TDM of Biologics In Inflammatory Bowel Disease

1. TDM OF BIOLOGICS IN
INFLAMMATORY BOWEL DISEASE
DR.RENJU.RAVI
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2. Evolution of Biologics
Current status
TDM of biologics
AGA guidelines 2017
Recommendations for future
Summary
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Overview

3. 1993 - treatment of Crohn's disease with an anti-TNF chimeric monoclonal
antibody was first reported
1995 - trial done in 10 patients on infliximab infusion normalized the
Crohn's disease activity index (CDAI) and healed the colonic ulcerations in 8
of them
1997 - first RCT confirming the therapeutic effect of infliximab on Crohn's
disease was published
1998 - Infliximab was approved for treatment of Crohn's disease followed
by Adalimumab, Certolizumab and Vedolizumab in 2002, 2008 and 2014
respectively
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Evolution of biologics in IBD

4.  Six agents are currently approved for refractory IBD :
Refractory IBD* – “persistent acute symptomatic disease despite anti-
inflammatory therapy or a chronically active disease requiring continuous
treatment for relief of symptoms”
 4 anti-TNF agents – 2 anti-integrin agents –
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Biologic agents for IBD
Infliximab
Adalimumab
Certolizumab
Golimumab
Natalizumab
Vedolizumab
*Tremaine WJ. Refractory IBD: medical management. Neth J Med. 1997 Feb;50(2):S12-4.

5. Selected based on
 Availability
 labelling
 Efficacy and safety profile
 Route of administration
 Cost-effectiveness
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Biologic agents for IBD

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Biologic agents for IBD
Drug FDA DCGI Specific labelling
CD UC
Infliximab Aug 1998 Jan 2000 Failure of corticosteroids
and/or immunosuppressants
indicated for fistulizing disease
Failure of corticosteroids and/or
immunosuppressants
Adalimumab Dec 2002 June 2015 Failure of corticosteroids
and/or immunosuppressants
Failure of corticosteroids and/or
immunosuppressants
Certolizumab Apr 2008 Not approved Failure of corticosteroids
and/or immunosuppressants
No data
Golimumab Apr 2009 Not approved No data Failure of corticosteroids and/or
immunosuppressants
Natalizumab Jan 2008 Not approved Failure of corticosteroids,
immunosuppressants and anti-
TNF agent
Insufficient level of evidence
Vedolizumab May 2014 Not approved Failure of corticosteroids
and/or immunosuppressants
Failure of corticosteroids and/or
immunosuppressants

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Biologic agents in IBD : Algorithm for clinical practice

8. Goal- to optimize the care of patients with IBD
Improves the efficacy, safety, and cost-effectiveness of biologic therapies
Loss of response - result of low drug concentrations due to formation of
antidrug antibodies
 ADA can reduce drug concentrations via antibody-mediated drug
clearance, and reduce efficacy by preventing the drug binding to its target
Induction phase - identify primary non responders
Maintenance phase – identify secondary loss of response
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Rationale of TDM in IBD

9. Higher target levels
Patients with secondary loss of response and perianal disease
Neutralize systemic inflammation
Achieve deep remission with mucosal healing than levels required for
clinical remission
Also needed during induction
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Rationale of TDM in IBD

10. • The measurement of anti-TNF drug levels is usually done by capture ELISA, whereby a
detection Ab is used to measure the level of drug in serum
• Capture ELISA cannot be used to measure anti-drug Abs, as both the antigen (the anti-TNF
agent) and the analyte of interest (the anti-drug Abs) consist of IgG
•Radioimmunoassay (RIA) and Homogeneous mobility shift assay (HMSA) – to overcome
limitations of ELISA
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Measuring anti-TNF drug and ADA levels

11. •RIA and HMSA are more sensitive and measure the TNF-binding capacity of the drug
•RIA - measures drug levels/ADA as the capacity of patient serum to bind radiolabeled TNF/
radiolabeled anti-TNF drug, followed by precipitation and quantification
•HMSA - high pressure liquid chromatography (HPLC)-based mobility shift assay
•HMSA – only assay which measures circulating non-functional anti-TNF drug
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Measuring anti-TNF drug and ADA levels

12. •HMSA -
Separates drug/anti-drug Ab-complexes - based on molecular size
Quantifies drug by its binding to fluorescence-labelled TNF
Anti-drug Abs by binding to fluorescence-labelled anti-TNF drug
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Measuring anti-TNF drug and ADA levels

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Confirm IBD
inflammation
IBD patients receiving Anti-TNF maintenance therapy on
relapse
Supra-therapeutic
TC
Undetectable or Sub-
Therapeutic TC
ADA High
• Stop Drug
• Switch to another Anti-TNF agent
ADA Low/Nil
• Dose Escalation
• Add IMM
• Stop drug
• Switch to
drug of
another class
TDM algorithm of patients with IBD on anti-TNF therapy
Measure ADA at
consecutive time
points
Papamichael K, Cheifetz AS. Frontline Gastroenterology 2016;7:289–300

14. •Published in September 2017
•Developed to inform appropriate utilization of TDM with anti TNF-α agents
and thiopurines
•Taken into consideration the risks and benefits of an intervention, patients’
values and preferences, and resource utilization
•Five recommendations
•Two of these recommendations considered anti TNF-α agents
•Remaining three relevant to thiopurines
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AGA guidelines for TDM in IBD

15. Reactive testing – “TDM performed in patients who have active IBD,
defined as having active symptoms related to IBD that are confirmed with
objective findings from biochemical markers, endoscopic, or radiologic
findings of active inflammation or in patients who are asymptomatic
clinically but have findings of objective inflammation on endoscopy or
radiology”
 Three possible causes for drug failure
Mechanistic failure
Immune-mediated pharmacokinetic failure
Non immune-mediated pharmacokinetic failure
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AGA guidelines for TDM in IBD

16. Mechanistic failure
Patient not responding despite optimal drug trough concentrations
Likely related to the disease process being driven by inflammatory
mediators that are not blocked by the particular drug
Unlikely to respond to other drugs within the same class
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AGA guidelines for TDM in IBD

17. Immune-mediated pharmacokinetic failure
Low or undetectable trough concentrations & high titers of anti-drug
antibodies
Immune-mediated formation of neutralizing anti- drug antibodies
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AGA guidelines for TDM in IBD

18. Non immune-mediated pharmacokinetic failure
Occurs when patients do not adequately respond to therapy in the setting
of sub-therapeutic trough concentrations and absence of anti-drug
antibodies
Results from rapid drug clearance, often in the setting of a high
inflammatory burden
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AGA guidelines for TDM in IBD

19. In adults with active IBD treated with anti-TNF agents, suggests reactive
TDM to guide treatment changes
Target trough concentrations in patients with active IBD during
maintenance therapy
Infliximab ≥5 μg/ml,
Adalimumab ≥7.5 μg/ml
Certolizumab ≥20 μg/ml
 Same lab should be used for each patient for consistency
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AGA guidelines for TDM of biologics in IBD

20. Six studies (929 patients) provided data on proportion of patients not in
remission above predefined infliximab thresholds (1, 3, 5, 7, and 10 mg/mL)
 Based on these, proportion of patients not in remission decreased from
25% when using an infliximab threshold of ≥ 1 µg/mL, to 15% with an
infliximab trough concentration of ≥ 3 µg/mL, to approximately 4% with an
infliximab trough concentration of ≥ 7 µg/mL or ≥ 10 µg/mL
≥ 5µg/ml
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AGA guidelines for TDM of biologics in IBD
Target Trough Concentrations of Infliximab

21. Four studies provided data on proportion of patients not in remission
above adalimumab trough concentration ≥ 5.0 ± 1 µg/mL or 7.5 ± 1 µg/mL
On analysis, proportion of patients not in remission progressively
decreased from 17% when using an adalimumab threshold ≥ 5.0 µg/mL, to
10% with an adalimumab trough concentration of ≥ 7.5 µg/mL
≥ 7.5µg/ml
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AGA guidelines for TDM of biologics in IBD
Target Trough Concentrations of Adalimumab

22. One study provided data from an exposure response pooled analysis from 9
trials
 On analysis of different thresholds, proportion of patients not in remission
progressively decreased from 42% when using a certolizumab threshold of ≥ 10
µg/mL to 26% with a certolizumab trough concentration of ≥ 20 µg/ml
≥ 20µg/ml
Unknown
There is a lack of sufficient evidence available to establish a target trough goal
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AGA guidelines for TDM of biologics in IBD
Target Trough Concentrations of Certolizumab Pegol
Target Trough Concentrations of Golimumab

23. In adult patients with quiescent IBD - no recommendation regarding the
use of routine proactive TDM
Proactive TDM not recommended –
Due to the limited evidence
Concerns regarding high health costs
Potential inappropriate treatment changes in asymptomatic patients on
remission
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AGA guidelines for TDM of biologics in IBD

24. The Australian consensus on TDM recommends proactive testing in the
following situations:
After successful induction at week 14
In those where a drug holiday is observed
Periodically during remission if the results would impact management
The building research in inflammatory bowel disease globally (bridge)
group also recommends proactive TDM
At least once during the first year of maintenance therapy
Following a drug holiday
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TDM in quiescent IBD

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Key Recommendations
Consider TDM in adult patients with active IBD who are on
anti-TNF agents
Suggested trough levels for infliximab are ≥5 µg/mL,
adalimumab ≥7.5 µg/mL, and certolizumab ≥20 µg/mL
No recommendation regarding TDM is made for patients
with quiescent disease on anti-TNFs

26. In adult patients with IBD - routine TPMT testing prior to initiating
thiopurines,
Monitor complete blood counts when thiopurines are used, regardless of
TPMT results
For active IBD, the target 6-TGN level is 230 to 450 pmol/800 million RBCs
Check thiopurine metabolites in patients when there is active disease or
suspecting toxicity
In adult patients with quiescent IBD treated with thiopurines, the AGA
suggests against routine thiopurine metabolite monitoring
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AGA guidelines for TDM of thiopurines in IBD

27. Different target levels for remission during induction and maintenance
Different recommendations for crohn’s disease and ulcerative colitis
Specific recommendations for TDM in pregnancy and in pediatric patients
Need for proactive TDM in certain circumstances- after induction or before
de-escalation of therapy
Drug level testing for newer biologics such as vedolizumab and
ustekinumab
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Recommendations for future guidelines
Su HY, Ward MG, Sparrow MP. Therapeutic drug monitoring in inflammatory bowel disease: too little too early?—comments on the
American Gastroenterology Association Guideline. Transl Gastroenterol Hepatol 2017;2:113.

28. Reactive TDM has the strongest clinical evidence base for both anti-TNF
agents & thiopurines and its use should be considered standard of care for
IBD
Proactive testing may also be appropriate in some cases and should be
considered on an individual basis
Hopefully, ongoing research in this rapidly evolving field will confirm the
validity of proactive TDM testing for future guidelines
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SUMMARY

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