Individual levels versus other factors. If 6-TGN

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patients with inflammatory bowel disease (IBD) may require different
medications based on their current level of disease activity, treatment goals,
and tolerance to various medications.1 The use of therapeutic drug
monitoring (TDM) has shown to benefit the management of these patients, due to
the need to maintain efficacy and minimize the risk of adverse events.1


Have a Long History of Use for the Treatment of Patients With IBD

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Thiopurines, including azathioprine (AZA) and mercaptopurine
(MP), are immunosuppressive drugs that have a long history of use in the
treatment of patients with Crohn’s disease and ulcerative colitis.1
Although thiopurine monotherapy has been found to be ineffective at inducing
remission in patients with IBD, it is effective for maintaining remission in
these patients. Additionally, thiopurines can be used in combination with
corticosteroids in short-term treatment to allow patients to discontinue
corticosteroid use.2


Monitoring Is Necessary to Ensure the Safety and Efficacy of Therapy3

Although many individuals tolerate and respond
well to treatment with thiopurines, roughly one-third of patients discontinue
use due to lack of efficacy or adverse reactions. Variability in thiopurine
metabolism may account for these differences. Both AZA and MP may be converted
into the active metabolites 6-thioguanine nucleotides (6-TGN), which induce cytotoxicity
and immunosuppression by preventing lymphocyte proliferation through the
inhibition of RNA, DNA, and protein synthesis. Alternatively, AZA and MP may be
inactivated through methylation by the enzyme thiopurine-S-methyltransferase
(TPMT), resulting in elevated levels of a second metabolite,
6-methylmercaptopurine (6-MMP), which has been associated with hepatotoxicity.3


“Experience with thiopurines has shown that the
presence of drug over a certain cut point is correlated with efficacy.” – Marla


Because TPMT activity is highly variable between
individuals and genetic mutations account for some of the interindividual
variability observed, TPMT genotyping prior to initiation of thiopurine
treatment allows clinicians to adjust the dosage according to enzymatic
activity in order to avoid hepatotoxicity and bone marrow suppression (Figure

Although TPMT activity can be used to determine
initial dosing, once a patient has initiated thiopurine treatment, it is
important to continue monitoring 6-TGN levels.3 A critical study
demonstrated that the likelihood of responding to thiopurines was 5 times
higher in patients with 6-TGN levels above a cutoff of 235 pmol/8 × 108
RBCs than in patients with 6-TGN levels below this therapeutic threshold.5
Therefore, if a patient does not respond to standard thiopurine dosing, assaying
6-TGN and 6-MMP levels can reveal whether nonresponse is due to inadequate drug
levels versus other factors. If 6-TGN levels are subtherapeutic (ie, less than
235 pmol/8 × 108 RBCs), the patient will likely benefit from dose
escalation; however, if 6-TGN levels are within a defined therapeutic window (235
to 400 pmol/8 × 108 RBCs) and the patient is still not responding,
switching medication classes would be recommended.6 Although 6-TGN
is the active metabolite linked to the efficacy of AZA and MP, excessive 6-TGN
levels carry a risk of bone marrow suppression. Therefore, ongoing monitoring
of 6-TGN levels can inform dose adjustments, ensuring that metabolite levels
remain within an appropriate therapeutic range in order to maximize efficacy
and limit the risk of drug-related toxicity.3


 “The concept of TDM for biologics was first introducedwith
data suggesting that having a detectable drug level at all was associated with
better outcomes, and has since evolved to developing a minimal threshold for
efficacy.” – Marla Dubinsky


Drug Levels Correlate
With the Efficacy of Biologic Agents Used to Manage IBD

Similar to thiopurines, the efficacy of biologic
therapies also correlates with drug level.7 All biologic agents,
including tumor necrosis factor-? (TNF?) inhibitors, have the potential to elicit
the development of antidrug antibodies; such immunogenic responses have been
observed in clinical trials with all available agents for the treatment of IBD
and may impact the efficacy of these medications, as detection of antibodies in
some cases is associated with undetectable drug concentration.7,8


Additional factors such as the rate of drug
clearance from circulation also impact drug levels independent of antibody
formation, as some patients experience rapid clearance leading to low or absent
drug levels.7 Thus, while detection of antibody formation may serve
as a proxy for active drug levels, serum drug concentration provides a direct
measurement of drug levels.


In 2006, a study by Maser and colleagues showed
that a greater proportion of patients who had detectable trough serum
infliximab (IFX) concentrations achieved complete clinical remission compared
with patients with undetectable IFX levels. C-reactive protein (CRP) levels
were also lower for patients with detectable trough IFX, and more of these
patients achieved a normal CRP level. Additionally, significantly more patients
with detectable trough serum IFX showed endoscopic improvements of at least 75%,
as well as complete endoscopic remission.7


“This study established the concept that having
any drug, meaning above zero, was helpful. Subsequent studies have defined an
optimal range in order to improve efficacy.” – Marla Dubinsky


of IFX and Adalimumab Levels Within a Therapeutic Window Is Associated With
Higher Rates of Mucosal Healing9

Mucosal healing is the ultimate treatment goal for
patients with IBD. In order to guide clinicians in monitoring and adjusting
therapy to improve long-term patient outcomes, a retrospective observational
study of patients with IBD aimed to identify optimal anti-TNF? levels for
achieving mucosal healing by analyzing patients treated with adalimumab (ADA)
or IFX who underwent colonoscopies. Based on endoscopic assessments of mucosal
healing and measurements of ADA and IFX drug levels, the rate of mucosal
healing for each drug serum level was defined (Figure 2). Patients with mucosal
healing had significantly higher ADA and IFX levels; however, the incremental
gain in mucosal healing reached a near plateau of 12 µg/mL for ADA and 8 µg/mL
for IFX. These findings suggest that a “mucosal-healing therapeutic window” can
be defined for each anti-TNF? agent and used as the target drug level range by
TDM in order to achieve mucosal healing in 80% to 90% of patients with IBD.
Furthermore, these findings suggest that additional dose escalations
above this range may be futile and should be avoided for cost-effective dose
escalation in a treat-to-target strategy.9

Patients With Primary and Secondary Nonresponse to Biologics

Clinicians can initiate treatment based on an individual
patient’s disease presentation and modify treatment based on response to
initial treatment, which may vary among individuals (Figure 3).8
Primary nonresponse may be attributed to various factors, including inadequate
drug levels, rapid drug clearing, and development of antidrug antibodies.10
In this case, patients should be switched to a different treatment class.8
In the case of patients experiencing secondary loss of response, clinicians may
decide to escalate dosage, cycle to another drug with the same mechanism, or
switch to a different class of medication.8 The use of TDM to measure
drug and antidrug antibody levels may serve as a powerful tool to reveal the
mechanisms by which loss of response occurs and, ultimately, to guide
therapeutic decision making for many patients with IBD.10 If the
concentration of a TNF? inhibitor is subtherapeutic and antidrug antibodies are
low or absent, the dose should be increased or administered more frequently. In
the case of patients with low levels of antidrug antibodies, use in combination
with an immunosuppressive agent, such as a thiopurine or methotrexate, may help
prevent a secondary loss of response resulting from the development of antidrug
antibodies against the TNF? inhibitor. If the drug concentration is
subtherapeutic and antidrug antibodies are high, those antibodies will be hard
to overcome, and the patient should be switched to a different TNF? inhibitor.2

Although this schematic shows how TDM can be used
reactively to reveal the mechanism of loss of response and inform the
subsequent course of therapy, evidence to support the use of proactive drug
monitoring to predict outcomes and modify treatment before a patient relapses
can keep patients in a state of tight control and minimize their risk of


“These drugs are easily cleared, and clinicians
need to be very proactive if they want patients to stay on a drug in the long
term.” – Marla Dubinsky


to ADA Are Predictive of Loss of Response in Patients With Crohn’s Disease11

In a retrospective study of patients with IBD who had
been treated with ADA, serial serum samples were analyzed for drug levels and
antibodies to ADA (ATA) using a homogeneous mobility shift assay. Patients with
lower drug levels were more likely to be positive for ATA. Additionally,
analysis of drug and antibody levels over time showed that patients with higher
drug levels by 4 weeks postinduction were at a decreased risk of ATA formation.
Serum samples were also analyzed for markers of inflammation, including CRP,
serum amyloid A proteins, intercellular adhesion molecule-1, and vascular cell
adhesion molecule-1, using a high-sensitivity enzyme-linked immunosorbent assay.
All inflammatory markers were higher in patients who tested positive for ATA
than in those who tested negative for ATA, suggesting that antidrug antibodies are
associated with an overall lack of disease control and poor clinical


TDM Extends
Responses to IFX in Patients With IBD12

observational pilot study demonstrated the long-term benefit of continued
concentration-based IFX dose titration in patients with IBD. Although no
differences in drug continuation were apparent by one year, patients who were
managed proactively with treatment decisions informed by TDM were more likely
to stay on IFX long term. Specifically, 86% of patients in the proactive TDM treatment
group remained on IFX therapy at 5 years compared with 52% in the group that
did not receive TDM-based treatment, suggesting that a higher proportion of
patients in the proactive TDM treatment group continued to respond to treatment
in the long term. None of the 48 patients in the proactive TDM group
discontinued IFX due to recurrent symptoms of IBD, whereas 15 of the 78
patients without proactive TDM discontinued treatment due to recurrent
symptoms. Because patients in clinical remission frequently experience low or
undetectable IFX levels, TDM and subsequent dose escalation are effective
strategies to keep IFX at therapeutically effective concentrations.12


Early Dose
Optimization Is Associated With Improved Long-term Therapeutic Outcomes13

A prospective, observational study measured trough IFX
levels in pediatric patients with Crohn’s disease or ulcerative colitis at week
14 after the initiation of IFX treatment. The investigators found that week-14
IFX levels positively correlated with IFX levels at week 54, and higher IFX
levels at week 14 were associated with persistent remission at week 54. The
median IFX level was 4.7 µg/mL at week 14 for patients in persistent remission
at week 54 compared with 2.6 µg/mL at week 14 for those who were not in
persistent remission at week 54. This was the first study to suggest that early
dose optimization is associated with long-term therapeutic outcomes for
patients treated with anti-TNF? agents.13


Another study further supports the benefits of early dose
optimization with evidence that IFX levels measured as early as week 2 are predictive
of short-term mucosal healing in patients with ulcerative colitis.14
Patients included in this retrospective analysis had undergone endoscopic
evaluations at baselines and following induction (between week 10 and 14). IFX
concentrations were measured at weeks 0, 2, 6, and 14 following the initiation
of treatment with IFX. Higher serum IXF concentrations at each time point
correlated with higher rates of short-term mucosal healing, as defined by a
Mayo endoscopic subscore of 0 or 1. 


“If you want patients to achieve a target of
mucosal healing, optimize drugs early. Do not wait for patients to fail,
because antibody rates can be as high as 40% to 50% by the time a patient
fails, at which time it becomes difficult to recapture their response.” – Marla


The patient was treated with IFX (5 mg/kg) combined with MP.
IFX infusions were given at weeks 0, 2, and 6, and at week 3 the levels of IFX
and antibodies to IFX (ATI) in the blood were assessed. The IFX concentration
one week after the second infusion was only 1.8 µg/mL, and ATI were
undetectable (


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