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Anti-TNF Monoclonal Antibodies in Inflammatory
Bowel Disease: Pharmacokinetics-Based
Dosing Paradigms
Ingrid Ordás1,2, Diane R. Mould3, Brian G. Feagan4 and William J. Sandborn1
Crohn’s disease and ulcerative colitis are chronic inflammatory disorders resulting from immune dysregulation. Patients
who fail conventional medical therapy require biological treatment with monoclonal antibodies (mAbs). Although
mAbs are highly effective for induction and maintenance of clinical remission, not all patients respond, and a high
proportion of patients lose response over time. One factor associated with loss of response is immunogenicity, whereby
the production of antidrug antibodies accelerates mAb clearance. However, other factors related to patient and disease
characteristics also influence the pharmacokinetics of mAbs. These factors include gender, body size, concomitant use
of immunosuppressive agents, disease type, serum albumin concentration, and the degree of systemic inflammation.
Because it is important to maintain clinically effective concentrations to provide optimal clinical response and drug
exposure is affected by patient factors, a better understanding of the pharmacology of mAbs will ultimately result in
better patient care.
In the past decade, therapy with monoclonal antibodies (mAbs)
has revolutionized the therapeutic paradigms of immune diseases
such as rheumatoid arthritis (RA), psoriasis, and the inflammatory bowel diseases (IBDs)—Crohn’s disease (CD) and ulcerative
colitis (UC). The process for generating hybridomas, discovered
by Köhler and Milstein in 1975, allowed for the production and
isolation of mAbs as therapeutic agents.1 Early therapeutic mAbs
were murine, and their use in clinical practice was limited because
of immunogenicity. Subsequently, modern genetic engineering
techniques led to the development of humanized and fully human
mAbs. Although, in general, humanized and fully human mAbs
are less immunogenic as compared with murine antibodies, they
also can induce antidrug antibody (ADA) formation.
Infliximab, the first mAb used for treatment of patients with
CD,2 was approved by the US Food and Drug Administration
for that indication in 1998. The rapid adoption of infliximab into
clinical practice, and its high level of efficacy in patients with CD
unresponsive to conventional therapies, led to great interest in
the development of additional mAbs to block tumor necrosis
factor (TNF) activity and other proinflammatory cytokines that
play key roles in the activation and perpetuation of the inflammatory response in patients with IBD.
Even though mAbs have been used in clinical practice for
more than a decade, little is known about their exposure–response relationship and the factors that may affect their disposition. Understanding these factors is essential to further
improving the therapeutic efficacy of these drugs.
This review evaluates the factors known to influence the pharmacokinetics (PK) of the currently approved mAbs for the treatment of IBD—infliximab, adalimumab, and certolizumab—and
speculates on the future role of therapeutic drug monitoring and
the role of individualized dosing for these agents.
Monoclonal Antibodies
Structure
mAbs are engineered immunoglobulin G (IgG) therapeutic
proteins. IgG molecules are constructed by a basic unit of four
polypeptide chains including two identical heavy chains (CH)
and two identical light chains (CL). Each antibody comprises two
domains: (i) the variable region or Fab (antigen-binding region),
which is specific for the antigen target (each antibody has two
Fabs), and (ii) the constant region or the Fc (Figure 1).3
Depending on their structure or isotype, mAbs can be classified as murine antibodies (suffix nomenclature: -omab;
1Division of Gastroenterology, University of California San Diego, La Jolla, California, USA; 2Gastroenterology Department, Hospital Clinic of Barcelona, CIBER-EHD,
IDIBAPS, University of Barcelona, Barcelona, Spain; 3Projections Research Inc., Phoenixville, Pennsylvania, USA; 4Robarts Research Institute, University of Western
Ontario, London, Ontario, Canada. Correspondence: WJ Sandborn ([email protected])
Received 4 October 2011; accepted 16 November 2011; advance online publication 22 February 2012. doi:10.1038/clpt.2011.328
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VH
VL
CH1
S
S
S
Fab
S
S
S
S
S
CL
CH2
CH
Fc
CH3
Figure 1 General structure of IgG antibodies. Each antibody is composed
of two identical heavy chains (CH) and two identical light chains (CL). The
light chain contains two domains: one variable (VL) and one constant
(CL). The heavy chain is composed of a variable domain (VH) and three
constant domains (CH1, CH2, and CH3). The antigen-binding region (Fab)
includes VH, VL, CL, and CH1, and the constant region (Fc) includes CH2
and CH3. -S-S-, disulfide bond.
e.g., tositumomab), chimeric (-ximab; e.g., infliximab), humanized (-zumab; e.g., certolizumab), or “fully human” (-umab; e.g.,
adalimumab) (Supplementary Figure S1 online).
Infliximab is a chimeric IgG1 mAb composed of a variable
murine Fab region linked by disulfide bonds to a human IgG1
κ constant region.4 Infliximab is produced by cell culture using
Chinese hamster ovary cells. Adalimumab is also a recombinant IgG1 mAb, but, unlike infliximab, it is fully human. It
is composed of human-derived variable regions (Fabs) and a
human IgG1 κ constant region.5 Adalimumab is produced by
cell culture using Chinese hamster ovary cells. Certolizumab
pegol, a pegylated humanized mAb, is composed of an IgG4
isotype Fab fragment chemically linked to a polyethylene glycol
moiety, which slows clearance, thereby increasing the half-life
of the drug.6 Certolizumab is produced by cell culture using
Escherichia coli.
Mechanism of action and therapeutic target
Improved understanding of the pathogenesis of RA, psoriasis,
and IBD at the cellular and molecular level led to the development of biological agents targeting TNF-α, a potent proinflammatory cytokine that plays a key role in orchestrating the
inflammatory process in multiple autoimmune diseases. IBD
is characterized by a dysregulated mucosal immune response
toward the commensal enteric flora in genetically susceptible
individuals.7 This immune dysregulation results in an overproduction of TNF-α by monocytes, macrophages, and T cells.8
Interestingly, mAbs targeting TNF-α (infliximab, adalimumab,
and certolizumab) induce the formation of regulatory macrophages with immunosuppressive properties. This population
2
of macrophages inhibits proliferation of activated T cells and
produces anti-inflammatory cytokines.9
TNF-α can be detected in serum in its soluble form or expressed
as a cell-surface polypeptide on activated macrophages, monocytes, and T cells in its transmembrane form.
Overall, infliximab, adalimumab, and certolizumab have similar intrinsic binding properties and affinities for both soluble
and transmembrane forms of TNF-α.10 Infliximab and adalimumab also have similar ability to mediate complement-dependent
cytotoxicity and antibody-dependent cell-mediated cytotoxicity.
By contrast, certolizumab, because of the absence of the IgG1
Fc portion, exhibits neither complement-dependent cytotoxicity nor antibody-dependent cell-mediated cytotoxicity.10 The
CH2 and CH3 domains of the IgG1 Fc portion are involved in
the binding to Fc receptors of natural killer cells, which leads to
the lysis of target cells. Therefore, unlike infliximab and adalimumab, certolizumab does not induce apoptosis of activated
immune cells.
Mechanisms of absorption, distribution, degradation, and
elimination
Absorption. The majority of approved mAbs are administered
intravenously; however, some of these agents are designed
for extravascular administration, either subcutaneous (s.c.)
or intramuscular. Infliximab is administered intravenously,
whereas adalimumab and certolizumab are administered by
s.c. injection. In general, the route of administration of mAbs
affects their pharmacokinetic behavior. Intravenous therapy
allows administration of large volumes of drug, achieves immediate central distribution, results in less variability in drug
exposure between subjects, and is usually less immunogenic.
The mechanism of absorption after s.c. administration is not
fully understood but is likely to occur by means of lymphatic
drainage. The main drawbacks of s.c. administration are that a
smaller volume must be administered (generally no more than
1 ml), in comparison with the intravenous route, and the fraction of dose absorbed is variable, which leads to higher pharmacokinetic variability between patients and doses. Reported
bioavailability of mAbs administered subcutaneously is
highly variable among individual patients, ranging from 50 to
100%.11 In addition, the s.c. route is often more immunogenic
than the intravenous route because the skin is highly specialized for processing foreign antigens. After s.c. injection, mAbs
undergo slow absorption, with maximum concentrations being
achieved 8 to 10 days after administration.
Distribution. After administration, mAbs distribute mainly
within the central compartment (extracellular fluid), whereas
penetration inside cells is limited because of their high molecular weight and hydrophilicity. mAbs seem to have a volume of
distribution on the order of 0.1 l/kg, approximately equal to the
extracellular fluid volume.12 For example, the volume of distribution of infliximab at steady state ranges from 4.5 to 6 l.13
Because of the relatively large loading doses and the intravenous route of administration, infliximab yields acute concentration–time profiles with very high peak concentrations
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and low trough levels and, hence, high peak-to-trough ratios
(Figure 2).14,15 By contrast, adalimumab and certolizumab,
given their slow absorption and elimination rates, exhibit more
uniform concentration–time profiles at steady state.16 The pharmacokinetic properties of infliximab, adalimumab, and certolizumab are shown in Table 1.
a
Infliximab concentration (µg/ml)
1,000
100
10
Degradation and elimination. Although the exact mechanisms
1
0.1
0
100
200
300
400
Time (days)
b
Infliximab concentration (µg/ml)
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1,000
100
10
1
0.1
0
100
200
300
400
Time (days)
Model predicted infliximab concentration
Observed infliximab concentration
Figure 2 Concentration vs. time curves of infliximab in (a) ulcerative colitis
(UC) and (b) Crohn’s disease (CD). Observed (dots) and simulated (lines)
median concentration–time profiles of patients with UC (data from ACT
trials) and CD (data from ACCENT I trial). Patients received treatment with
infliximab 5 mg/kg at weeks 0, 2, and 6 and every 8 weeks thereafter. The
serum infliximab concentrations are higher at early time points in the graph,
corresponding with the induction phase of treatment (loading doses). After
14 weeks (100 days), infliximab serum concentrations tend to stabilize.
ACCENT I, A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New, ­Longterm Treatment Regimen; ACT, Active Ulcerative Colitis Trial. Adapted with
permission from refs. 14 and 15.
by which mAbs are cleared from the circulation is not well
understood, the primary route of antibody clearance is via
proteolytic catabolism after receptor-mediated endocytosis in
the cells of the reticuloendothelial system (RES).17 Antibody
salvage and recirculation is mediated by the Brambell receptor (FcRn), which is essential for maintaining immunoglobulin and albumin homeostasis.18 In adults, FcRn is primarily
expressed in the vascular endothelial cells or the RES and at
lower levels on monocyte cell surfaces, tissue macrophages,
and dendritic cells.19 This Fc receptor plays a critical role in
protecting IgG antibodies and albumin from the ongoing catabolic activities, thus prolonging their half-lives.20 However,
this system is saturable at high IgG concentrations, resulting
in an inverse relationship between concentration and halflife (the higher the concentration of the antibody, the lower
its half-life).21 Thus, one would anticipate that high levels of
endogenous IgG, as is seen in chronic inflammatory diseases,
could potentially shorten the half-life of exogenously administered mAbs.
In addition to FcRn, three other classes of Fc receptors
(FcγRI, FcγII, and FcγIII) for IgG binding have been identified
in humans.22 These receptors are expressed by macrophages,
natural killer cells, B and T cells, and platelets. Fc gamma receptor (FcγR) polymorphisms have been associated with clinical
response to TNF antagonists in patients with IBD.23 Whether
FcγRs polymorphisms may contribute to clearance of TNF
antagonists needs further investigation.
FcRn binds to IgG with pH-dependent affinity.24 Antibodies
bind tightly to FcRn inside endosomes, which have an acidic
environment. Inside endolysosomes, the IgG–FcRn complexes
do not undergo catabolism, whereas the antibody bound to FcγR
is degraded. Eventually, the antibody bound to FcRn is returned
Table 1 Pharmacokinetic properties of infliximab, adalimumab, and certolizumab
Infliximab
CD
UC
Adalimumab
Certolizumab
CDa 70
UC
CD71
UC
Cmax
118 µg/ml
4.7 ± 1.6 µg/ml
N/A
43–49 µg/ml
N/A
T1/2
7.7–9.5 days72
10–20 days
N/A
14 days
N/A
Tmax
Within an hour
2.25–7.12 days
Vd
4.5–6 liters
4.5–6 liters
V1
52.4 ml/kg15
3.29 liters14
V2
19.6 ml/kg15
4.13 liters14
Cl
5.42 ml/kg/d15
(15.8 ml/h)b
0.4 liters/d14 (16.7 ml/h)
5.46 ± 2.3 days
N/A
4.7–6 liters
N/A
12 ml/h
N/A
N/A
N/A
17 ml/h
N/A
CD, Crohn’s disease; Cl, clearance; Cmax, maximum concentration; N/A, not available; T1/2, half-life; Tmax, time to reach maximum plasma concentration; UC, ulcerative colitis;
V1, volume of distribution in the central compartment; V2, volume of distribution in the peripheral compartment.
aFollowing a single 40-mg s.c. administration to healthy adult subjects. bAssuming a mean body weight of 70 kg.
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5. Cell surface (pH 7.4)
Antibody is released from
FcRn back into circulation
Antibody
1. mAb uptake via FcRn
and FcγR interaction
FcRn
2. Endosome formation (pH 6)
FcγR
4. Antibody bound to
FcRn is returned to
cell surface
3. Antibody bound to FcγR is degraded
and antibody bound to FcRn protected
Figure 3 Mechanism of degradation of monoclonal antibodies. FcgR, Fc gamma receptor; FcRn, Brambell receptor. Adapted with permission from ref. 54.
to the cell surface where, at physiologic pH, it dissociates from
the receptor and is released again back into the circulation
(Figure 3).
It has been shown that in mice genetically lacking expression of FcRn, IgG follows hypercatabolism and thus accelerated
clearance.25 These results support the importance of FcRn in
regulating the catabolism of antibodies and therefore their pharmacokinetic behavior. In addition, IgG affinity for FcRn is species-specific. Human FcRn shows high affinity for human IgG,
whereas the human receptor shows little affinity for IgG derived
from most other species, including mice. This observation helps
to explain the higher clearance that murine mAbs experience in
humans.26 Thus, the structure of mAbs influences their pharmacokinetic behavior; the Fc region is responsible for the prolonged half-life of IgG antibodies through its binding to FcRn.
Fc conjugation is a common method used to extend the half-life
of mAbs by decreasing their clearance through improvement
of FcRn binding. As expected, the half-life of mAbs generally
increases with their level of humanization. Murine antibodies
display a short half-life (1–2 days); chimeric antibodies have a
half-life of approximately 10 to 14 days, and humanized and fully
human antibodies exhibit longer half-lives of approximately 10
to 20 days.27
PEGylation is another modification that has been used to
increase the half-life of mAbs that do not have a functional Fc
region. The addition of polyethylene glycol to mAbs structurally
protects them from proteolytic breakdown and immunologic
4
recognition, thus decreasing the likelihood of neutralizing antibody formation.
Clearance of mAbs can be either linear or nonlinear. Generally,
mAbs targeting cell-surface receptors tend to exhibit nonlinear
clearance that is dependent on antigen expression, whereas
mAbs directed against soluble antigens (e.g., cytokines) typically
exhibit dose-proportional behavior with linear clearance, which
is often affected by body weight.28 However, it should be noted
that the relationship between mAb clearance and body weight
is generally less than linear, suggesting that mg/kg dosing may
lead to patient exposure that is below the target range in patients
with low body weight. There is some suggestion, however, that
the clearance of mAbs targeting soluble receptors may be influenced by receptor expression as well.28
The contribution of receptor-mediated clearance to overall
clearance depends on several factors such as mAb concentration and distribution together with target receptor expression,
internalization, and turnover rates. In some cases, cell-surface
receptors are released into the serum, circulating as free antigens. mAbs can bind to these shed receptors, resulting in the
formation of antibody–antigen complexes that may result in an
accelerated mAb clearance.12
Overview of Ibd Treatment with Mabs
CD and UC, the two main forms of IBD, are chronic diseases
that result from immune dysregulation in genetically susceptible individuals.7 Because the specific cause of CD and UC is
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unknown, they have conventionally been treated using a broad
spectrum of anti-inflammatory agents, including aminosalicylates, corticosteroids, and standard immunosuppressive agents
such as purine analogs (azathioprine and 6-mercaptopurine),
methotrexate, and cyclosporine.29 However, a high proportion
of patients fail to respond to these therapies and require biological treatment with TNF antagonists (mAbs). TNF antagonists
have shown clear benefits in randomized controlled trials for
inducing and maintaining clinical remission in both CD and
UC.30–35 However, despite their therapeutic efficacy, more than
one-third of patients show no response to induction therapy
(primary nonresponders), and in up to 50% of responders, TNF
antagonist therapy becomes ineffective over time (secondary
nonresponders).36 Thus, a critical need exists to develop new
approaches and strategies that further optimize the efficacy of
these drugs.
In recent years, interest in the mechanistic causes of TNF
antagonist treatment failure has intensified. It is now well
established that patients lacking objective evidence of inflammation, such as presence of ulcers at the endoscopic examination or increased serum C-reactive protein concentrations,
do not benefit from treatment with TNF antagonists. 37,38
Furthermore, symptoms usually do not correlate well with
the presence of mucosal lesions or with elevated biomarkers
of inflammation.39,40 Hence, when loss of response to TNF
antagonists occurs, dose intensification or switching between
mAbs based exclusively on symptoms will frequently lead
to incorrect therapeutic decisions and should be avoided.
Instead, before making any decision, patients with suspected
active inflammation based on symptoms should undergo
endoscopic or radiologic evaluation to ensure that they exhibit
objective evidence of inflammation that could potentially benefit from dose intensification. A therapeutic algorithm for the
treatment of patients with moderate and severe IBD is shown
in Supplementary Figure S2 online. The structural characteristics and dosage of mAbs for the treatment of IBD are
detailed in Table 2.
The development of immunogenicity due to inappropriate administration strategies (episodic administration rather
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than scheduled administration and monotherapy instead of
­combined therapy with an immunosuppressive) is a common
cause of treatment failure.
The optimal strategies to minimize the risk of immunogenicity and the potential benefits of tailoring therapy based on the
determination of serum drug concentrations and the presence
or absence of neutralizing ADAs are examined below.
Strategies to minimize the risk of immunogenicity
The development of immunogenicity is an important determinant of both the efficacy and safety of TNF antagonists. As discussed above, a high proportion of patients who initially respond
to mAbs lose response over time, owing, in part, to development
of ADAs.41–43
Two therapeutic strategies have been associated with a reduction in ADA formation: (i) use of TNF antagonists in a scheduled
maintenance regimen rather than episodic administration and
(ii) concomitant use of immunosuppressive agents (azathioprine,
mercaptopurine, or methotrexate) with a TNF antagonist.
Scheduled vs. episodic treatment. Episodic infliximab treatment
strategy in patients with CD has been associated with a higher
rate of antibody formation and a higher rate of infusion reactions as compared with scheduled maintenance therapy.44
Infusion reactions to infliximab are strongly associated with
the presence of ADAs. Intravenous hydrocortisone premedication reduces the formation of ADAs but does not eliminate the
risk of infusion reactions.45 The best strategy to minimize this
risk is to administer infliximab on a scheduled basis and to use
concomitant immunosuppressive therapy.
In addition, detectable trough infliximab concentrations,
which are associated with better outcomes, are higher in patients
undergoing a regularly scheduled treatment strategy.44 Therefore,
the optimal strategy to reduce the risk of ADAs to infliximab is to
use an induction dosing regimen (5 mg/kg intravenously at weeks
0, 2, and 6) followed by a maintenance strategy every 8 weeks
rather than episodic therapy. With adalimumab, episodic administration has been associated with inferior clinical outcomes, but
data regarding immunogenicity have not been obtained.33 With
Table 2 Characteristics and dosage of mAbs for inflammatory bowel disease
Natalizumab73
Ustekinumab74
Golimumab75
CD MS
Psoriasis Phase II/III
studies for CD
RA PsA AS Phase
II/III studies for UC
Humanized
Humanized IgG4
pegylated Fab IgG4
Human IgG1 κ
Human IgG1 κ
TNF-α
TNF-α
α4 integrin
IL-12/23 (p40 subunit)
TNF-α
5 mg/kg 0-2-6 and
every 8 wk
160-80-40 mg/2 wk
and 40 mg eow
400 mg 0-2-4 wk
and every 4 wk
300 mg every 4 wk
50 mg monthly
45 mg at baseline,
4 wk after, and every
12 wk thereafter (90 mg
if weight >100 kg)
Administration route
i.v.
s.c.
s.c.
i.v.
s.c.
s.c.
Brand name
Remicade
Humira
Cimzia
Tysabri
Stelara
Simponi
Infliximab
Adalimumab
Certolizumab
Approved indications
CD UC RA PsA AS
CD UC RA PsA AS JRA CD RA
Psoriasis
Structure
Chimeric IgG1 κ
Human IgG1 κ
Therapeutic target
TNF-α
Dosage in IBD
AS, ankylosing spondylitis; CD, Crohn’s disease; eow, every other week; Fab, antigen-binding region; IBD, inflammatory bowel disease; IgG, immunoglobulin G; IL, interleukin; i.v.,
intravenous; JRA, juvenile rheumatoid arthritis; mAbs, monoclonal antibodies; MS, multiple sclerosis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; s.c., subcutaneous; TNF-α,
tumor necrosis factor–α; UC, ulcerative colitis; wk, weeks.
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certolizumab, episodic treatment strategy in patients with CD
has been associated with a higher rate of antibody formation as
compared with scheduled maintenance therapy.32
Combined therapy vs. monotherapy. Combination therapy with
TNF antagonists and immunosuppressive agents has been
shown to reduce the risk of ADA formation in patients with
CD using episodic or scheduled treatment strategy; the magnitude of reduction is amplified when the TNF antagonist is
administered following a scheduled strategy.37,41,46,47 Baert
et al. showed that the rate of ADA formation in patients with
refractory CD treated with infliximab episodically was significantly lower in those receiving concomitant immunosuppressive therapy as compared with those who were not taking
these agents (43% vs.75%, respectively; P < 0.01).41 Vermeire
et al. reproduced those results in a prospective cohort study
evaluating the effectiveness of concomitant immunosuppressive therapy in suppressing the formation of ADAs in patients
with CD treated with infliximab in an on-demand schedule.
Concomitant use of azathioprine or methotrexate was associated with a lower incidence of ADAs as compared with patients
not taking immunosuppressive agents (46% vs. 73%, respectively; P < 0.001). No difference was found between azathioprine (48%) and methotrexate (44%) in reducing this risk.46
Hanauer et al. demonstrated that concomitant use of immunosuppressives in patients receiving infliximab in a scheduled
strategy significantly reduces the risk of immunogenicity as
compared with patients receiving infliximab monotherapy
(10% vs. 18%, respectively; P = 0.02).47 The SONIC trial—in
which patients with CD who were naive to immunosuppressive and TNF antagonist therapy were randomized to receive
azathioprine or infliximab or a combination of both—demonstrated that the rate of ADA formation was significantly lower
in the subgroup of patients receiving combination therapy
(0.9%) as compared with patients receiving infliximab monotherapy (14.6%).37 Feagan et al. also demonstrated that the
use of concomitant methotrexate with infliximab in patients
with CD significantly reduces the rate of ADA formation (4%
in patients receiving combined therapy vs. 20.4% in patients
treated with infliximab monotherapy—following a scheduled
strategy).48
Adalimumab and certolizumab can also induce the formation
of neutralizing antibodies.32,42,49 Similarly to infliximab, this risk
is also decreased when these mAbs are given concomitantly with
immunosuppressives and administered as a scheduled maintenance regimen.32,49 In patients with UC, combined immunosuppression with azathioprine and infliximab also reduces ADA
formation and increases infliximab trough concentrations.31,50,51
It is therefore clear that concomitant use of immunosuppressive
agents with a TNF antagonist reduces the risk of ADA development in patients with CD and UC.
In terms of efficacy, it has recently been shown that combined therapy with infliximab and azathioprine is more efficacious than either drug alone for induction of clinical remission
and mucosal healing in both CD and UC.37,51 It is likely that, at
least in part, this increased efficacy is due to lower rates of ADA
6
formation and higher infliximab drug concentrations among
patients receiving combined therapy.
Therapeutic monitoring: determination of trough concentrations and ADAs
Loss of response to TNF antagonists, mainly due to development
of neutralizing ADAs and subtherapeutic drug concentrations, is
a challenging problem in the management of patients with IBD.
Emerging data indicate that a strong relationship exists between
serum drug concentrations (PK) and efficacy (pharmacodynamics, PD). Studies conducted in both RA and IBD have shown
that patients with higher trough drug concentrations achieve
superior outcomes.43,44,52 This observation holds out the possibility that therapeutic drug monitoring may direct dose adjustment and clinical decision making. Infliximab concentrations
≥12 µg/ml 4 weeks after infusion or >1.4 µg/ml at dosing trough
are considered to be predictive of therapeutic response.41 These
cutoff values are based on a study in which patients were treated
using infliximab episodically rather than on a scheduled basis
and have not been prospectively validated. In a retrospective
study, Afif et al. evaluated the clinical utility of measuring ADAs
and trough drug concentrations in patients with loss of response
to infliximab.53 In patients with antibodies against infliximab,
switching to another TNF antagonist was associated with a complete or partial response in a very high proportion of patients
(92%), whereas increasing infliximab dose had a response in
only 17% of patients. Conversely, dose escalation in patients
with subtherapeutic infliximab concentrations was associated
with clinical response in 86% of patients, whereas the rate of
clinical response in patients changing to another TNF antagonist
agent was 33%. Therefore, increasing the dose of infliximab in
patients who have developed ADAs is ineffective. Accordingly,
measurement of ADAs and trough drug concentrations in
patients with loss of response is potentially a clinically useful
strategy (Supplementary Figure S2 online). Nevertheless, the
added value of tailoring TNF antagonist maintenance therapy
in individual patients based on trough drug concentrations and
the presence or absence of ADAs deserves further evaluation by
prospective studies.
Factors Affecting the Pk and Pd of Mabs
The pharmacology of therapeutic mAbs is complex and depends
not only on the structure of the antibody but also on the properties of the target antigen and on patient- and disease-related
factors. To date, only limited information exists regarding the
factors, other than the formation of neutralizing antibodies, that
influence the PK of mAbs. Identification of factors that influence
disposition and elimination of mAbs is essential to understanding their PK–PD relationship.
PK is a branch of pharmacology dedicated to study the mechanisms of absorption, distribution, metabolism, and elimination
of an administered drug (i.e., what the body does to the drug),
whereas PD studies the relationship between drug exposure and
therapeutic effect (i.e., what the drug does to the body). PK and
PD are interrelated. PK–PD analyses play an important role during drug development and are critical to select the appropriate
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dose regimens.54 Furthermore, PK–PD modeling analyses are
essential to understanding the relationship between drug concentration (PK) and therapeutic response (PD). PK–PD modeling is a valuable tool in drug research and development for
several reasons: (i) it may help to reduce the number of unnecessary and unproductive studies, (ii) it may help generate pivotal
decision-making algorithms (e.g., dose optimization), (iii) it
may help to improve the overall drug safety and efficacy, and (iv)
it may lead to savings in time and money.55 PK–PD modeling
has evolved rapidly over the past decade, but unfortunately no
formal prospective studies evaluating the PK–PD relationship
of mAbs in patients with IBD have been conducted.
Serum mAb concentrations have been shown to be highly
variable between individuals and differ over time even within
an individual patient. The differences in the observed concentration–time profiles and the exposure characteristics among
mAbs can be explained by different molecular properties (such
as structure, physiology of the therapeutic target, and clearance mechanisms), differences in the dosage or administration
regimens (e.g., route of administration and administration frequency), and patient and disease characteristics. These factors
are discussed below.
Population PK studies seek to identify the factors that influence changes in the relationship between the administered dose
and the achieved serum concentrations. Hence, if therapeutic
concentrations are not reached, dosage can be appropriately
modified according to these factors. Unfortunately, several
uncertainties regarding the pharmacokinetic profile of mAbs
persist. Specifically, the covariates that may influence drug clearance are not well defined.
Considering trough serum drug concentrations as a surrogate
for pharmacokinetic analysis may be misleading and related to
errors. Estimates from nontrough PK observations are more
robust, providing more information on the disposition of the
drug, and are thus preferred for PK–PD modeling studies.
Population PK models, using random variables with mean and
variance parameters instead of an individual data analysis, help
to identify and quantify the sources of variability through the
identification of covariates on each pharmacokinetic parameter.
In addition, population PK analyses supported by large data
sets with sparse sampling yield good-quality pharmacokinetic
parameter estimates and can be better extrapolated to the target patient population as compared with the values obtained
from studies involving single-dose administrations and a small
number of subjects because the results obtained from population
PK analyses reflect information from a wide range of patients
undergoing treatment at multiple clinical centers. Therefore,
PK modeling studies using intensive blood sampling instead
of measuring only trough drug concentrations, together with
evaluation of several patient and disease covariates, are more
accurate and yield more information on the sources of betweenpatient variability in mAb exposure.
Although therapeutic mAbs have been commercially available
for two decades, little is known about their PK–PD relationship.
Conventional wisdom implicates neutralizing ADAs as a primary cause of therapeutic failure. However, although ADAs can
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Table 3 Factors affecting the pharmacokinetics of monoclonal
antibodies
Impact on pharmacokinetics
Presence of ADAs
Decreases serum (mAbs)
Threefold-increased clearance
Worse clinical outcomes
Concomitant use of IS
Reduces ADA formation
Increases serum (mAbs)
Decreases mAbs clearance
Better clinical outcomes
High baseline (TNF-α)
May decrease (mAbs) by increasing
clearance
Low albumin
Increases clearance
Worse clinical outcomes
High baseline CRP
Increases clearance
Body size
High body mass index may increase
clearance
Gender
Males have higher clearance
ADA, antidrug antibody; CRP, C-reactive protein; IS, immunosuppressive agent; mAb,
monoclonal antibody; TNF-α, tumor necrosis factor-α. Terms in parentheses refer to
serum concentration.
profoundly affect drug clearance, resulting in low or nonmeasurable trough drug concentrations and loss of response, other
factors that affect the PK of TNF antagonists exist, including concomitant use of immunosuppressives, serum albumin concentration, body weight, the degree of systemic inflammation (e.g.,
serum albumin concentration and TNF burden), and disease type
(e.g., CD vs. UC). Collectively, these factors probably account for
the large interindividual differences in PK and clinical efficacy
observed after standard dosing of mAbs (Table 3).
Determinants of the PK–PD of mAbs: challenges in interpreting the literature
It should be noted that, to date, the majority of publications
evaluating the relationship between the PK and PD of mAbs
have been compromised by the following problems: (i) retrospective study designs that are not optimally designed to identify
relevant PK–PD relationships; (ii) failure to accurately sample
serum at the time of treatment failure/success; (iii) failure to perform pharmacokinetic sampling at informative times, thus limiting analytical power (peak and concentrations measured during
the beta decline phase are more informative of drug clearance
than trough samples); (iv) use of ADA assays that cannot detect
ADAs in the presence of circulating drug; (v) use of inappropriate statistical methods (“as observed” analyses do not adequately
account for patients who withdraw from treatment prematurely
and who are therefore more likely to have measurable ADAs and
low serum drug concentrations; intent-to-treat evaluations suffer from other issues);56 (vi) failure to account analytically for
the effects of confounders; (vii) inclusion of patients without
evidence of active inflammation, thus reducing statistical power;
and (viii) failure to use objective PD end points (the majority
of studies have used symptoms instead of objective findings of
inflammation).
Factors that may influence the PK and hence the PD of mAbs
in patients with IBD are reviewed below.
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Role of ADAs. Immunogenicity is a major issue related to thera-
peutic efficacy of mAbs. Development of ADAs can affect
the safety profile of these drugs because of hypersensitivity
­reactions. mAbs are exogenous proteins and can therefore
induce an immune response leading to the production of
endogenous ADAs, which in turn leads to a reduced therapeutic efficacy of the drug. Depending on the structure of mAbs,
ADAs can be classified as human antimouse antibodies, human
antichimeric antibodies, or human antihuman antibodies.
Theoretically, immunogenicity decreases with the degree of
humanization. Although infliximab, because of its chimeric
structure, is theoretically more immunogenic than adalimumab and certolizumab, data from clinical trials evaluating the
efficacy of these mAbs in patients with IBD confirm that both
adalimumab and certolizumab can also induce immunogenicity and that the degree of immunogenicity seems to be relatively similar to that seen with infliximab.32,42,49,57
Development of ADAs results in the formation of immune
complexes that accelerate drug clearance by the RES and/or
impaired binding to target.
If the drug–antibody complex is inactive (“neutralizing antibody”)
and if the antibody binding capacity is similar to the total concentration of the therapeutic protein, decreased efficacy may ensue
as a result of a decline in free concentrations of the active agent.
Alternatively, if the drug–antibody complex is active, enhanced bioactivity may result.55 In some cases, the drug–antibody complex
will be cleared (“clearing antibody”), which provides an alternative
clearance pathway for the therapeutic protein, decreasing total and
free concentrations and leading to decreased bioactivity.
Therefore, immunogenicity usually impacts clinical response
to therapy in a negative manner by affecting bioavailability, PK,
and PD.58 However, this topic has been controversial because
of methodological challenges. The majority of published data
evaluating the influence of ADAs on the pharmacokinetic
properties of mAbs are based on solid-phase enzyme-linked
immunosorbent assays in which the presence of circulating
drug renders the test insensitive in detecting ADAs. In addition, solid-phase enzyme-linked immunosorbent assay are
associated with false-positive results due to nonspecific binding
to immunoglobulins other than infliximab. However, highly
sensitive liquid-phase mobility-shift assays and liquid-phase
radioimmunoassays that measure ADAs in the presence of circulating drug are emerging, which should provide more accurate evaluation of the rate and intensity of sensitization early in
the course of treatment with mAbs. This advance highlights the
potential of therapeutic drug monitoring to direct interventions, such as dose intensification or immunosuppression, that
may prevent primary and secondary loss of response.
Several studies have consistently linked the presence of ADAs
to inferior outcomes.37,41,42 Baert et al. showed that the presence
of a high titer of ADAs in patients with CD was associated with
a reduced duration of response in comparison with nonsensitized patients (35 days vs. 71 days, respectively; P < 0.001).41
Similarly, the formation of ADAs in patients with CD has been
associated with lower rates of prednisone-free clinical remission (57.1% (prednisone-free clinical remission in patients with
8
positive ADAs) vs. 70.6% (prednisone-free clinical remission in
patients with negative ADAs), respectively).37
Role of concomitant immunosuppressive therapy. Although the
mechanism by which immunosuppressives (azathioprine, mercaptopurine, and methotrexate) increase the concentration of
serum mAbs is not well established, they are likely to exert this
function by reducing the formation of ADAs and/or downregulating RES-mediated drug clearance. In some cases, immunosuppressives downregulate receptors for mAbs, which also slows
the clearance of mAbs. Because of the methodological problems
previously described, the role of concomitant immunosuppressive therapy as a determinant of the PK of mAbs is poorly
understood. Post hoc analysis of four randomized controlled
trials showed that concomitant use of immunosuppressives
with ­infliximab was associated with higher serum infliximab
concentrations.50 In the SONIC trial, patients with active CD
who received combination therapy (infliximab plus azathioprine) had higher trough infliximab concentrations than those
who received infliximab monotherapy (3.5 μg/ml vs. 1.6 μg/
ml, respectively; P < 0.001). These findings correlated with better outcomes in terms of higher corticosteroid-free remission
rates in the combination therapy arm.37 Although it is apparent
that coadministration of azathioprine decreased drug clearance
in the SONIC trial, the mechanisms responsible are unclear.
One likely mechanism is reduction of ADA formation (0.9%
in patients receiving combination therapy vs. 14.6% in patients
receiving infliximab monotherapy).
As mentioned above, coadministration of immunosuppressives with TNF antagonists increases serum drug concentrations
and decreases the formation of ADAs.41,46,47,50 In patients with
UC, however, factors other than immunosuppressive-mediated
clearance may have, quantitatively, the most critical effect in
determining the PK of infliximab, at least during the acute phase
of therapy.
Role of the RES and disease severity. Because of their high molecular
weight, mAbs do not undergo renal elimination or metabolism
by hepatic enzymes; rather, as previously described, ­proteolytic
catabolism within the cells of the RES is the primary route of
elimination.12 Disease severity may influence elimination of
mAbs through RES-mediated mechanisms. In regard to this
observation, it has been shown that patients with elevated
C-reactive protein and serum albumin ­concentrations below
the normal range have accelerated drug clearance.14,15,59 The
presence of systemic inflammation may therefore increase
mAbs catabolism in the RES. Unfortunately, there is no practical way to measure this phenomenon. However, generating data
for each mAb and disease using a range of covariates related
to the inflammatory burden of the disease could be an indirect
way to determine the degree of systemic ­inflammation required
before the PK of mAbs is substantially affected.
This assumption holds out the possibility that patients with
more severe inflammation may require higher than average drug
exposure for optimal results. This hypothesis may account for the
suboptimal infliximab concentrations that have been observed
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in patients with severe UC undergoing infliximab induction
therapy.43
As an additional route of mAb clearance, the intestinal clearance of IgG was investigated in patients with IBD (inactive and
active CD and UC) as well as in a control group. The authors
reported increases in intestinal clearance of monomeric IgG that
were closely related to the severity of the intestinal lesions.60
Role of the “antigen sink”. The antigen-dependent clearance pathway is often referred as an “antigen sink.”
It has been shown that receptor density (i.e., antigen targeted by
mAbs) clearly influences the PK of mAbs. Therefore, differences in
PK do exist with different indications, and, indeed, changes in PK
with patient response have been reported. In the case of gemtuzumab, an antibody targeting CD33-positive blast cells with chemotherapeutic properties in patients with acute myeloid leukemia,
serum concentrations and half-life increased after a second dose
as compared with the first dose of the drug. This observation was
attributed to a decreased clearance by CD33-positive blast cells
due to a reduced tumor burden after the first dose.61
One potential explanation for lack of response to TNF antagonists is incomplete suppression of TNF-α activity because of
insufficient serum drug concentrations to block the excess of
TNF. A high inflammatory burden at baseline is associated
with higher concentrations of TNF-α in both tissue and serum.
Patients with a higher degree of systemic inflammation may
therefore require, in a stoichiometric fashion, greater amounts
of drug to neutralize this excess of TNF-α. In turn, this could
result in lower mAb serum concentrations and less functional
available drug. In this paradigm, the higher the baseline TNF-α
concentration, the higher the dose of drug required to achieve a
pharmacodynamic response. In addition, baseline TNF-α serum
concentrations may predict the need of dose escalation in cases
of loss of response.62 Ainsworth et al. evaluated 33 patients with
CD treated with infliximab classified by response status (primary
nonresponse, secondary loss of response, and sustained response)
and found that patients who were primary nonresponders to
­infliximab had higher affinity to bind TNF-α in serum than
patients with secondary loss of response and had no antibodies against infliximab (Supplementary Figure S3 online). The
authors concluded that measurement of serum TNF-α binding
capacity in conjunction with ADAs may provide new insights
into the causes of treatment failure (sensitization vs. non-TNF
inflammatory pathway vs. inadequate drug concentration in the
absence of sensitization).63 Interestingly, not only can the measurement of serum TNF-α concentration be used as a surrogate
marker of the PK of mAbs but its measurement in colonic tissue
seems to also be useful for this purpose. Olsen et al. demonstrated
that the likelihood of inducing clinical or endoscopic remission
after induction therapy with infliximab in patients with UC was
inversely associated with pretreatment concentration of TNF-α
in colorectal mucosa.64 The clinical implication of this observation is that pretreatment values of colorectal TNF-α may be used,
together with other factors, as a surrogate marker to individualize
infliximab dosing regimen. Patients with higher pretreatment
TNF-α colonic concentration may require higher doses.
Clinical pharmacology & Therapeutics
art
Role of disease type: CD vs. UC. Potential pharmacokinetic differ-
ences between CD and UC exist that may or may not result
from differences between the previously discussed factors.
Infliximab clearance seems to be similar for CD, RA, and psoriasis. In distinction, potentially important pharmacokinetic
differences exist between CD and UC.43,44 Seow et al. demonstrated that patients with moderate UC had higher rates of
clinical response (70% vs. 41%; P = 0.004), clinical remission
(41% vs. 17%; P = 0.015), and endoscopic remission (26% vs.
4%; P = 0.046) than those with severe disease after infliximab
induction treatment. Undetectable trough infliximab concentrations were associated with less favorable outcomes.43 In
the study by Seow et al., the proportion of patients with nonmeasurable infliximab trough concentrations was higher than
that in a previous study performed by the same investigators
in patients with CD.44 One potential explanation of these findings is that patients with UC have a more rapid clearance of
infliximab than patients with CD. It is noteworthy that two
large-scale randomized con­trolled trials have shown relatively
low rates of remission with s.c. adalimumab induction therapy
in UC35,65 at doses that result in relatively high rates of remission in CD. In distinction, both intravenously administered
infliximab and subcutaneously administered adalimumab are
effective in CD.30,49 These findings raise the possibility that fundamental pharmacokinetic differences with important clinical
consequences may exist between the two diseases. One hypothesis that may account for these differences is that the overall
inflammatory burden in patients with severe and extensive
UC is higher than that in patients with CD owing to a greater
inflamed intestinal surface. This higher inflammatory burden
may result in higher production of TNF-α. Therefore, higher
doses of mAbs may be required to neutralize the excessive production of the target antigen. Alternatively, patients with UC
may have a greater area of the mucosal surface affected than is
observed in patients with CD, resulting in greater loss of drug
in the intestinal lumen. Although the concept of a “drug-losing
enteropathy” is entirely hypothetical, future pharmacokinetic
studies should explore this hypothesis.
Role of patient factors. It is worth noting that the influence of
weight on the clearance, and therefore area under the curve,
of mAbs is not linear. Hence, dosing based on weight does not
always produce drug exposure that is efficacious. Monitoring
of serum drug concentrations is consequently more important in patients with both low weight and high inflammatory
burden than in patients with higher weight and/or less inflammation. Gender has also been shown to independently influence the disposition of mAbs, with clearance being higher in
men.14,66 However, because weight and gender are generally
somewhat correlated (men weighing more than women), this
finding may be related to weight.
The clearance of mAbs is not affected by either renal or hepatic
dysfunction. However, an interesting association between baseline serum albumin concentrations and serum infliximab concentrations in both UC and CD has recently been reported.15,67
Patients with a baseline serum albumin concentration below the
9
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art
a
Base model
1.0
CL (ml/kg/d)
0.5
0.0
−0.5
−1.0
2.5
3.0
3.5
4.0
4.5
5.0
SAC (g/dl)
b
Base model
CL (ml/kg/d)
20
15
10
5
2
3
4
Conclusions and Future Directions
5
SAC (g/dl)
c
% Responders
80
60
P = 0.0021
P = 0.0001
P = 0.2236
40
20
0
Albumin level <3.5 ≥3.5
Placebo
(g/dl)
<3.5 ≥3.5
IFX-Treated
All albumin concentrations
Placebo IFX-Treated
Figure 4 Albumin as a predictive factor of infliximab clearance. Serum
albumin concentration (SAC) is inversely related to infliximab clearance (CL)
in both (a) ulcerative colitis (UC) and (b) Crohn’s disease. (c) Relationship
between serum album concentrations and clinical response rates in patients
with UC treated with infliximab (IFX) and placebo. Patients with serum
albumin concentration below the normal range achieved lower response
rates. Adapted with permission from refs. 15 and 67.
normal range (a common finding associated with severe inflammation) have lower remission rates after treatment with infliximab. This observation suggests that an inverse relationship exists
between serum albumin concentration and infliximab clearance
10
(the lower the albumin concentration, the higher the infliximab
clearance) (Figure 4).
Recently, a study of patients with RA treated with infliximab
has shown that a high body mass index negatively influences
clinical response.68 Research into the role of mesenteric fat in
chronic inflammatory diseases has intersected with investigation
into the importance of adipose tissue as a metabolically active
source of proinflammatory cytokines (e.g., TNF) in patients with
insulin resistance. It would be expected, therefore, that obese
patients with CD would inherently have higher TNF production than patients with normal weight, suggesting also that the
mg/ kg dose paradigm might be inappropriate for obese patients;
these patients may require higher drug doses than those currently recommended. This observation requires confirmation
in additional studies.
Accordingly, measurement of body mass index (and potentially quantitative assessment of mesenteric fat) should be
incorporated into future pharmacokinetic studies, especially
in patients with CD, in whom adipose tissue is involved in the
inflammatory process.69
In summary, preliminary evidence suggests that multiple factors influence the PK of mAbs. Understanding the determinants
of the PK of mAbs has great potential to improve and optimize
the therapeutic management of patients with IBD.
The use of anti-TNF mAbs in the treatment of IBD has led to
improved disease outcomes. However, further optimization is
needed because a high proportion of patients fail to respond
to these therapies. Monitoring serum drug concentrations and
ADAs (immunogenicity) may lead to more appropriate therapeutic management of patients with loss of response.
The PK of mAbs seems to be strongly influenced by several
factors related to patient and disease characteristics. Evaluation
of the covariates that influence the disposition of mAbs may
help in identifying patients who are more likely to benefit from
receiving higher doses as a result of accelerated drug clearance.
Unfortunately, studies integrating these variables into a single PK
model in targeted populations have not been performed yet.
The number of approved mAbs for the treatment of IBD is
expected to increase. Therefore, a better understanding of the
factors that impact the PK and PD of mAbs is crucial to ensure
more efficient dosing regimens, which in turn may enhance
the therapeutic success of these therapies. Combined clinical, imaging, and PK studies should lead to further advances
in customizing drug dosage and monitoring therapeutic
response. Finally, individualized and tailored dosing approaches
guided by PK algorithms may be safer, more effective, and even
­cost-effective.
SUPPLEMENTARY MATERIAL is linked to the online version of the paper at
http://www.nature.com/cpt
Conflict of Interest
The authors declare no financial or other conflict of interest in relation to
the content of this article. I.O. does not have any stocks, equity, a contract
of employment, or a named position on a company board in companies
www.nature.com/cpt
state
related to IBD; does not hold any relevant patents that are licensed; and
does not have any research support, lecture fees, or consultancies related to
IBD. D.R.M. has been a paid consultant for Centocor but does not own any
stock in this company. B.G.F. has received research support consulting and
lecture fees from Janssen (previously Centocor), Merck (previously Schering
Plough), Abbott Laboratories, and UCB Pharma. W.J.S. has received research
support and consulting fees from Janssen (previously Centocor), Merck
(previously Schering Plough), Abbott Laboratories, and UCB Pharma and has
received lecture fees from Janssen and Abbott Laboratories
© 2012 American Society for Clinical Pharmacology and Therapeutics
1. Köhler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody
of predefined specificity. Nature 256, 495–497 (1975).
2. Present, D.H. et al. Infliximab for the treatment of fistulas in patients with
Crohn’s disease. N. Engl. J. Med. 340, 1398–1405 (1999).
3. Edelman, G.M. Antibody structure and molecular immunology. Science 180,
830–840 (1973).
4. Knight, D.M. et al. Construction and initial characterization of a mouse-human
chimeric anti-TNF antibody. Mol. Immunol. 30, 1443–1453 (1993).
5. Salfeld, J. et al. Human antibodies that bind human TNFα. US patent 6090382
(2000).
6. Athwal D. et al. Biological products. US patent 7012135 (2006).
7. Xavier, R.J. & Podolsky, D.K. Unravelling the pathogenesis of inflammatory
bowel disease. Nature 448, 427–434 (2007).
8. Reinecker, H.C. et al. Enhanced secretion of tumour necrosis factor-alpha, IL-6,
and IL-1 beta by isolated lamina propria mononuclear cells from patients with
ulcerative colitis and Crohn’s disease. Clin. Exp. Immunol. 94, 174–181 (1993).
9. Vos, A.C., Wildenberg, M.E., Duijvestein, M., Verhaar, A.P., van den Brink, G.R. &
Hommes, D.W. Anti-tumor necrosis factor-a antibodies induce regulatory
macrophages in an Fc region-dependent manner. Gastroenterol. 140,
221–230 (2011).
10. Nesbitt, A. et al. Mechanism of action of certolizumab pegol (CDP870): in vitro
comparison with other anti-tumor necrosis factor alpha agents. Inflamm.
Bowel Dis. 13, 1323–1332 (2007).
11. Lobo, E.D., Hansen, R.J. & Balthasar, J.P. Antibody pharmacokinetics and
pharmacodynamics. J. Pharm. Sci. 93, 2645–2668 (2004).
12. Mould, D.R. & Green, B. Pharmacokinetics and pharmacodynamics of
monoclonal antibodies: concepts and lessons for drug development.
BioDrugs 24, 23–39 (2010).
13. Klotz, U., Teml, A. & Schwab, M. Clinical pharmacokinetics and use of
infliximab. Clin. Pharmacokinet. 46, 645–660 (2007).
14. Fasanmade, A.A. et al. Population pharmacokinetic analysis of infliximab in
patients with ulcerative colitis. Eur. J. Clin. Pharmacol. 65, 1211–1228 (2009).
15. Fasanmade, A.A., Adedokun, O.J., Blank, M., Zhou, H. & Davis, H.M.
Pharmacokinetic properties of infliximab in children and adults with Crohn’s
disease: a retrospective analysis of data from 2 phase III clinical trials. Clin. Ther.
33, 946–964 (2011).
16. Nestorov, I. Clinical pharmacokinetics of TNF antagonists: how do they differ?
Semin. Arthritis Rheum. 34, 12–18 (2005).
17. Wang, W., Wang, E.Q. & Balthasar, J.P. Monoclonal antibody pharmacokinetics
and pharmacodynamics. Clin. Pharmacol. Ther. 84, 548–558 (2008).
18. Brambell, F.W., Hemmings, W.A. & Morris, I.G. A theoretical model of gammaglobulin catabolism. Nature 203, 1352–1354 (1964).
19. Zhu, X. et al. MHC class I-related neonatal Fc receptor for IgG is functionally
expressed in monocytes, intestinal macrophages, and dendritic cells.
J. Immunol. 166, 3266–3276 (2001).
20. Telleman, P. & Junghans, R.P. The role of the Brambell receptor (FcRB) in liver:
protection of endocytosed immunoglobulin G (IgG) from catabolism in
hepatocytes rather than transport of IgG to bile. Immunol. 100, 245–251 (2000).
21. Morell, A., Terry, W.D. & Waldmann, T.A. Metabolic properties of IgG subclasses
in man. J. Clin. Invest. 49, 673–680 (1970).
22. Cohen-Solal, J.F., Cassard, L., Fridman, W.H. & Sautès-Fridman, C. Fc gamma
receptors. Immunol. Lett. 92, 199–205 (2004).
23. Louis, E. et al. Association between polymorphism in IgG Fc receptor IIIa
coding gene and biological response to infliximab in Crohn’s disease. Aliment.
Pharmacol. Ther. 19, 511–519 (2004).
24. Junghans, R.P. Finally! The Brambell receptor (FcRB). Mediator of transmission
of immunity and protection from catabolism for IgG. Immunol. Res. 16, 29–57
(1997).
25. Israel, E.J., Wilsker, D.F., Hayes, K.C., Schoenfeld, D. & Simister, N.E. Increased
clearance of IgG in mice that lack beta 2-microglobulin: possible protective
role of FcRn. Immunology 89, 573–578 (1996).
Clinical pharmacology & Therapeutics
art
26. Ober, R.J., Radu, C.G., Ghetie, V. & Ward, E.S. Differences in promiscuity for
antibody-FcRn interactions across species: implications for therapeutic
antibodies. Int. Immunol. 13, 1551–1559 (2001).
27. Ternant, D. & Paintaud, G. Pharmacokinetics and concentration-effect
relationships of therapeutic monoclonal antibodies and fusion proteins.
Expert Opin. Biol. Ther. 5 (suppl. 1), S37–S47 (2005).
28. Tabrizi, M.A., Tseng, C.M. & Roskos, L.K. Elimination mechanisms of therapeutic
monoclonal antibodies. Drug Discov. Today 11, 81–88 (2006).
29. Travis, S.P. et al.; European Crohn’s and Colitis Organisation. European
evidence based consensus on the diagnosis and management of Crohn’s
disease: current management. Gut 55 (suppl. 1), i16–i35 (2006).
30. Hanauer, S.B. et al.; ACCENT I Study Group. Maintenance infliximab for Crohn’s
disease: the ACCENT I randomised trial. Lancet 359, 1541–1549 (2002).
31. Rutgeerts, P. et al. Infliximab for induction and maintenance therapy for
ulcerative colitis. N. Engl. J. Med. 353, 2462–2476 (2005).
32. Schreiber, S. et al.; PRECISE 2 Study Investigators. Maintenance therapy
with certolizumab pegol for Crohn’s disease. N. Engl. J. Med. 357, 239–250
(2007).
33. Colombel, J.F. et al. Adalimumab for maintenance of clinical response and
remission in patients with Crohn’s disease: the CHARM trial. Gastroenterol.
132, 52–65 (2007).
34. Sandborn, W.J. et al.; PRECISE 1 Study Investigators. Certolizumab pegol for
the treatment of Crohn’s disease. N. Engl. J. Med. 357, 228–238 (2007).
35. Reinisch, W. et al. Adalimumab for induction of clinical remission in
moderately to severely active ulcerative colitis: results of a randomised
controlled trial. Gut 60, 780–787 (2011).
36. Peyrin-Biroulet, L., Deltenre, P., de Suray, N., Branche, J., Sandborn, W.J. &
Colombel, J.F. Efficacy and safety of tumor necrosis factor antagonists in
Crohn’s disease: meta-analysis of placebo-controlled trials. Clin. Gastroenterol.
Hepatol. 6, 644–653 (2008).
37. Colombel, J.F. et al.; SONIC Study Group. Infliximab, azathioprine, or
combination therapy for Crohn’s disease. N. Engl. J. Med. 362, 1383–1395
(2010).
38. Bruining, D.H. & Sandborn, W.J. Do not assume symptoms indicate failure
of anti-tumor necrosis factor therapy in Crohn’s disease. Clin. Gastroenterol.
Hepatol. 9, 395–399 (2011).
39. Modigliani, R. et al. Clinical, biological, and endoscopic picture of attacks of
Crohn’s disease. Evolution on prednisolone. Groupe d’Etude Thérapeutique
des Affections Inflammatoires Digestives. Gastroenterol. 98, 811–818
(1990).
40. Jones, J. et al. Relationships between disease activity and serum and fecal
biomarkers in patients with Crohn’s disease. Clin. Gastroenterol. Hepatol. 6,
1218–1224 (2008).
41. Baert, F. et al. Influence of immunogenicity on the long-term efficacy of
infliximab in Crohn’s disease. N. Engl. J. Med. 348, 601–608 (2003).
42. Karmiris, K. et al. Influence of trough serum levels and immunogenicity on
long-term outcome of adalimumab therapy in Crohn’s disease. Gastroenterol.
137, 1628–1640 (2009).
43. Seow, C.H., Newman, A., Irwin, S.P., Steinhart, A.H., Silverberg, M.S. &
Greenberg, G.R. Trough serum infliximab: a predictive factor of clinical
outcome for infliximab treatment in acute ulcerative colitis. Gut 59, 49–54
(2010).
44. Maser, E.A., Villela, R., Silverberg, M.S. & Greenberg, G.R. Association of trough
serum infliximab to clinical outcome after scheduled maintenance treatment
for Crohn’s disease. Clin. Gastroenterol. Hepatol. 4, 1248–1254 (2006).
45. Farrell, R.J., Alsahli, M., Jeen, Y.T., Falchuk, K.R., Peppercorn, M.A. & Michetti, P.
Intravenous hydrocortisone premedication reduces antibodies to infliximab
in Crohn’s disease: a randomized controlled trial. Gastroenterol. 124, 917–924
(2003).
46. Vermeire, S., Noman, M., Van Assche, G., Baert, F., D’Haens, G. & Rutgeerts, P.
Effectiveness of concomitant immunosuppressive therapy in suppressing the
formation of antibodies to infliximab in Crohn’s disease. Gut 56, 1226–1231
(2007).
47. Hanauer, S.B. et al. Incidence and importance of antibody responses to
infliximab after maintenance or episodic treatment in Crohn’s disease. Clin.
Gastroenterol. Hepatol. 2, 542–553 (2004).
48. Feagan, B.G. et al. Methotrexate for the prevention of antibodies to infliximab
in patients with Crohn´s disease (abstract S1051). Presented at Digestive
Disease Week, New Orleans, LA, 2 May 2010.
49. Sandborn, W.J. et al. Adalimumab for maintenance treatment of Crohn’s
disease: results of the CLASSIC II trial. Gut 56, 1232–1239 (2007).
50. Lichtenstein, G.R. et al. Clinical trial: benefits and risks of immunomodulators
and maintenance infliximab for IBD-subgroup analyses across four
randomized trials. Aliment. Pharmacol. Ther. 30, 210–226 (2009).
11
state
art
51. Panaccione, R. et al. Infliximab, azathioprine, or infliximab + azathioprine
for treatment of moderate to severe ulcerative colitis: The UC SUCCESS trial.
J Crohn’s and Colitis 5, S3–S12. (2011).
52. Radstake, T.R. et al. Formation of antibodies against infliximab and
adalimumab strongly correlates with functional drug levels and clinical
responses in rheumatoid arthritis. Ann. Rheum. Dis. 68, 1739–1745 (2009).
53. Afif, W. et al. Clinical utility of measuring infliximab and human anti-chimeric
antibody concentrations in patients with inflammatory bowel disease. Am. J.
Gastroenterol. 105, 1133–1139 (2010).
54. Mould, D.R. & Sweeney, K.R. The pharmacokinetics and pharmacodynamics of
monoclonal antibodies–mechanistic modeling applied to drug development.
Curr. Opin. Drug Discov. Devel. 10, 84–96 (2007).
55. Galluppi, G.R. et al. Integration of pharmacokinetic and pharmacodynamic
studies in the discovery, development, and review of protein therapeutic
agents: a conference report. Clin. Pharmacol. Ther. 69, 387–399 (2001).
56. Sheiner, L.B. Is intent-to-treat analysis always (ever) enough? Br. J. Clin.
Pharmacol. 54, 203–211 (2002).
57. Schreiber, S. et al.; CDP870 Crohn’s Disease Study Group. A randomized,
placebo-controlled trial of certolizumab pegol (CDP870) for treatment of
Crohn’s disease. Gastroenterol. 129, 807–818 (2005).
58. Bendtzen, K., Ainsworth, M., Steenholdt, C., Thomsen, O.Ø. & Brynskov,
J. Individual medicine in inflammatory bowel disease: monitoring
bioavailability, pharmacokinetics and immunogenicity of anti-tumour
necrosis factor-alpha antibodies. Scand. J. Gastroenterol. 44, 774–781
(2009).
59. Wolbink, G.J. et al. Relationship between serum trough infliximab levels,
pretreatment C reactive protein levels, and clinical response to infliximab treatment
in patients with rheumatoid arthritis. Ann. Rheum. Dis. 64, 704–707 (2005).
60. Kapel, N., Meillet, D., Favennec, L., Magne, D., Raichvarg, D. & Gobert,
J.G. Evaluation of intestinal clearance and faecal excretion of alpha
1-antiproteinase and immunoglobulins during Crohn’s disease and ulcerative
colitis. Eur. J. Clin. Chem. Clin. Biochem. 30, 197–202 (1992).
61. Dowell, J.A., Korth-Bradley, J., Liu, H., King, S.P. & Berger, M.S. Pharmacokinetics
of gemtuzumab ozogamicin, an antibody-targeted chemotherapy agent for
the treatment of patients with acute myeloid leukemia in first relapse. J. Clin.
Pharmacol. 41, 1206–1214 (2001).
12
62. Takeuchi, T. et al. Baseline tumour necrosis factor alpha levels predict
the necessity for dose escalation of infliximab therapy in patients with
rheumatoid arthritis. Ann. Rheum. Dis. 70, 1208–1215 (2011).
63. Ainsworth, M.A., Bendtzen, K. & Brynskov, J. Tumor necrosis factor-alpha
binding capacity and anti-infliximab antibodies measured by fluid-phase
radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn’s
disease. Am. J. Gastroenterol. 103, 944–948 (2008).
64. Olsen, T., Goll, R., Cui, G., Christiansen, I. & Florholmen, J. TNF-alpha gene
expression in colorectal mucosa as a predictor of remission after induction
therapy with infliximab in ulcerative colitis. Cytokine 46, 222–227 (2009).
65. Sandborn, W.J. et al. Adalimumab induces and maintains clinical remission
in patients with moderate-to-severe ulcerative colitis. Gastroenterol. 142,
257–265 (2012).
66. Ternant, D. et al. Infliximab pharmacokinetics in inflammatory bowel disease
patients. Ther. Drug Monit. 30, 523–529 (2008).
67. Fasanmade, A.A., Adedokun, O.J., Olson, A., Strauss, R. & Davis, H.M. Serum
albumin concentration: a predictive factor of infliximab pharmacokinetics
and clinical response in patients with ulcerative colitis. Int. J. Clin. Pharmacol.
Ther. 48, 297–308 (2010).
68. Klaasen, R., Wijbrandts, C.A., Gerlag, D.M. & Tak, P.P. Body mass index and
clinical response to infliximab in rheumatoid arthritis. Arthritis Rheum. 63,
359–364 (2011).
69. Peyrin-Biroulet, L. et al. Mesenteric fat in Crohn’s disease: a pathogenetic
hallmark or an innocent bystander? Gut 56, 577–583 (2007).
70. Adalimumab (Humira). FDA prescribing information. Revised March 2011.
71. Certolizumab (Cimzia). FDA prescribing information. Revised November 2009.
72. Infliximab (Remicade). FDA prescribing information. Revised February 2011.
73. Ghosh, S. et al.; Natalizumab Pan-European Study Group. Natalizumab for
active Crohn’s disease. N. Engl. J. Med. 348, 24–32 (2003).
74. Sandborn, W.J. et al.; Ustekinumab Crohn’s Disease Study Group. A
randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal
antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterol.
135, 1130–1141 (2008).
75. ClinicalTrials.gov. A Study of the Safety and Effectiveness of CNTO 148
(Golimumab) in Patients With Moderately to Severely Active Ulcerative Colitis
<http://clinicaltrials.gov/ct2/show/NCT00488631>.
www.nature.com/cpt