflamed tis-
sue. A total of 25 CD patients were treated with infliximab (n = 15) or
adalimumab (n = 10). During maintenance therapy, tissue concentrations
were measured 2 weeks after drug administration. Inflamed tissue had
higher TNF antagonist concentrations and lower TNF concentrations than
uninflamed tissue. No correlation between tissue concentrations and pro-
spectively scored clinical or endoscopic outcomes was found. Drug con-
centrations only correlated between uninflamed tissue and serum. Using a
non-conventional outcome (therapeutic intervention requirement after
6 months), the optimal cutoff concentration in non-inflamed tissue was
1.3 μg/g. In patients with a TNF antagonist concentration 9 1.3 μg/g in non-
inflamed tissue, the time to therapeutic intervention was longer compared
to that in patients with lower concentrations.
However, further work on this subject is needed for several reasons. The
ATLAS study did not provide quantitative data on TNF antagonist concen-
trations. Only 12 patients were on infliximab, with an unknown proportion
of CD and UC within this group. Only 6 patients with UC were included in
 Advances in TDM for IBD Ma et al.

the study, of which an unspecified portion received infliximab or

adalimumab. Furthermore, while 43 uninflamed biopsies were analyzed,
only 17 inflamed biopsies were analyzed and an unknown proportion of
these were from either infliximab- or adalimumab-treated patients. Lastly,
neither objective endoscopic nor histologic scores were assessed. In the
study by Yoshihara et al., tissue concentrations of individual therapies were
not provided, and only one patient receiving adalimumab had measurable
concentrations in non-inflamed tissue.

Drug development of locally acting agents

A better understanding of the disposition of systemically absorbed drugs
into the mucosal tissue and the correlation with clinically important out-
comes will be key for developing compounds with proven mechanism of
action that are being designed to act locally in the gut and limit systemic
absorption. Sandborn et al. [79] recently presented the results of a Phase 2b
randomized, double-blind, placebo-controlled induction study in patients
with moderately-to-severely active UC who were treated with PTG-100, an
orally administered gut-restricted peptide α4β7 antagonist. PTG-100
showed a dose-dependent increase in clinical remission, endoscopic re-
sponse, and histologic remission with maximal efficacy at the 900-mg dose.
These efficacy results require confirmation in subsequent trials, including
systemic and local exposure-response analyses to understand inter- and
intra-individual variability in pharmacokinetics and pharmacodynamics.
Panes et al. recently presented the results of a Phase 1b randomized, double-
blind, placebo-controlled study in patients with moderately-to-severely
active UC who were treated with TD-1473, an orally administered and
intestinally restricted pan-JAK inhibitor [80]. TD-1473 was generally well
tolerated over 4 weeks with evidence of signals for clinical and biomarker
activity and colonic tissue concentrations of TD-1473 that were higher than
plasma concentrations and in the range needed for JAK inhibition. Based on
these early results, the local delivery of compounds (both peptides and
small molecules) with proven systemic mechanism of action may prove to
be a promising strategy leading to orally administered, effective, yet safer
drugs because of limited systemic exposure. Understanding drug disposi-
tion after systemic or oral administration will be key for efficient dose
finding and early drug development.

Conclusions
The adoption of TDM for patients with IBD undergoing treatment with
thiopurines or TNF antagonists has offered a more personalized approach
to optimizing therapy. The benefits of reactive TDM for defining mecha-
nisms of loss of response or adverse events have been well established.
Despite these advances, our review also highlights areas that require further
investigation. First, although many clinicians employ proactive TDM for
TNF antagonists, the evidence to support this practice is primarily observa-
tional. Second, the role of TDM for patients treated with biologics with
 Inflammatory Bowel Disease (G Lichtenstein, Section Editor)

alternative mechanisms of action other than TNF blockade is unclear, as

these agents have different immunogenicity and pharmacokinetic profiles.
Third, recent drug development of effective locally acting therapies may
change our approach from measuring systemic drug concentrations to
measuring drug at site of action. The development of these concepts will
mark another important step forward in personalized IBD care.

Authorship contributions
CM, RB, VJ, and, NVC contributed to the study design, manuscript drafting, and manuscript editing. All authors
approve the final version of the manuscript.

Funding Support

Dr. Christopher Ma is supported by a Clinician Fellowship from the Canadian Institutes of Health Research
and the Canadian Association of Gastroenterology. Dr. Niels Vande Casteele is supported by a Research
Scholar Award from the American Gastroenterological Association.

Compliance with Ethical Standards

Conflict of Interest
Christopher Ma and Robert Battat have no conflicts of interest to declare.
Vipul Jairath has received consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena pharmaceuticals,
Genetech, Pendopharm, Sandoz, Merck, Takeda, Janssen, Robarts Clinical Trials, Topivert, and Celltrion, and
speaker’s fees from Takeda, Janssen, Shire, Ferring, Abbvie, and Pfizer.
Niels Vande Casteele has received grant/research support from R-Biopharm and Takeda, and consulting fees from
Pfizer, Progenity, Prometheus, and Takeda.

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.

Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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