CLINICAL REVIEW

Therapeutic Drug Monitoring of Biologics for InflammatoryBowel DiseaseJean-Fr�ed�eric Colombel, MD,* Brian G. Feagan, MD,† William J. Sandborn, MD,‡

Gert Van Assche, MD, PhD,§ and Anne M. Robinson, PharmDk

Background: Although tumor necrosis factor (TNF) antagonists are effective for the treatment of Crohn’s disease and ulcerative colitis, lack

and loss of clinical response is a clinical challenge. Accordingly, the use of therapeutic drug monitoring has been proposed as a means to opti-

mize treatment. This article reviews the mechanisms of and factors which influence clearance of biologics, the relationship between serum drug

concentrations and antidrug antibody presence and treatment efficacy, and identifies areas for future research needs regarding the use of therapeu-

tic drug monitoring in clinical practice.

Methods: Publications regarding these topics were identified from literature searching and supplemented by review of gastroenterology meeting

presentations and reference lists.

Results: The clearance of monoclonal antibodies and pegylated antibody fragments is complex, and may be affected by demographic variables,

concomitant medications, inflammatory burden, and immunogenicity, leading to high interpatient variability in plasma concentration of drug and

clinical response. Several observational studies have demonstrated a relationship between anti-TNF agent serum drug concentrations and/or anti-

drug antibody presence and various symptomatic and objective clinical endpoints. However, these relationships are not absolute, and although

some algorithms for the use of therapeutic drug monitoring in clinical practice have been proposed, none have yet been validated in a prospective

clinical trial.

Conclusions: Further research to identify the most appropriate use of therapeutic drug monitoring is needed.

(Inflamm Bowel Dis 2012;18:349–358)

Key Words: biologic therapies, therapeutic drug monitoring, pharmacokinetics, concentration-efficacy relationship, immunogenicity

T umor necrosis factor (TNF) antagonists are effective to

induce and maintain response and remission in Crohn’s

disease (CD) patients.1 Approved agents for CD include

the chimeric monoclonal IgG antibody infliximab (Remi-

cade, Centocor, Malvern, PA) and the human monoclonal

IgG antibody adalimumab (Humira, Abbott Laboratories,

Abbott Park, IL).2,3 Infliximab is also approved for the treat-

ment of ulcerative colitis (UC).2 The pegylated humanized

Fab’ fragment certolizumab pegol (Cimzia, UCB, Smyrna,

GA) is approved in the United States, Switzerland, and Rus-

sia for CD.4 The initial failure of some patients to respond

and remit to anti-TNF therapy1 is a clinical challenge, as is

the loss of response with continued treatment, with reported

rates ranging from �10%–50% per year in CD.5

Because several analyses have implicated low serum

anti-TNF concentrations (which are variably associated

with the formation of antidrug antibodies [ADAs]) with

lack or loss of response, some authors have recommended

therapeutic drug monitoring (TDM, defined as of measure-

ment of serum drug and/or ADA concentrations) to guide

clinical decision-making for patients with inflammatory

bowel disease (IBD).6,7

The use of TDM for anti-TNF agents poses chal-

lenges, including assay standardization, interpretation of

serum drug and/or ADA assay values, and validation of a

treatment algorithm using TDM in clinical practice. This

article reviews the pharmacokinetics of anti-TNF agents

and evaluates existing evidence regarding the relationship

between serum drug concentrations, ADAs, and therapeutic

outcomes. The value of proposed treatment algorithms

based on clinical and laboratory factors, including TDM, to

guide individual patient management decisions is assessed.

Received for publication June 6, 2011; Accepted June 20, 2011.

From the *Department of Hepatogastroenterology, Hopital Claude Huriez,

Centre Hospitalier Universitaire de Lille, Lille, France, and Department of

Gastroenterology, Mount Sinai School of Medicine, New York, New York, USA,†Robarts Research Institute, University of Western Ontario, London, Ontario,

Canada, ‡Division of Gastroenterology, University of California San Diego, La

Jolla, California, USA, §Department of Gastroenterology, University Hospital of

Gasthuisberg, Leuven, Belgium, kAbbott Laboratories, Abbott Park, Illinois,

USA.

Reprints: Jean-Fr�ed�eric Colombel, MD, Department of Gastroenterology,

Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1069, New

York, NY 10029 (e-mail: jean-frederic.colombel@mssm.edu).

Copyright VC 2011 Crohn’s & Colitis Foundation of America, Inc.

DOI 10.1002/ibd.21831

Published online inWiley Online Library (wileyonlinelibrary.com).

Inflamm Bowel Dis � Volume 18, Number 2, February 2012 349

PHARMACOKINETICS OF ANTI-TNF BIOLOGICS

Half-lives/Dose-concentration RelationshipsElimination half-lives for adalimumab, certolizumab

pegol, and infliximab are shown in Table 1.2–4 All three

agents demonstrate linear relationships between doses and

serum concentrations.2–4 However, available pharmacoki-

netic data for adalimumab and infliximab demonstrate con-

siderable interindividual variability in trough levels for a

given dose, even when (in the case of infliximab) the dose

is based on the patient’s weight.8,9 For example, the coeffi-

cient of variation (the standard deviation divided by the

mean) calculated for adalimumab serum trough concentra-

tions in the CLASSIC II study ranged from 52%–81%.8

Mechanisms of Clearance of Anti-TNF AgentsElimination mechanisms for monoclonal antibodies

are not well described.10 One route may be proteolytic ca-

tabolism, but the exact locations of this have not been

identified.11 The reticuloendothelial system (RES, i.e., the

phagocytic cells of the immune system) may play a role

(Fig. 1A); however, the importance of this pathway is

incompletely understood and probably differs for different

antibodies.10 Internalization of the antibody by phagocytic

cells is primarily driven by Fc-c receptors.10 Binding to

and internalization by Fc-c receptors is more efficient when

the antibody is cross-linked, as when bound to a multiva-

lent antigen.12

Binding to membrane-associated antigens, which

leads to internalization of the antibody and subsequent deg-

radation in lysosomes, is another potential route of clear-

ance (Fig. 1B).10,13 This pathway, also called the ‘‘antigen

sink,’’ is saturable when sufficient amounts of therapeutic

antibody are present.10,13 TNF, a trimer which exists in

both soluble and membrane-bound forms,14 is present in

abnormally high concentrations in serum and gut mucosa

in IBD.15,16 Evidence of the influence of the contribution

of the antigen sink has been demonstrated by analyses of

the influence of C-reactive protein (CRP) concentrations on

anti-TNF pharmacokinetics. CRP, an indirect marker of

inflammation,17 correlates with perienteric findings of

inflammation (increased fat density on computed tomogra-

phy) in CD patients.18 Baseline CRP was significantly

associated with infliximab clearance in UC patients.19 In

rheumatoid arthritis (RA), pretreatment CRP levels nega-

tively correlated with serum infliximab levels in patients

treated with infliximab plus methotrexate,20 and CRP pre-

dicted minor increases in adalimumab clearance.3

Finally, neonatal Fc receptors (FcRn) also influence

monoclonal antibody and IgG homeostasis and clearance.

In adults, FcRn are expressed primarily in vascular endo-

thelial cells or the RES, and function as a recycling or

salvage mechanism to prolong IgG half-life. FcRn bind

IgG bound to soluble antigens; the complex is internalized

into the cell, the antigen is degraded, and the antibody is

returned to the cell surface and released into the circulation

(Fig. 1C).11,13 In UC, baseline serum albumin concentrations

(which may also be affected by FcRn-mediated recycling)

correlated with infliximab clearance.21 As serum albumin

has been shown to correlate with colonic endoscopic activity

in IBD,22 low serum albumin may also reflect higher inflam-

matory burden in patients with active disease, which could

influence biologic clearance via the antigen sink.

Fc receptor-mediated routes of elimination do not

apply to certolizumab pegol, which lacks an Fc domain.

Antibody fragments without the Fc domain are subject to

renal clearance and proteolysis; the addition of polyethyl-

ene glycol increases the half-life to that approximating a

full IgG1 molecule.23

In addition to its effect on clearance, antigen-biologic

binding can influence the drug’s pharmacokinetic profile.13

In the case of IBD, the amount TNF at the site of inflam-

mation may vary between patients, and even within an

individual patient over time, and likely influences the nec-

essary dose of and potentially the minimum threshold con-

centration of an anti-TNF agent necessary for efficacy.24

TNF can also have concentration gradients in different

compartments and binding of TNF can lead to subsequent

redistribution, with further effects on the drug’s pharmaco-

kinetic profile.24

Other factors that may influence the clearance of bio-

logics, including demographic variables, concomitant medi-

cations, and the presence of ADAs (which will be explored

in more detail later), are shown in Table 2.3,4,19,25–28 Con-

comitant drugs may influence clearance, possibly via an

effect on Fc-c receptor expression; for example, methotrex-

ate may downregulate Fc-c receptor expression on mono-

cytes.11 Other potential mechanisms include modulation of

the Fc-c receptor-antibody interaction and reduction of im-

munogenicity development.13 The influence of thiopurines

on clearance has been less well characterized; one study

found little or no impact on adalimumab clearance,8 and

another found no effect on adalimumab trough concentra-

tions.29 In the SONIC trial, the combination of azathioprine

TABLE 1. Half-life Values for Anti-TNF Agents Approvedfor IBD

Biologic Agent Half-life

Adalimumab Approximately 2 weeks(mean; range of 10-20 days)

Certolizumab pegol Approximately 14 days (mean)

Infliximab 7.7 to 9.5 days (median)

IBD, inflammatory bowel disease; TNF, tumor necrosis factor.

Inflamm Bowel Dis � Volume 18, Number 2, February 2012Colombel et al

350

and infliximab increased infliximab trough concentrations

by more than 50% as compared with infliximab alone.30 In

a study evaluating the effect of withdrawal of concomitant

immunosuppressants (most of which were thiopurines) in

patients on infliximab, patients who continued the immuno-

suppressant had higher median infliximab concentrations

FIGURE 1. Mechanisms of antibody clearance. (A) Degradation of IgG by the reticuloendothelial system (phagocytic cells). 1. The Fc portionof IgG cross-linked by bound antigen binds to Fc-c receptors. 2. Uptake into the cell. 3. IgG-antigen complex transported to lysosomes. 4.Degradation of IgG in lysosomes. (B) Degradation of IgG by the antigen sink. 1. Circulating antibody binds to membrane-bound antigen. 2.Antibody is internalized. 3. Degradation of IgG in lysosomes. (C) FcRn-mediated protection from degradation. 1. Uptake of circulating antibodybound to antigen via endocytosis. 2. pH-dependent binding of the complex to FcRn is facilitated by the acidic environment of the endosome.3. Antigen is degraded and FcRn-bound IgG is transported back to the plasma membrane. 4. Antibody is released at physiological pH.

Inflamm Bowel Dis � Volume 18, Number 2, February 2012 TDM of Biologics for IBD

351

and were more likely to have detectable infliximab at

trough than the discontinuation group.31

Influence of Immunogenicity on ClearanceThe development of ADAs, which have been demon-

strated with all currently marketed biologics, can be influ-

enced by several factors, including biologic structure, the

patient’s immune status, use of concomitant medications,

route of administration, and dosing regimen.13 The influ-

ence of ADAs on the clearance of anti-TNF agents is com-

plex and dynamic.32 Presence of immunogenicity against a

therapeutic biologic may reduce its exposure through

formation of immune complexes which accelerate RES-

mediated clearance and/or impair binding.11,13 The pre-

scribing information for infliximab, adalimumab, and certo-

lizumab pegol all note the association of ADAs with

increased clearance.2–4 In a series of CD patients treated

with episodic infliximab the concentration of ADAs was

inversely correlated with infliximab concentrations measured

4 weeks postinfusion.33 Another CD study found that the

presence of detectable ADAs to infliximab was associated

with a 34% shorter half-life and 2.7-fold increased clear-

ance.25 Patients treated with adalimumab for CD who devel-

oped ADAs demonstrated a lower median adalimumab

trough serum concentration throughout the entire period of

follow-up.29 Reductions in serum concentrations in patients

who were positive for ADAs were seen with certolizumab

pegol in the PRECiSE-2 and PRECiSE-4 trials.34,35

OVERVIEW OF TECHNICAL ASPECTSCurrent tests for anti-TNF and ADA concentrations

are mostly based on enzyme immunoassays.6 Radioimmu-

noassay technology has also been developed.36 For existing

commercially available assays for antibodies, the presence

of persistent drug in the circulation generally interferes

with the detection of ADAs, by some tests more than

others.37 On the other hand, solid-phase enzyme-linked tests

can also produce false-positive ADA results.37 Newer assays,

based on high-performance liquid chromatography or the pH

shift-anti-idiotype method, which can detect ADAs in the

presence of circulating drug have been developed.38–40 These

assays also can detect antibodies with weak affinities, elimi-

nate nonspecific binding of irrelevant IgG, detect IgG4

ADAs, and overall have increased sensitivity and specificity

compared to enzyme immunoassays.

Since assay methodology and sensitivity differ, com-

parisons between results obtained using different assays

and/or assay techniques should be made with caution.

DRUG/ADA CONCENTRATIONS AND EFFICACYThe existing data regarding the relationship between

anti-TNF serum concentrations and ADAs have limitations.

Many of the analyses are retrospective. Often studies

collected serum samples at predefined times, and not neces-

sarily at the time a patient experienced a flare or lost

response. Patients who fail treatment are likely to discon-

tinue treatment, which could lead to bias if low concentra-

tions were responsible for the lack of response. Often

patients are not analyzed according to initial response sta-

tus. Analysis of patients with disease that is not amenable

to TNF blockade (at any dose) with treatment-responsive

patients (in whom a concentration–response relationship

might be more likely to be observed) could blur the ability

to detect a link between concentrations and outcomes.

Some studies evaluated clinical efficacy via only symptom-

based endpoints, such as the Crohn’s Disease Activity

Index (CDAI), which are relatively subjective and could

also be influenced by symptoms arising from disorders

other than the underlying disease.41,42 Finally, the follow-

up of patients in studies is often limited; it is possible that

there may be a time lag from the detection of low drug

concentrations and/or ADAs and the development on clini-

cal symptoms.

In this section we review data evaluating anti-TNF

serum concentrations and ADAs and clinical outcomes.

The focus is IBD, but selected studies in RA are included

for additional evidence.

TABLE 2. Other Factors Influencing Anti-TNF AgentClearance

Factor Evidence

Body weight � Affected infliximab drug exposurein UC and CD

� Low but significant association betweenbody weight and adalimumab clearance(r2 ¼ 0.14; P < 0.05) in RA

Sex � Affected infliximab drug exposurein UC and CD

� Higher adalimumab clearance in menthan women

Age � Age associated with lower clearancein patients over 40 years in RA

Methotrexate � Methotrexate reduced adalimumabclearance by 44%

� Methotrexate increased serumconcentrations when used withinfliximab in RA

� The effect of methotrexate oncertolizumab pegol pharmacokineticshas not been studied

Corticosteroids � Concurrent prednisone use reducedADA formation in patients receivingepisodic infliximab

ADA, anti-drug antibodies; CD, Crohn’s disease; RA, rheumatoid arthritis;TNF, tumor necrosis factor; UC, ulcerative colitis.

Inflamm Bowel Dis � Volume 18, Number 2, February 2012Colombel et al

352

Clinical Impact of Serum Drug ConcentrationsSeveral analyses have found numerically greater rates

of attainment of efficacy endpoints in subjects with higher

serum trough drug concentrations. An analysis from

ACCENT I found that early treatment responders with

higher infliximab trough concentrations had a greater

CDAI decline than patients in lower concentration catego-

ries.43 In ACCENT II, patients with lower trough serum

infliximab concentrations were less likely to achieve com-

plete fistula response (25.0% in subjects with concentration

<0.06 lg/mL vs. 64.3% with >10 lg/mL).44 In the SONIC

study, week 30 rates of corticosteroid-free clinical remis-

sion were greater in patients with higher serum concentra-

tions of infliximab at trough but were still high among

patients with lower trough levels.30 Similar results were

seen at week 46. An analysis of the COMMIT study found

that patients with detectable infliximab concentration at

trough were more likely to achieve treatment success than

subjects with undetectable troughs, although this was not

statistically significant (P ¼ 0.08).45

In the previously mentioned infliximab immunosup-

pressant discontinuation study, CRP and CDAI correlated

weakly with infliximab troughs (CRP: r ¼ 0.387; CDAI:

r ¼ 0.205, P < 0.01), and subjects in the lowest quartile of

infliximab troughs had significantly higher median CRP

values.31 While patients in the lowest infliximab trough

concentration quartile had the highest CDAI (P < 0.03),

there was substantial overlap between quartiles. Low serum

trough concentrations early after immunosuppressant dis-

continuation were also associated with more frequent

infliximab dose intensification (P < 0.01).

An observational single-center study evaluated the rela-

tionship between infliximab trough concentrations and CD

clinical outcomes.46 In 105 patients receiving scheduled or ep-

isodic infliximab, a positive relationship was seen between

infliximab troughs and the percentage of time between infu-

sions that patients had a Harvey–Bradshaw Index (HBI) �2

(R2 ¼ 0.61; P < 0.001). Patients with detectable infliximab at

trough were less likely to discontinue therapy before one year

(odds ratio [OR] 23.1, P < 0.001). A subanalysis of 90

patients who received scheduled maintenance therapy for

more than 52 weeks found strong relationships between detect-

able infliximab troughs and clinical remission, CRP, and endo-

scopic improvement (P < 0.001 for all parameters). Detecta-

ble infliximab at trough was a significant positive predictor for

maintaining HBI �2 100% of the time between infusions

(OR, 38.1; 95% confidence interval [CI] 9.1–60.5; P < 0.001)

In a small retrospective series of CD patients who

had received at least two infliximab infusions, 95% (18/19)

of patients who maintained response had detectable inflixi-

mab (as measured by TNF-alpha binding capacity) at

trough, as compared to only 12.5% (1/8) of patients with

secondary loss of response.36

An association between infliximab serum trough con-

centrations and endoscopic mucosal healing was seen in an

analysis of 210 patients with CD. Patients with complete

mucosal healing had the highest troughs (median 5.77 lg/mL, interquartile range [IQR] 1.05–10.72), followed by

those with partial healing (3.89 IQR 0.35–8.28). Patients

without healing had the lowest median troughs (0.95 lg/mL 0.35–6.56; P ¼ 0.013 for the comparison of all three

groups)47; however, there was significant overlap in

concentrations between the groups. A limitation of this

analysis is that ‘‘trough’’ sampling could have occurred

over a 4-week span (from 2–6 weeks after dosing).

An observational analysis of 108 UC patients treated

with scheduled infliximab maintenance therapy found de-

tectable trough serum infliximab concentration to be a sig-

nificant positive predictor for clinical remission (OR,

12.5; 95% CI: 4.6–33.9; P < 0.001) and endoscopic

improvement (OR, 7.3; 95% CI: 2.9–18.4; P < 0.001).48

Undetectable trough serum infliximab concentration was a

significant predictor for colectomy (OR, 9.3; 95% CI:

2.9–29.9; P < 0.001).

An analysis of adalimumab trough concentrations

from the CLASSIC I and II studies found slightly higher

mean concentrations in patients who achieved remission af-

ter induction and during maintenance treatment than those

who did not.49 However, there was high variability in the

trough serum concentration values and substantial overlap

between concentration ranges between groups. Troughs

achieved after induction dosing (week 4) were weakly cor-

related with remission (Spearman correlation ¼ 0.173; P ¼0.01), but no significant correlation was seen during main-

tenance therapy (Spearman correlation values ranged from

0.068–0.136; P-values all > 0.09). Analysis of remission

status at different serum concentration threshold values

(including undetectable concentrations) was not able to find

a concentration that would distinguish patients by remis-

sion status.49

On the other hand, an observational cohort study in a

Belgian referral center of 191 patients treated with adali-

mumab (168 of whom had previously failed infliximab)

found no relationship between adalimumab serum concen-

trations or ADAs and short-term clinical outcome,

although median adalimumab concentrations were lower

in patients who discontinued therapy by 6 months than

those who continued.29 Patients who responded to dose

escalation had an increase in their adalimumab serum lev-

els after dose escalation.

The mean troughs of patients treated with certolizu-

mab pegol have been published.35,50 In a study evaluating

the efficacy of certolizumab pegol in patients previously

treated with infliximab, serum drug concentrations were

mentioned to not have a major influence on clinical

responses or HBI.35,51

Inflamm Bowel Dis � Volume 18, Number 2, February 2012 TDM of Biologics for IBD

353

Clinical Impact of ADAsThe clinical influence of ADAs was evaluated in a

cohort of 125 CD patients in Leuven, Belgium, who were

treated with episodic infliximab infusions.33 A high propor-

tion (61%) of patients had detectable ADAs after the fifth

infusion, and there was a negative relationship between

ADA concentration and the duration of response (P <0.001). While patients with infliximab concentrations

(measured 4 weeks postinfusion) lower than the median

concentration of 12.0 lg/mL had a shorter median duration

of response (68.5 days) than patients with higher levels

(81.5 days; P < 0.01), infliximab concentrations were not

associated with duration of response by logistic regression

(P ¼ 0.70). Presence of ADAs was independently associ-

ated with a shorter duration of response (P < 0.001). The

authors concluded that the development of ADAs correlates

with a shorter duration of response as a result of their

effect on infliximab concentrations.

In ACCENT I, episodic infliximab use was associated

with a higher incidence of ADA formation than scheduled

therapy (30% vs. 8%, P < 0.001) and higher ADA titers.52

In the pooled analysis of both methods of administration,

ADAs did not affect week 54 clinical response and remis-

sion rates. In the episodic retreatment group, patients with

early (week 14) ADA-positive assays had lower infliximab

concentrations 2 weeks postinfusion, less improvement in

CDAI, and shorter duration of response than patients with-

out detectable ADAs. Despite this, 67% of ADA-positive

patients had a clinical response at week 54. The proportion

in clinical remission at week 54 was substantially lower

(33%) in the ADA-positive subjects than the ADA-incon-

clusive group (73%, P ¼ 0.078).

In an analysis of CD patients receiving infliximab, all

patients (8/8) who lost response had ADAs present,

whereas 53% (10/19) who maintained response had them,

indicating that ADA presence is not always associated with

lack of response. On the other hand, patients with loss of

response had higher median ADA titers than the patients

who maintained response.36 A study of CD patients treated

with episodic infliximab found that ADA-positive patients

with a titer <8 lg/mL had similar serum infliximab levels

4 weeks postinfusion as those without antibodies, whereas

the infliximab concentration for patients with higher ADA

titers was significantly lower than either of these two

groups (P < 0.001).53 A retrospective, single-center study

of 62 infliximab-treated patients with IBD found ADAs in

47% of patients.54 While 83% (10/12) of the patients with

complete loss of response were ADA-positive, 22% (6/24)

of treatment responders were also ADA-positive, although

the titer was low in the majority (5/6) of patients.

A small (N ¼ 30) retrospective single-center study of

patients with CD treated with adalimumab found ADAs in

5 of 30 patients (17%); the presence of ADAs was associ-

ated with a lack of response to adalimumab (OR, 13.1,

95% CI: 1.7–99.2, P ¼ 0.006).55

In the adalimumab CLASSIC II study, 7 of 269

(2.7%) patients tested positive for ADAs.56 The proportion

of patients in clinical remission at week 56 was lower in

the ADA-positive patients (29%), although the small num-

ber of patients precludes a definitive conclusion about the

impact of ADAs to adalimumab.

A recent cohort study of 272 adalimumab-treated

patients with RA followed for up to 3 years found that

28% developed ADAs (some as early as 4 weeks after

starting therapy).57 Patients without ADAs had higher adali-

mumab concentrations (median, 12 mg/L; IQR, 9–16 mg/L)

compared with patients with ‘‘intermediate’’ antibody titers

(median, 5 mg/L; IQR, 3–9 mg/L) and those with ‘‘high’’

ADA titers (median, 0 mg/L; IQR, 0–3 mg/L). Patients with

ADAs were more likely to discontinue treatment due to

treatment failure (38% vs. 14% for ADA-negative subjects,

P < 0.001), less likely to have minimal disease activity

(48% vs. 13% for ADA-negative subjects), and less likely to

achieve sustained minimal disease activity or sustained

remission compared with ADA-negative patients.

In the pivotal studies for certolizumab pegol, ADAs

were detected in 8% (26/331) of patients randomized to the

drug arm in the PRECiSE 1 study58; a similar value (8%,

17/213) was seen in PRECiSE 2.50 Clinical response status

through week 26 was similar in subjects regardless of

ADA status.50

SummaryAvailable evidence suggests that there is a relation-

ship between clinical efficacy endpoints (both objective

and symptom-related) in IBD patients and anti-TNF trough

serum concentrations, although the strength of the relation-

ship varied and was not consistently statistically significant.

For ADAs, available data suggest that their presence has a

potential, but not absolute, negative impact on clinical out-

comes, which is probably related to their influence on drug

clearance.

USING TDM IN CLINICAL PRACTICETDM has been traditionally used for drugs such as

anticonvulsants, antiarrhythmics, aminoglycoside antibiot-

ics, and theophylline that possess a narrow therapeutic

index (i.e., a small range between the minimum effective

concentration and the maximum safe concentration).59 Cri-

teria that have been suggested as necessary for serum con-

centration monitoring to be useful include difficulty in

interpretation of clinical evidence of therapeutic or toxic

effects, established relationship between drug concentration

and therapeutic and/or toxic effect of the drug (i.e., ‘‘thera-

peutic window’’), narrow therapeutic index, and a drug that

lacks important active metabolites.60

Inflamm Bowel Dis � Volume 18, Number 2, February 2012Colombel et al

354

Interpreting Serum Drug Concentration ValuesWhile there are several commercially available tests to

measure serum concentrations of anti-TNF agents (and ADAs),

most manufacturers do not offer guidance for interpretation of

the results. An exception is Prometheus Laboratories in the

U.S., which offers serum concentration and ADA testing for

infliximab. The Prometheus product data sheet61 references the

Belgian study reviewed above33 and suggests sampling inflixi-

mab levels 4 weeks postinfusion, although the type of patient

who should receive testing (i.e., stable patients or patients with

limited or loss of response) is not specified. Patients with a se-

rum level less than the median level seen in the Belgian study

with episodic dosing (12 lg/mL) are suggested to have an anti-

infliximab antibody test and suggestions are made to alter the

infliximab dose or interval based on the ADA titer.

Two recent publications have proposed a different

approach for patients who have ongoing inflammation and are

not responding to therapy (Fig. 2). For patients with low drug

serum concentrations who are negative for ADAs, increasing

the anti-TNF dose is suggested. In the event that high drug con-

centrations are present in patients with documented inflamma-

tion, shifting to another class of drug is proposed (Fig. 2).6,7

A retrospective evaluation of TDM following this

algorithm from the Mayo Clinic was recently published.7

In this study a subtherapeutic infliximab concentration was

defined as <12 lg/mL 4 weeks postinfusion or undetect-

able (<1.4 lg/mL) at trough. In patients with subtherapeu-

tic drug concentrations (and no ADAs), increasing the

infliximab dose achieved complete or partial response more

frequently (25/29 of patients) than changing to another

anti-TNF agent (2/6, P < 0.016). Ten patients with sub-

therapeutic concentrations continued on the same dose;

information on their clinical course was not reported.

A potential limitation of the above algorithm is that

the therapeutic range for anti-TNF agents may not be a

‘‘one size fits all’’ scenario. Many of the analyses cited

above found increasingly higher rates of efficacy with

higher concentration ranges, suggesting that some patients

will only respond at a level higher than that sufficient for a

different individual. For example, a retrospective analysis

from France of CD patients who had infliximab serum con-

centrations and ADAs measured at the time of loss of

response (although the treating physician was blinded to

the test results) found that half of patients who had dosage

intensification had a high (>1.5 lg/mL) infliximab trough

level at inclusion and 70% of these patients had a clinical

response after intensification.62 The median infliximab con-

centration in patients who responded to intensification was

not different (3.2 lg/mL, n ¼ 28) than those who did not

respond (2.3 lg/mL, n ¼ 12; P > 0.3). Four of the five

patients who were moved to adalimumab responded; two of

the responders had measurable infliximab trough concentra-

tions (1.7 and 9.4 lg/mL) at the time of loss of response to

infliximab. Another potential interpretation of these data are

that the trough cutoff value to use to define patients in

whom dose escalation may be of benefit may be higher than

‘‘undetectable.’’

The referral center analysis of adalimumab use in CD

found that patients who dose-escalated had a median adali-

mumab concentration of 4.8 lg/mL on every other week

dosing; patients who responded to escalation to weekly dos-

ing had a median increase of 5.9 lg/mL.29 An analysis of

the effects of infliximab dose adjustment in patients with

loss of response from the same center also found large inter-

individual variability in trough levels, suggesting that troughs

needed to maintain remission may be patient-specific.63

Interpreting the Presence of ADAsThe TDM algorithm in Figure 2 proposes moving to a

different anti-TNF in the setting of detectable ADAs and low

serum drug concentrations, due to the suggestion that patients

have been ‘‘immunized’’ to the drug and that subsequent dose

escalation will not be beneficial.6,7 In the Mayo series, 11/12

(92%) of patients with detectable ADAs achieved a complete

or partial response to a different anti-TNF agent, whereas

only 1/6 (17%) of patients with dose escalation responded

(P < 0.004), and none of the patients managed with dose

escalation regained infliximab concentrations defined as thera-

peutic.7 The titer of the ADAs was not reported.

On the other hand, the French study found that 6/10

patients with ADAs to infliximab responded to infliximab

intensification, including 4/6 patients with elevated

(>200 ng/mL) ADA concentrations.62 Seven patients had

an ADA measurement after intensification; concentrations

decreased in three patients and were no longer detectable

in two.

A previously mentioned study evaluating the pharma-

cokinetics of infliximab in CD patients found that dosage

FIGURE 2. Proposed TDM algorithm for anti-TNF agents in patientswith ongoing inflammation or uncontrolled disease.

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355

intensification in two ADA-positive patients led to a rever-

sal in infliximab clearance toward that in patients without

ADAs. The authors suggest that the higher infliximab expo-

sure after dosage increase binds and hence reduces the influ-

ence of the ADAs on drug clearance.25 Similarly, in an anal-

ysis of RA patients treated with adalimumab, five

nonresponding ADA-positive patients moved to weekly dos-

ing. Afterwards, the ADAs were no longer detectable and the

mean adalimumab trough concentrations increased from 2.0

mg/L to 15.0 lg/L (P ¼ 0.043).63 An update of patients

treated at the same institution similarly found that 6 of 20

ADA-positive subjects who underwent dose escalation

became ADA-negative; however, none of these patients

achieved minimal disease activity.57

An analysis of 30 adalimumab-treated RA patients

found ADAs in 21/30 of the subjects using a pH-shift-anti-

idiotype antigen binding test (which is able to detect ADAs

in the presence of adalimumab), whereas the traditional

antigen binding test detected ADAs in only 5 of the same

30 patients.40 However, the presence of the ‘‘hidden’’

ADAs were associated with only a minor reduction in cir-

culating adalimumab, indicating that the majority of

patients who make anti-adalimumab antibodies do not

make sufficient quantities to clear or neutralize all of the

drug, or that perhaps the ADAs have low binding affinity

or neutralizing capacity. The titer of ADAs may affect the

degree to which they influence clearance; RA patients with

‘‘intermediate’’ concentrations of anti-adalimumab antibod-

ies had similar clinical response as patients without detect-

able ADAs.64 The authors theorize that these patients have

adequate serum drug concentrations for most of the dosing

interval, with levels dropping below the threshold to allow

ADA detection just prior to the next injection.

A further challenge with the issue of evaluating ADA

status is that they are not always present in patients with

low drug concentrations and lack of response.31,46 The

lower rate of responses seen in the presence of ADAs in

some datasets may be more of a reflection of the fact that

patients who have detectable ADAs with traditional assays

have very low or undetectable circulating drug at the time

of measurement. The summary conclusion is that the loss

of response is often related to increased clearance; ADAs

may not all influence clearance to the same degree and

ADAs are not the only factors that can influence clearance.

USING TDM TO AVOID TOXICITYThere are few data regarding the use of TDM to pre-

vent toxicity with anti-TNF agents. Large clinical trials of

all three anti-TNF agents did not show meaningful differ-

ences in adverse reactions between the recommended initial

maintenance doses and higher doses that were tested.51,65,66

On the other hand, a study of infliximab therapy in combi-

nation with methotrexate in RA found a higher relative risk

versus placebo plus methotrexate (3.1; 95% CI: 1.2–7.9,

P ¼ 0.013) of serious infections with a regimen of three

doses of 10 mg/kg followed by 10 mg/mg maintenance

therapy administered every 8 weeks that seen with a

3 mg/kg regimen (relative risk [RR] 1.0, 95% CI: 0.3–3.1,

P ¼ 0.995).67 An analysis of skin-related adverse events

during anti-TNF therapy for IBD found that patients experi-

encing an event were less likely to have undetectable inflixi-

mab concentrations at trough than those who did not.68

FUTURE RESEARCH NEEDSWhile the concept of TDM is appealing, more

research is needed to clarify its utility and to document its

ability to improve patient outcomes. While the detection of

ADAs or undetectable serum drug concentrations in a

patient who is losing response should probably lead to a

change in management, the optimal intervention (e.g., dose

escalate, add an immunomodulator, or change to a different

anti-TNF, or change to a drug with a different mechanism

of action) remains to be determined. Additionally, studies

designed to evaluate the concentration-effect relationship of

anti-TNFs in order to define the ‘‘therapeutic window’’ are

needed,25 this is also true for the concentration-toxicity rela-

tionship. Future evaluations should include assessment of

the relationship with symptomatic as well as more objective

measures of response (such as mucosal healing or change in

CRP). The thresholds for serum drug and/or ADA concen-

trations should demonstrate an acceptable predictive value to

reliably discriminate patients based on efficacy status. As

seen from an analysis of RA patients treated in Sweden, a

composite biomarker index (defined as the presence of unde-

tectable infliximab concentrations and/or ADAs) with a

strong association with loss of response (OR, 5.9, 95% CI:

1.3–26.6) was seen in only 42% of patients who lost

response.69 The best approach for the remaining patients (all

with detectable infliximab trough concentrations) remains to

be determined in order to determine if dose escalation would

be of benefit or if the patient should be moved to a different

class of therapy altogether.

The best approach to TDM of biologic agents may

not be only monitoring of trough concentrations. Other pa-

rameters of drug exposure (peak concentration, time above

a minimum threshold, area under the curve, etc., all of

which are affected by drug frequency and route of adminis-

tration as well as the patient’s individual clearance) could

be related to outcomes and should be explored. It may also

be that drug exposure variables associated with efficacy

may vary depending on the point in time of treatment; for

example, optimal pharmacokinetic parameters during

induction therapy may differ from that those needed during

maintenance therapy. Subcutaneously administered agents,

which have more uniform concentration-time profiles as

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356

compared to intravenously administered agents, may have

different application of TDM.

Optimal use of TDM might not be limited to one-time

measurements in patients losing efficacy. In the Belgian refer-

ral center analysis, adalimumab-treated patients who ended up

discontinuing therapy had significantly lower serum trough

levels as early as weeks 2–4.29 Based on this, a potential

approach for TDM could be modeled after the individualized

dosing used for aminoglycoside antibiotics,70 wherein dosing

is determined and adjusted based on the patient’s specific

clearance and the minimum inhibitory concentration of the or-

ganism being treated. In the case of anti-TNF agents, the dose

could be changed or concomitant medications could be added

or adjusted in patients with rapid or increasing clearance in

order to boost concentrations, reduce immunogenicity, and

potentially avoid loss of response. Adoption of this approach

will first require determination and validation of the therapeu-

tic range for the agent being used.

CONCLUSIONSThe pharmacokinetic profile of anti-TNF agents exhib-

its substantial interindividual variability. Anti-TNF pharma-

cokinetics can be affected by the use of concurrent medica-

tions such as methotrexate and thiopurines, which affect

drug clearance and the development of immunogenicity.

Current literature shows variable associations of the relation-

ships between serum drug levels and ADA status and clini-

cal efficacy. The concept of TDM is appealing to optimize

therapy in order to help patients achieve long-term IBD con-

trol. Currently the use of TDM has not been prospectively

validated and a therapeutic range for anti-TNF biologics has

not been established. Well-designed, prospective, blinded,

controlled trials to definitely answer the question of the util-

ity and positive predictive value of use of TDM versus

standard symptom-based approaches are needed.

ACKNOWLEDGMENTThis article was independently developed by the

authors. Based on employment of one of the authors

(A.M.R.), Abbott Laboratories was provided an opportunity

to review and provide feedback, but the authors had the

ultimate decision for final content.

REFERENCES1. Peyrin-Biroulet L, Deltenre P, Suray ND, et al. Efficacy and safety

of tumor necrosis factor antagonists in Crohn’s disease: meta-analy-sis of placebo-controlled trials. Clin Gastroenterol Hepatol. 2008;6:644–652.

2. REMICADE [prescribing information]. Malvern, PA: Centocor OrthoBiotech, Inc.; 2011.

3. HUMIRA [prescribing information]. North Chicago, IL: Abbott Labo-ratories; 2011.

4. CIMZIA [prescribing information]. Smyrna, GA: UCB; 2009.

5. Allez M, Karmiris K, Louis E, et al. Report of the ECCO pathogene-sis workshop on anti-TNF therapy failures in inflammatory bowel dis-

eases: definitions, frequency and pharmacological aspects. J Crohn’sColitis. 2010;4:355–366.

6. Bendtzen K, Ainsworth M, Steenholdt C, et al. Individual medicine ininflammatory bowel disease: monitoring bioavailability, pharmacoki-netics and immunogenicity of anti-tumour necrosis factor-alpha anti-bodies. Scand J Gastroenterol. 2009;44:774–781.

7. Afif W, Loftus EV, Faubion WA, et al. Clinical utility of measuringinfliximab and human anti-chimeric antibody concentrations inpatients with inflammatory bowel disease. Am J Gastroenterol. 2010;105:1133–1139.

8. Garimella T, Peng J, Beck K, et al. Pharmacokinetics of adalimumabin a long-term investigation of the induction and maintenance ofremission in patients with Crohn’s disease (CLASSIC I and CLASSICII). Gastroenterology. 2006;130(4 suppl 2):A481.

9. St. Clair EW, Wagner CL, Fasanmade AA, et al. The relationship ofserum infliximab concentrations to clinical improvement in rheumatoidarthritis. Arthritis Rheum. 2002;46:1451–1459.

10. Keizer RJ, Huitema ADR, Schellens JHM, et al. Clinical pharmacoki-netics of therapeutic monoclonal antibodies. Clin Pharmacokinet.2010;48:493–507.

11. Mould D, Green B. Pharmacokinetics and pharmacodynamics ofmonoclonal antibodies: concepts and lessons for drug development.Biodrugs. 2010;24:23–39.

12. Raghavan M, Bjorkman P. Fc receptors and their interactions withimmunoglobulins. Annu Rev Cell Dev Biol. 1996;12:181–220.

13. Tabrizi M, Tseng C-M, Roskos L. Elimination mechanisms of thera-peutic monoclonal antibodies. Drug Discov Today. 2006;11:81–88.

14. Fiers W. Tumor necrosis factor: characterization at the molecular, cel-lular and in vivo level. FEBS Lett. 1991;285:195–212.

15. Murch S, Lamkin V, Savage M, et al. Serum concentrations of tumournecrosis factor alpha in childhood chronic inflammatory bowel dis-ease. Gut. 1991;32:913–917.

16. Murch S, Braegger C, Walker-Smith J, et al. Location of tumour ne-crosis factor alpha by immunohistochemistry in chronic inflammatorybowel disease. Gut. 1993;34:1705–1709.

17. Vermeire S, Van Assche G, Rutgeerts P. C-reactive protein as amarker for inflammatory bowel disease. Inflamm Bowel Dis. 2004;10:661–665.

18. Colombel JF, Solem CA, Sandborn WJ, et al. Quantitative measure-ment and visual assessment of ileal Crohn’s disease activity by com-puted tomography enterography: correlation with endoscopic severityand C reactive protein. Gut. 2006;55:1561–1567.

19. Fasanmade AA, Adedokun OJ, Ford J, et al. Population pharmacoki-netic analysis of infliximab in patients with ulcerative colitis. Eur JPharmacol. 2009;65:1211–1228.

20. Wolbink GJ, Voskuyl AE, Lems WF, et al. Relationship between se-rum trough infliximab levels, pretreatment C reactive protein levels,and clinical response to infliximab treatment in patients with rheuma-toid arthritis. Ann Rheum Dis. 2005;64:704–707.

21. Fasanmade AA, Adedokun OJ, Olson A, et al. Serum albumin concen-tration: a predictive factor of infliximab pharmacokinetics and clinicalresponse in patients with ulcerative colitis. Int J Clin Pharmacol Ther.2010;48:297–308.

22. Moran A, Jones A, Asquith P. Laboratory markers of colonoscopic ac-tivity in ulcerative colitis and Crohn’s colitis. Scand J Gastroenterol.1995;30:356–360.

23. Champman AP. PEGylated antibodies and antibody fragments forimproved therapy: a review. Adv Drug Del Rev. 2002;54:531–545.

24. Nestorov I. Clinical pharmacokinetics of tumor necrosis factor antago-nists. J Rheumatol. 2005;32(suppl):13–18.

25. Ternant D, Aubourg A, Magdelaine-Beuzelin C, et al. Infliximab phar-macokinetics in inflammatory bowel disease patients. Ther DrugMonit. 2008;30:523–529.

26. Weisman MH, Moreland LW, Furst DE, et al. Efficacy, pharmacoki-netic, and safety assessment of adalimumab, a fully human anti-tumornecrosis factor-alpha monoclonal antibody, in adults with rheumatoidarthritis receiving concomitant methotrexate: a pilot study. Clin Ther.2003;25:1700–1721.

27. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy ofmultiple intravenous infusions of anti-tumor necrosis factor a

Inflamm Bowel Dis � Volume 18, Number 2, February 2012 TDM of Biologics for IBD

357

monoclonal antibody combined with low-dose weekly methotrexate inrheumatoid arthritis. Arthritis Rheum. 1998;41:1552–1563.

28. Farrell RJ, Alsahli M, Jeen YT, et al. Intravenous hydrocortisone pre-medication reduces antibodies to infliximab in Crohn’s disease: arandomized controlled trial. Gastroenterology. 2003;124:917–924.

29. Karmiris K, Paintaud G, Noman M, et al. Influence of trough serumlevels and immunogenicity on long-term outcome of adalimumab ther-apy in Crohn’s disease. Gastroenterology. 2009;137:1628–1640.

30. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathio-prine, or combination therapy for Crohn’s disease. N Engl J Med.2010;362:1383–1395.

31. Van Assche, G., Magdelaine-Beuzelin C, D’Haens G, et al. With-drawal of immunosuppression in Crohn’s disease treated with sched-uled infliximab maintenance: a randomized trial. Gastroenterology.2008;134:1861–1868.

32. Van Assche G. Immunogenicity of anti-TNF antibodies. Has the veilbeen lifted? Gut. 2011;60:285–286.

33. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicityon the long-term efficacy of infliximab in Crohn’s disease. N Engl JMed. 2003;348:601–608.

34. Lichtenstein G, Thomsen O, Schreiber S, et al. Continuous therapywith certolizumab pegol maintains remission of patients with Crohn’sdisease for up to 18 months. Clin Gastroenterol Hepatol. 2010;8:600–609.

35. Sandborn WJ, Schreiber S, Hanauer SB, et al. Reinduction withcertolizumab pegol in patients with relapsed Crohn’s disease: resultsfrom the PRECiSE 4 study. Clin Gastroenterol Hepatol. 2010;8:696–702.

36. Ainsworth MA, Bendtzen K, Brynskov J. Tumor necrosis factor-alphabinding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of inflixi-mab in Crohn’s disease. Am J Gastroenterol. 2008;103:944–948.

37. Cassinotti A, Travis S. Incidence and significance of immunogenicityto infliximab in Crohn’s disease: a critical systematic review. InflammBowel Dis. 2009;15:1264–1275.

38. Wang S, Ohrmund L, Ling N, et al. Analysis of anti-drug antibodies(ADA) to adalimumab in patient serum using a novel homogeneous mo-bility shift assay. Am J Gastroenterol. 2010;105(suppl 1):S444–S445.

39. Wang S, Ohrmund L, Singh S. Measurement of human anti-chimericantibodies (HACA) and infliximab levels in patient serum using anovel homoegeous assay. Gastroenterology. 2010;138(5 suppl 1):S684–S685.

40. Van Schouwenburg P, Bartelds G, Hart M, et al. A novel method forthe detection of antibodies to adalimumab in the presence of drugreveals ‘‘hidden’’ immunogenicity in rheumatoid arthritis. J ImmunolMethods. 2010;362:82–88.

41. Sandborn W, Feagan B, Hanauer S, et al. A review of activity indicesand efficacy endpoints for clinical trials of medical therapy in adultsWith Crohn’s disease. Gastroenterology. 2002;122:512–530.

42. Bruining DA, Sandborn WJ. Do not assume symptoms indicate failureof anti-tumor necrosis factor therapy in Crohn’s disease. Clin Gastro-enterol Hepatol. 2011;9:395–399.

43. Fasanmade A, Olson A, Bag W, et al. Relationship between infliximabpharmacokinetics and improvement in Crohn’s disease. Gastroenterol-ogy. 2002;122(suppl 4):A617–A618.

44. Fasanmade AA, Marsters P, Munsanje E, et al. Infliximab pharmaco-kinetics and improvement in fistulizing Crohn’s disease. Gastroenterol-ogy. 2003;124(4 suppl 1):A61.

45. Feagan BG, McDonald JW, Panaccione R, et al. Methotrexate for theprevention of antibodies to infliximab in patients with Crohn’s disease.Gastroenterology. 2010;138(5 suppl 1):S167–S168.

46. Maser EA, Villela R, Silverberg MS, et al. Association of troughserum infliximab to clinical outcome after scheduled maintenancetreatment for Crohn’s disease. Clin Gastroenterol Hepatol. 2006;4:1248–1254.

47. Van Moerkercke W, Ackaert C, Compernolle G, et al. High infliximabtrough levels are associated with mucosal healing in Crohn’s disease.Gastroenterology. 2010;5(suppl 1):S60.

48. Seow CH, Newman A, Irwin SP, et al. Trough serum infliximab: apredictive factor of clinical outcome for infliximab treatment in acuteulcerative colitis. Gut. 2010;59:49–54.

49. Li J, Chiu Y, Robinson A, et al. Evaluation of potential correlations betweenserum adalimumab concentration and remission in patients with Crohn’sdisease in CLASSIC I and II. J Crohn’s Colitis. 2010;4(suppl):S73.

50. Schreiber S, Khaliq-Kareemi M, Lawrance I, et al. Maintenance ther-apy with certolizumab pegol for Crohn’s disease. N Engl J Med.2007;357:239–250.

51. Sandborn WJ, Abreu MT, D’Haens G, et al. Certolizumab pegol inpatients with moderate to severe Crohn’s disease and secondary failureto infliximab. Clin Gastroenterol Hepatol. 2010;8:688–695.

52. Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance ofantibody responses to infliximab after maintenance or episodic treat-ment in Crohn’s disease. Clin Gastroenterol Hepatol. 2004;2:542–553.

53. Vermeire S, Noman M, Van Assche G, et al. Effectiveness of con-comitant immunosuppressive therapy in suppressing the formation ofantibodies to infliximab in Crohn’s disease. Gut. 2007;56:1226–1231.

54. Ben-Horin S, Yavzori M, Katz L, et al. The immunogenic part ofinfliximab is the F(ab’)2, but measuring antibodies to the intact inflixi-mab molecule is more clinically useful. Gut. 2011;60:41–48.

55. West RL, Zelinkova Z, Wolbink GJ, et al. Immunogenicity negativelyinfluences the outcome of adalimumab treatment in Crohn’s disease.Aliment Pharmacol Ther. 2008;28:1122–1126.

56. Sandborn W, Hanauer S, Rutgeerts P, et al. Adalimumab for mainte-nance treatment of Crohn’s disease: results of the CLASSIC II trial.Gut. 2007;56:1232–1239.

57. Bartelds GM, Krieckaert CLM, Nurmohamed MT, et al. Developmentof antidrug antibodies against adalimumab and association with dis-ease activity and treatment tailure during long-term follow-up. JAMA.2011;305:1460–1468.

58. Sandborn W, Feagan B, Stoinov S, et al. Certolizumab pegol for thetreatment of Crohn’s disease. N Engl J Med. 2007;257:228–238.

59. Spector R, Park G, Johnson G, et al. Therapeutic drug monitoring.Clin Pharmacol Ther. 1988;43:345–353.

60. Reynolds D, Aronson J. Making the most of plasma drug concentra-tion measurements. BMJ. 1993;306:48–51.

61. Serum infliximab/HACA data sheet. San Diego, CA: Prometheus Lab-oratories; 2006.

62. Vermeire S, Gabriels F, Ballet V, et al. The effect of dose escalationon trough levels in patients who lost response to infliximab. Gut.2010;59(suppl III):A81.

63. Pariente B, Pineton de Chambrun G, Krysiek R, et al. Clinical signifi-cance of infliximaband human antichimeric antibodies concentrationsin patientswith inflammatory bowel disease who lost response toinfliximabtherapy. Inflamm Bowel Dis. 2011, DOI: 10.1002/ibd.21839.

64. Bartelds GM, Wijbrandts CA, Nurmohamed MT, et al. Clinicalresponse to adalimumab: relationship to antiadalimumab antibodiesand serum adalimumab concentrations in rheumatoid arthritis. AnnRheum Dis. 2007;66:921–926.

65. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance inflixi-mab for Crohn’s disease: the ACCENT I randomised trial. Lancet.2002;359:1541–1549.

66. Colombel J-F, Sandborn WJ, Rutgeerts P, et al. Adalimumab for main-tenance of clinical response and remission in patients with Crohn’s dis-ease: the CHARM trial. Gastroenterology. 2007;132:52–65.

67. Westhovens R, Yocum D, Han J, et al. The safety of infliximab, com-bined with background treatments, among patients with rheumatoid ar-thritis and various comorbidities. Arthritis Rheum. 2006;54:1075–1086.

68. Cleynen I, Van Moerkercke, W, Juergens M, et al. Anti-TNF inducedcutaneous lesions in IBD patients: characterization and search for pre-disposing factors. Gut. 2010;59(suppl III):A1.

69. Finckh A, Dudler J, Wermelinger F, et al. Influence of anti-infliximabantibodies and residual infliximab concentrations on the occurrence ofacquired drug resistance to infliximab in rheumatoid arthritis patients.Joint Bone Spine. 2010;4:313–318.

70. Rea R, Blair C. Optimizing use of aminoglycosides in the criticallyill. Semin Respir Crit Care Med. 2007;28:596–603.

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