1. Management of Biologic Therapies in IBD
Stephen B. Hanauer, MD
Clifford Joseph Barborka Professor of Medicine
Northwestern University Feinberg School of Medicine

2. Defining Maintenance Treatment
Simply: A maintenance therapy prevents “relapse”
In contrast to episodic therapy or re-treatment
Levels of Maintenance
Maintenance of Response
Maintenance of Clinical (or Post-operative) Remission
Maintenance of Steroid-free remission
Maintenance of Mucosal Healing
Prevention of Hospitalizations/Surgery
Disease Modification

3. Clinical Trial Data

4. Re-Treatment Benefit With Infliximab
Response (%)
Week Infusion
Clinical response defined as a ³ 70-point decrease in CDAI score from baseline.
* Patients responding to an initial infusion.
Rutgeerts et al. (1999). Gastroenterology 117(4):

5. CD: Comparing ACCENT I, CHARM, and PRECiSE 2 Remission Results
(infliximab)
Patients (%)
CHARM**
(adalimumab)
PRECiSE 2
(certolizumab pegol)
100 80 60 60 40
Patients (%) 24
This composite is not a formal meta-analysis, but gives a perspective of remission results for similar trials with infliximab, adalimumab and certolizumab pegol.
All 3 trials enrolled patients with “refractory” active disease despite ongoing therapy with aminosalicylates, steroids or immunosuppressives. The trials randomized patients who responded to initial, open label therapy to receive active maintenance treatment or placebo. 40
Patients (%) 20
Week 4
Week 26
Overall
Response
Remission
Remission
Week 26
*5 mg/kg dose.
**Maintenance trial with 80/40 mg induction dosing. Randomized responders = CR-70 at week 4.
Week 26 remission among randomized responders on 40 mg every other week dosing.  5 5 5

6. Health Claims Data

7. Loss of Response to Infliximab in Crohn’s Disease: Health-Care Claims Data
2 years, 77%
Health-care claims database (1999–2005)
Selected patients with CD receiving infliximab maintenance therapy with an initial response
Loss of response inferred from:
Upward dose adjustment
New drug therapy for CD
CD-related emergency room or inpatient visits
Annual total health-care and CD-related costs estimated and adjusted for inflation to 2005 US dollars
1 year, ~50%
– Loss of response
Wu EQ et al. Value Health. 2008;11:

8. Comparative Effectiveness of Infliximab and Adalimumab for Crohn's Disease
Retrospective cohort study by using U.S. Medicare data from 2006 through 2010.
Patients with CD who were new users of infliximab (n = 1459) or adalimumab (n = 871) after January 31, 2007.
Primary outcome measures were disease persistence on therapy at week 26
After 26 weeks of treatment,
49% of patients receiving infliximab remained on drug,
compared with 47% of those receiving adalimumab
Osterman, M. CGH 2014;12:811-17

9. Causes of Treatment Failure With Anti-TNF Agents
Poor adherence reported in one-third of patients
Suboptimal drug concentrations result from pharmacokinetic (PK) differences
Weight-based dosing
Measure serum concentrations
Antidrug antibodies (ADAs) production
Concomitant Infection (C. Diff & CMV)
Kane Svet al. Adv Ther. 2009;26(10): ; Fasanmade AA, et al. Eur J Clin Pharmacol.2009;65(12): ;
Ben-Horin S, et al. Autoimmun Rev. 2014;13(1):24-30; Farrell RJ, et al. Gastroenterology. 2003;124(4):

10. Therapeutic Windows with Biologics
µg/mL
Peak
AUC
100 10 1
Trough
Nestorov J Rheum Suppl ON ORDER 2 6 14
22 wks.
Sub-treshold trough levels associated with:
Loss of response
Immunogenicity

11. Trough Levels of Infliximab Are Predictor of Continued Response
CLINICAL REMISSION
C- REACTIVE PROTEIN
ENDOSCOPIC CHANGE * * *
P < 0.001 *
P < 0.001 *
P < 0.001 *
Undetectable
 2.0 ug/ml
Undetectable
 2.0 ug/ml
Undetectable
 2.0 ug/ml
Maser EA et al. Clin Gastroenterol Hepatol. 2006;4:

12. Levesque BG, et al. Aliment Pharmacol Ther. 2014;39:1126-35.
Prospective cohort study of relationship between serum infliximab level and efficacy in luminal CD
Levesque BG, et al. Aliment Pharmacol Ther. 2014;39:

13. Duration of Response Based on IFX Concentrations
Higher Serum Infliximab Concentration is Associated with a Higher Response Rate in CD
Study design: prospective, cohort study
N=125, 30% Rx for fistula
Median follow-up: 36 months
Efficacy
Infliximab concentrations ≥12 μg/mL were associated with greater median duration of response
Immunosuppressant use was associated with IFX concentrations ≥12 μg/mL
Duration of Response Based on IFX Concentrations
P<0.01
KEY SLIDE
Baert et al conducted a prospective cohort study of infliximab in 125 patients with refractory luminal or fistulizing CD; median follow-up was 36 months. [Baert/2003/p602/C1/para 3/ll 1-3 and p603/C2/para1/ll1-3]
Of the 125 patients including 38 (30%) that were receiving treatment for fistula. Overall, 89 (71%) had a response to infliximab. [Baert/2003/p603/C2/para1/ll1-6]
Infliximab concentrations were positively correlated with duration of response. Concentrations ≥12 μg/mL were associated with median duration of response of 81.5 days, and concentrations <12 μg/mL were associated with median duration of response of 68.5 days (P<0.01). [Baert/2003/p605/C2/para3/ll3-9]
Patients taking immunosuppressants were more likely to have IFX concentrations of >12.0 μg/mL (RR 1.93; 95% CI ). A logistic regression analysis showed that taking immunosuppressive agents was the only variable of significance (P<0.001) that was predictive of IFX levels. [Baert/2003/p605/C2/para1/ll2-14]
Reference
Baert F, et al. N Engl J Med 2003;348:601-8.
Baert F, et al. N Engl J Med. 2003;348:601. 13

14. Proportion of Patients (%) IFX Concentration (mcg/ml) at Wk 30
Clinical Remission Without Corticosteroids by Trough IFX Concentration at Week 26: SONIC
Primary Endpoint
Proportion of Patients (%)
19/32
13/23
43/59
36/49
31/43
IFX Concentration (mcg/ml) at Wk 30
*IFX and IFX+AZA patients who had 1 or more PK samples obtained after their first study agent administration were included in the analysis
Colombel JF, et al. N Engl J Med 14

15. Higher Serum Infliximab Level is Associated with Longer Remission and Better Endoscopy Score in CD
Study design: prospective cohort in moderate-severe CD
N=105
Median follow-up: 88 weeks
Efficacy
Infliximab concentrations were positively correlated with the interval of clinical remission and change in endoscopic score
100 90 80
Remission (%) 70 60 50
R2= 0.61
P<0.001 40 2 4 6 8 10 12
Serum Infliximab (µg/ml)
100
KEY SLIDE
Maser et al reported findings from a prospective study in a consecutive cohort of 105 patients with refractory CD who were started on infliximab therapy and were followed for a median of 88 weeks. [Maser/2006/p1248/C2/para3/ll1-3; Maser/2006/p1249/C1/para4/ll5-6]
For the 105 patients studied, a positive relationship was found between the serum concentration of infliximab and the interval of clinical remission (R2 = 0.61; P<0.001) and the change in endoscopic score (R2 = 0.46, P<0.001). [Maser/2006/p1251/C1/para3/ll1-3; C1/para4/ll6-8]
An inverse relationship was found between serum infliximab concentrations and CRP (R2 = 0.26; P<0.001). [Maser/2006/p1251/C1/para3/ll4-5]
This study showed that clinical remission is associated with detectable trough concentrations of infliximab in CD patients who are treated with scheduled infusions. [Maser/2006/p1254/C1/para3/ll1-5] .
Reference
Maser EA, et al. Clin Gastroenterol Hepatol 2006;4: 50
Endoscopic Improvement (%) 50
R2= 0.46
P<0.001
-100 2 4 6 8 10 12
Serum Infliximab (µg/ml)
Maser EA, et al. Clin Gastroenterol Hepatol. 2006;4:1248. 15

16. High Infliximab Levels are Associated with Mucosal Healing in Crohn’s Disease
Serum samples in 210 CD patients undergoing treatment with infliximab were collected
Infliximab trough levels were correlated with endoscopic healing (complete, partial or none)
Commentary: Proof of principle that trough levels may help predict endoscopic healing. However, it is unclear if the IFX trough levels were truly ‘trough levels’ as they were drawn anywhere between 2-6 weeks after infusion. Timing of endoscopy also varied between the different groups.
405 High Infliximab Trough Levels Are Associated With Mucosal Healing in Crohn's Disease Wouter Van Moerkercke1, Chloé Ackaert2, Griet Compernolle2, Matthias Jürgens1, Isabelle Cleynen1, Gert A. Van Assche1, Paul J. Rutgeerts1, Ann Gils2, Severine Vermeire1 1. Department of gastroenterology, University Hospitals Leuven, Leuven, Belgium, 2. Laboratory for Pharmaceutical Biology, Catholic University Leuven, Leuven, Belgium Background and aims The introduction of anti-TNF biological agents in the last decade is seen as the largest evolution in the management of IBD. Infliximab (IFX) is very efficacious and has shown to induce rapid and profound healing. Mucosal healing is associated with deep clinical remission, reduction of hospitalisations and surgical rates and is an important treatment goal. Nevertheless, primary failure occurs. Little is known about the importance of trough levels (TR) in optimizing the therapy. We wanted to study whether IFX TR are important to achieve mucosal healing and if they are related to the degree of healing. Methods We studied serum samples in 210 patients with Crohn’s disease, all in whom clinical, biochemical and endoscopic data before and after start of IFX were present. Serum was available at t0 (before the start of IFX), t1 (2 to 6 weeks after the first infusion) and t2 (at the time of the endoscopy). IFX TR were determined by an in-house developed ELISA method, in which 1:150 and 1:300 diluted serum samples were applicated to TNF alpha coated plates. On each plate, an internal standard curve was introduced and a polyclonal HRP-conjugated goat anti-human antibody was used for detection. Endoscopic healing was defined as complete (disappearance of all lesions), partial (clear endoscopic improvement but still ulceration present) or no healing. Data were analysed using non-parametric Kruskal Wallis and Mann Witney test. Results Complete healing was observed in 39 %, partial in 22 % and no healing in 39 % of patients. Patients who showed (partial or complete) healing had significantly higher IFX TR (median 5.00 µg/mL; P P ) compared to patients without healing (median 0.95 µg/mL, IQR respectively; p= 0.006). Furthermore, a dose-dependent effect was observed with the highest TR detected in patients with complete healing (median 5.77 µg/mL, IQR ) followed by partial healing (median 3.89 µg/mL, IQR ) and absence of healing (0.95 µg/mL, IQR ; p= 0.013) (see figure). Conclusions Infliximab trough levels are related with the degree of mucosal healing. In this study, we showed that patients with complete healing under IFX have significantly higher TR than patients without healing. Measurement of infliximab trough levels is therefore useful in optimizing therapy since they may allow dose adjustment in patients with low drug levels. For patients with low TR and no healing, we suggest to increase dose and/or decrease the interval. In patients with high TR and no healing switching the therapy is mandatory. Obviously, in patients with high TR and healing we can continue the treatment.
Van Moerkercke W. et al. DDW Abs #405 16

17. Implications of Low Trough Levels
Disease Recurs
No longer maintenance but re-treatment
Development of anti-drug antibodies
Eventual loss of response
Do Not Administer Intermittently!

18. Factors that Influence the PK of TNF Antagonists
Impact on TNF antagonist PK
Presence of ADAs
Decreases drug concentration Increases clearance Worse clinical outcomes
Concomitant use of immunosuppressives
Reduces ADA formation Increases drug concentration
Decreases drug clearance Better clinical outcomes
Low serum albumin concentration
Increases drug clearance Worse clinical outcome
High baseline CRP concentration
Increase drug clearance
High baseline TNF concentration
May decrease drug concentration by increasing clearance
High body size
May increase drug clearance
Sex
Males have higher clearance
Ordas I et. al. Clin Gastroenterol Hepatol. 2012; 10:

19. Therapeutic drug monitoring with biologic therapy
Relationship of exposure to response?
Define a minimum effective concentration?
Define a maximum therapeutic concentration above which
no additional benefit?
increased risk of toxicity?
Relationship between drug concentration and anti-drug antibodies, and treatment strategy?
Is TDM cost-effective?
In what clinical situations should TDM be used?
Induction?
Maintenance?
Loss of response?
Toxicity?

20. ACCENT I: Week 54 Sustained Clinical Outcome and Week 14 Serum Infliximab Level in CD
<3.5 μg/mL Week 14 Serum IFX Level
≥3.5 μg/mL Week 14 Serum IFX Level
P-value*
Subjects included in analysis 96 51
Subjects with sustained response
17 (17.7%)
20 (39.2%)
0.0042
Subjects without sustained response
79 (82.3%)
31 (60.8%)
Reference found via the UEGW website in the 2011 Program:
Cornillie F et al. Presented at the 19th Annual 19th United European Gastroenterology Week (UEGW); October 25, Abstract P0919.
P0919
CAN CLINICAL, BIOLOGICAL OR PHARMACOLOGICAL MARKERS PREDICT SUSTAINED RESPONSE TO INFLIXIMAB? A RETROSPECTIVE ANALYSIS OF ACCENT 1
Freddy Cornillie, Belgium; Stephen Hanauer;
Robert Diamond; Jim Wang; Dave Zelinger;
Zhenhua Xu; Severine Vermeire; Paul Rutgeerts
*Chi-square test .
Cornillie F, et al., Gut. 2014;63:

21. Infliximab Trough Between Weeks 14 and 22 May
Predict Sustained Response in Crohn’s Disease
Retrospective adult cohort
84 patients
IFX trough level measured at 14 or 22 wks
Sustained clinical response
IFX Trough level > 3 μg/ml
Increase in ATI
IFX Trough level < 3 μg/ml
Bortlik M, et al. J Crohns Colitis 2013;7:

22. Detectable Serum Trough Infliximab Associated with Higher Remission Rate and Endoscopic Improvement in UC
Study design: cohort study
N=115 patients with moderate to severe UC
Follow-up time: median 13.9 months
Efficacy
Detectable serum IFX was associated with
Higher remission rates (69% vs. 15%; P<0.001)
Endoscopic improvement (76% vs. 28%; P<0.001)
P<0.001
KEY SLIDE
Seow and colleagues performed a cohort study in order to determine the predictive value of trough serum infliximab. One hundred fifteen patients with moderately severe to severe UC were enrolled for a median of 13.9 months. [Seow/2010/p49/abstract/II4-6; Seow/2010/p49/C2/para4/ll1-3; Seow/2010/p50/C2/para5/ll1-4]
All patients received induction therapy with infliximab 5 mg/kg on weeks 0, 2, and 6. The patients who responded to the induction therapy received additional infliximab infusions every 8 weeks.[Seow/2010/p49/C2/para4/ll6-9]
Patients with detectable serum IFX levels had significantly higher remission rates compared with those with undetectable serum IFX levels; 69% vs. 15% respectively, P< [Seow/2010/p51/C2/para4/ll6-9; Seow/2010/p52/Figure 3A]
Patients with undetectable IFX serum levels were at an increased risk for colectomy; 55% vs 7%; P< [Seow/2010/p51/C2/para4/ll6-12]
Reference
Seow CH, et al. Gut 2010;59:49-54.
Seow CH, et al. Gut. 2010;59:49-54. 22

23. Presence of Detectable Trough Infliximab Levels Reduces Colectomy Rates in Ulcerative Colitis
BACKGROUND AND AIMS:
Antibodies to infliximab reduce serum infliximab with loss of clinical benefit, but undetectable trough serum concentrations of infliximab may occur without antibody formation. The relationship between trough serum infliximab and clinical outcomes was evaluated in acute ulcerative colitis.
METHODS:
In a cohort of 115 patients with ulcerative colitis treated with three-dose induction followed by scheduled maintenance infliximab, rates of clinical remission, colectomy, antibodies to infliximab and trough serum infliximab were determined.
RESULTS:
Rates of remission were 32% at week 10 and 37% at week 54. Colectomy occurred in 40% of patients, at a median of 5.3 (IQR ) months. Detectable trough serum infliximab was present in 39% of patients and, among patients with undetectable infliximab, 41% were antibody positive and 20% were antibody negative. For antibody-positive and antibody-negative patients, rates of remission (18% vs 14%), endoscopic improvement (25% vs 35%) and colectomy (52% vs 59%) were not different. A detectable serum infliximab was associated with higher rates of remission (69% vs 15%; p<0.001) and endoscopic improvement (76% vs 28%, p<0.001). An undetectable serum infliximab predicted an increased risk for colectomy (55% vs 7%, OR 9.3; 95% CI 2.9 to 29.9; p<0.001). Concurrent immunosuppression was not associated with clinical outcomes.
CONCLUSIONS:
For patients with ulcerative colitis treated with infliximab, a detectable trough serum infliximab predicts clinical remission, endoscopic improvement and a lower risk for colectomy. An undetectable trough serum infliximab, irrespective of antibody status, is associated with less favourable outcomes.
Seow CH, et al. Gut. 2010;59:49.

24. Proportion of Patients Achieving Clinical Remission by Serum IFX Concentration: ACT 1 and 2
At wks 8, 30 and 54, the proportion of patients achieving clinical remission increased with increasing quartiles of IFX concentrations.
IFX Conc.
(% patients)
1st Quartile
2nd
Quartile
3rd
4th Quartile
P-values
Week 8
26.3%
(<21.3μg/mL)
37.9%
(≥21.3-<33μg/mL)
43.9%
(≥33-<47.9μg/mL)
43.1%
(>47.9μg/mL)
P=0.0504
Week 30
14.6%
(<0.11μg/mL)
25.5%
(≥0.11-<2.4μg/mL)
59.6%
(≥2.4-<6.8μg/mL)
52.1%
(>6.8μg/mL)
P<0.0001
Week 54
21.1%
(<1.4μg/mL)
55.0%
(≥1.4-<3.6μg/mL)
79.0%
(≥3.6-<8.1μg/mL)
60.0%
(>8.1μg/mL)
P=0.0066
Reinisch W et al., Gastro Vol 142, Issue 5, suppl-1, May 2012, page S-114

25. Week 14 IFX levels predict week 54 outcomes
IFX14 median level (μg/ml)
P-value*
Persistent Remission (Y vs. N)
4.7 vs. 2.6
P = 0.03
Clinical Remission (Y vs. N)
3.2 vs. 2.2
P = 0.07
Deep Remission (Y vs. N)
4.2 vs. 3.0
Sustained Durable Remission (Y vs. N)
5.5 vs. 3.1
P = 0.05
Sustained Durable Remission (Y vs. N)
5.1 vs. 3.0
P = 0.04
Singh N, et al. Inflamm Bowel Dis 2014;10:

26. Clinical outcomes in patients with detectable HACA (n=35)*
Increasing dose of infliximab in the presence of ATI formation is inferior to changing anti-TNF
Clinical outcomes in patients with detectable HACA (n=35)*
Clinical outcomes in patients with sub-therapeutic concentrations (n=69)*
P<0.016
P<0.004
Complete / partial response (%)
Complete / partial response (%)
* 6 discontinued IFX, 3 continued same dose 3, 3 proceeded to surgery, 5 patients could not be assessed
* 10 continued same dose, 9 discontinued IFX, 8 proceeded to surgery and 7 patients could not be assessed
Afif W, et al. Am J Gastroenterol 2010;105:

27. Adalimumab & ATA Levels at LOR correlate with response to dose intensification
(B) Adalimumab levels at the time of LOR in patients who subsequently responded to dose intensification compared with those who did not.
(A) ROC analysis of adalimumab level and active inflammation.
(D) ATA levels at the time of LOR in patients who subsequently responded to dose intensification compared with those who did not.
(C) ROC analysis of adalimumab level and failure of early response to dose intensification.
Yanai, CGH 2015;13:522–530

28. Combined analysis for patients with a suspected LOR to either infliximab or adalimumab
Survival curve of regained response to dose intensification according to ADA titer status.
Survival curve for regained response among patients with high-titer ADA.
Yanai, CGH 2015;13:522–530

29. Combined analysis for patients with a suspected LOR to either infliximab or adalimumab
Survival curve for regained response among patients with no/low-titer ADA.
Anti-TNF drug level before and after dose intensification
Yanai, CGH 2015;13:522–530

30. Combined analysis for patients with a suspected LOR to either infliximab or adalimumab with adequate drug levels
Survival curve for regained response among patients who received anti-TNF optimization (dose intensification or a switch within the anti-TNF class) vs expectant management
survival curve for regained response among patients who received anti-TNF optimization vs out-of-class intervention
Yanai, CGH 2015;13:522–530

31. Adalimumab Infliximab
Survival curves of regained response to adalimumab or infliximab dose intensification according to ATA/ATI titer status at the time of LOR.
Adalimumab Infliximab
Yanai, CGH 2015;13:522–530

32. Potential yield of drug/ADA tests as illustrated by cohort subgroups of PK measurements
Yanai, CGH 2015;13:522–530

33. Proposed algorithm for patients with loss of response to infliximab
Curatio PowerPoint Template
4/23/2017 4:34 AM
Proposed algorithm for patients with loss of response to infliximab
Therapeutic IFX concentration
Subtherapeutic IFX concentration
Positive HACA
Increase infliximab dose or frequency
Change to different
anti-TNF agent
Active disease on endoscopy/radiology?
Change to another anti-TNF agent
yes no
persistent disease
Fact Check:
Figure based on Afif fig 1, pg 1138 (PERMISSION NEEDED)
Change to different
anti-TNF agent
Investigate alternate etiologies
Change to different
anti-TNF agent
Change to non–
anti-TNF agent
Change to non– anti-TNF agent
Afif W et al. Am J Gastroenterol 2010;105:1133.

34. What About ADA in the Presence of Drug?

35. Therapeutic IFX Concentration had no effect on CRP in presence of ADA

36. Serum Adalimumab (ADA) Levels and Anti-Adalimumab Antibodies (ATA) Correlate with Endoscopic Inflammation and Inflammatory Markers
66 patients: 27% with detectable ATA
59 (89%) CD, 7 (11%) UC
Mean ADA levels were higher in patients with
Undetectable ATA
Mucosal healing
Concomitant use of immunosuppressants
ADA level ≥ 5 µg/ml is associated with lower CRP and healed mucosa
Variables associated with positive ATA (≥ 1.7 µg/ml)
ADA < 5µg/ml: OR 8.6, 95%CI (2.3-31)
Mucosal inflammation: OR 3.8, 95% CI (1.1-13)
Steroid use: OR 3.7, 95% CI (1.1-13)
Yarur, AJ, et al. Presented at DDW; May 21, Abstract Tu1147.

37. Mazor Y, et al. Aliment Pharmcol Ther 2014;40:620-8.
Cross-sectional study of ADA drug level as predictor of clinical response and CRP in CD
ADA level of 5.85 μg/mL was optimal
Sensitivity 68%
Specificity 71%
Positive LR 2.3
AAA were inversely related to ADA drug levels
Mazor Y, et al. Aliment Pharmcol Ther 2014;40:620-8.

38. Roblin X, et al. Clin Gastroenterol Hepatol 2014;12:80-84.
Higher trough levels of adalimumab are associated with higher rates of mucosal healing
Roblin X, et al. Clin Gastroenterol Hepatol 2014;12:80-84.

39. Trough adalimumab levels are higher in patients with mucosal healing
6.5 μg/mL
4.2 μg/mL
Roblin X, et al. Clin Gastroenterol Hepatol 2014;12:80-84.

40. Adalimumab Trough Serum Levels < 0
Adalimumab Trough Serum Levels < 0.33 µg/mL Predicts a Lower Rate of Sustained Complete Response in Patients with Crohn’s Disease
1.0
0.8
LogRank: P=.01
0.6
Patients with Sustained Clinical Response (%)
0.4
Reference corrected.
0.2
ADA TR>0.33 µg/mL, n=104
ADA TR<0.33 µg/mL, n=16
0.0 30 60 90
120
150
180
210
240
Sustained Clinical Response (weeks)
Karmiris K, et al. Gastroenterology. 2009;137:1628.

41. ADA levels in CLASSIC I (induction) and CLASSIC II (maintenance)
Median ADA level significantly higher in patients with clinical remission at week 4 (8.10 vs mcg/mL, P<0.05)
Clinical remission rate at week 24 of CLASSIC II for patients with undetectable ADA was 58% (7 of 12), compared with 53% (98 of 186) for patients with detectable concentrations (P=0.77)
Clinical remission rates at week 56 were 50% (7 of 14) and 64% (98 of 154; P= 0.39), respectively
Chiu YL, et al. Inflamm Bowel Dis 2013;19:

42. Proposed algorithm incorporating pharmacokinetics of adalimumab in IBD
Low TRA: <4.9 μg/ml
AAA present: >10 ng/ml
AAA: antibodies against adalimumab
ADA: adalimumab
TRA: trough levels of adalimumab
Roblin X, et al. Am J Gastroenterol 2014;109:

43. Trough Infliximab >2 µg/ml is Associated with Clinical Remission in Steroid-Refractory UC
Steroid-free Remission by IFX Trough Status
Single-center cohort of 125 steroid- refractory acute UC patients
Standard infliximab induction/maintenance
Fluid-phase assay for [IFX] and ATI
100
P<0.001 80
69.4
Patients in Remission (%) 60 40 20
17.5
Serum IFX ≤ 2µg/ml
Serum IFX > 2µg/ml
Colectomy by IFX Trough Status
Steroid-free Remission by IFX/ATI Status
100
P<0.001
100
P<0.001 80
P=0.073 80 60
55.5
70.0
Colectomy (%) 40
Reference Verification Note: Presented on Saturday (poster).
ATI, antibodies to infliximab
Background/Aims: Infliximab (IFX) induces clinical response and remission in ulcerative colitis (UC). Previous studies have shown that formation of antibodies to infliximab (ATI) is associated with loss of clinical benefit and colectomy. However, solid phase ELISA ATI assay measurements are limited as they cannot detect ATI in the presence of circulating drug. We therefore evaluated the relationship between trough serum infliximab and ATI to long-term clinical outcome in acute UC using a recently developed fluid phase assay that simultaneously detects ATI and drug.
Methods: A cohort of 134 patients with steroid refractory acute UC treated with three-dose IFX 5 mg/kg induction followed by scheduled maintenance therapy were included. Serum concentrations of IFX and ATI were measured by a fluid phase assay (Prometheus Laboratories, San Diego CA). Rates of steroid free clinical remission (Mayo score 0) and colectomy were assessed in relation to the presence or absence of detectable trough serum levels of IFX with or without ATI formation.
Results: Of the 134 patients, 103 had pancolitis and 31 had disease to the splenic flexure. The median Mayo score was 9 (range: 6-12). After a median follow-up of 19.9 months (IQR: ), the rate of steroid-free remission was 43.3% and 53 patients (39.6%) had undergone colectomy (median time of 6.5 months (IQR: ). For patients with evaluable serum samples (n=125), a detectable trough serum infliximab was present in 68 patients (54.4%), of whom 6 (8.8%) had detectable ATI. Amongst the 57 patients (45.6%) with undetectable serum IFX, 45 patients (78.9%) were ATI positive and 12 patients (21.1%) were ATI negative. A detectable trough infliximab > 2μg/ml, without or with ATI, was associated with a higher rate of clinical steroid free remission (69% vs. 16%; P<0.001), that was sustained over the follow-up period. For patients with a detectable trough serum infliximab and no ATI, only one developed lower titre ATI (< 10U/ml) with detectable drug and no loss of response. A trough serum infliximab < 2μg/ml with or without ATI formation was associated with an increased risk for colectomy (64% vs. 13%; P<0.001).
Conclusions: For patients with steroid refractory ulcerative colitis treated with infliximab, a detectable trough serum infliximab > 2μg/ml is associated with sustained clinical remission and a lower risk for colectomy. A threshold serum infliximab ≤ 2μg/ml, irrespective of ATI status, is associated with a less favorable outcome.
Association of Serum Infliximab and Antibodies to Infliximab to Long-Term Clinical Outcome in Acute Ulcerative Colitis Sa2047 |
Sanjay Murthy1, 2, David Kevans1, 2, Cynthia H. Seow1, 2, Alvin Newman1, 2, A. Hillary Steinhart1, 2, Mark S. Silverberg1, 2, Gordon R. Greenberg1, 2
Affiliation 1Division of Gastroenterology, Mount Sinai Hospital, Toronto, ON, Canada; 2Department of Medicine, University of Toronto, Toronto, ON, Canada 60
17.7 20
Patients in Remission (%) 40
Serum IFX ≤ 2µg/ml
Serum IFX > 2µg/ml
28.5
P=0.84 20
16.6
13.0
Remission aOR [95%CI]
Colectomy aOR [95%CI]
Trough IFX > 2 µg/ml (vs. ≤ 2 µg/ml)
10 [3,35]
0.18 [0.07,0.44]
ATI (vs. no ATI)
0.64 [0.2,2.4]
1.0 [0.5,2.1]
IFX+ ATI-
IFX+ ATI+
IFX- ATI-
IFX- ATI+
IFX, infliximab
Murthy S, et al. Presented at DDW; May 19, Abstract Sa2047.

44. Rapid IFX Clearance: Mechanism of Non-Response in UC
Kevans D, et al. Presented at DDW; May 19, 2012.

45. Pharmacokinetics of Infliximab Induction Therapy in Patients With Moderate to Severe UC
Multicenter, propspective observational study in anti-TNF-naïve patients (N=19) with moderate-to-severe UC (Endoscopic Mayo 2/3)1
IFX measured at 10 time points during first 6 weeks of induction therapy
Nonlinear mixed-effects modelling
No difference in IFX concentration area under the curve (AUC) between endoscopic responders and endoscopic non-responders at week 8 (P=0.65 )
Patients with CRP>50 µg/mL had lower IFX concentration (P=0.001)
7/19 had positive ATI (homogeneous mobility shift assay)
6 of 8 endoscopic non-responders were ATI +
2 of 8 endoscopic non-responders were ATI –
Concomitant immunomodulator = 12/19 (P=NS)
IFX presumed to be lost in stool in severe IBD colitis2
The Pharmacokinetics of Infliximab Induction Therapy in Patients With Moderate to Severe Ulcerative Colitis
4:48 | 786 | Johannan F. Brandse1, Desiree van der Kleij2, Gert-Jan Wolbink3, 4, Irma M. Rigter5, Paul A. Baars6, M. Lowenberg1, Cyriel Ponsioen1, Jeroen M. Jansen7, Gijs R. van den Brink1, Ron A. Mathôt5, Geert R. D'Haens1
Print Affiliation
1Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; 2Biologicals Laboratory, Sanquin Laboratory, Amsterdam, Netherlands; 3Sanquin Research, Sanquin Laboratory, Amsterdam, Netherlands; 4Rheumatology, Jan van Bremen Institute, Reade, Amsterdam, Netherlands; 5Hospital Pharmacy, Academic Medical Center, Amsterdam, Netherlands; 6Clinical Immunology, Academic Medical Center, Amsterdam, Netherlands; 7Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands
Abstract:
Background: The mechanism behind primary non-response to infliximab (IFX) in patients with Ulcerative Colitis (UC) is not fully understood. Although insufficient serum concentrations of IFX have been suggested as a cause of lack of response associated with a high inflammatory load (and hence large quantities of TNF to be neutralized), the early pharmacokinetics (PK) of IFX during induction therapy have been poorly studied. We studied the PK of IFX induction treatment related to inflammatory load and response in patients with moderate and severe UC.
Methods: In this multicenter prospective observational study anti-TNF naïve patients with moderate-to-severe Ulcerative Colitis (Endoscopic Mayo 2/3) starting on IFX were included after baseline endoscopy. Serum IFX concentrations, antibodies to IFX and fecal samples (IFX concentration) were collected at 10 serial time points during the first 6 weeks of induction therapy. Response was defined by endoscopic improvement at week 6-8. PK was analysed by nonlinear mixed-effects modelling and described using a 2-compartiment PK model.
Results: Fifteen UC patients were included. All but one patient received IFX according to the regular induction regime of 5mg/kg at week 0,2,6 and 7/15 with concomitant thiopurines. 8/15 patients had no endoscopic improvement. Typical values and corresponding inter-patient variability (IPV) for clearance, intercompartimental clearance, central and peripheral volume of distribution were 0.44 L/day (IPV 26%), 0.52 L/day, 3.5 L (IPV 20%) and 3.2 L (IPV 130%). Median ‘trough' level before third infusion (week 6) was 2.5 ug/ml for endoscopic non-responders versus 8.2 ug/ml for responders (P=0.03). Serum IFX of ≤7ug/ml at day 42 was defined as a cut-off with OR:36 (95%CI , P=0.03) to predict endoscopic non-response. Four patients (1/4 used concomitant thiopurine) developed antibodies to IFX at week 6, clearance was 4.4 fold increased and peripheral volume of distribution was 0.05 fold decreased in these patients. Fecal IFX at day 1 was significantly higher (P=0.02) for non-responders compared to responders. Average (± SD) post-hoc area under the IFX concentration versus time curve (AUC) was 1204 ± 507 mg/L/day 49 in the non-responders compared to 1417 ± 444 mg/L/day for the responders (p=0.42).
Conclusions: A wide variation in early serum concentrations of infliximab was observed. Primary non-responders have lower serum concentrations at induction compared to responders, as well as increased fecal concentrations in the first days of treatment and in some instances early development of antibodies to infliximab.
Disclosure(s):
Johannan F. Brandse - Advisory Committees or Review Panels: Ferring; Speaking and Teaching: MSD, Tramedico
Cyriel Ponsioen - Advisory Committees or Review Panels: Abbott Laboratories, Glaxo Smith Kline; Grant/Research Support: Abbott Laboratories, Schering-Plough Corp., Falk Pharma, Tramedico
Jeroen M. Jansen - Advisory Committees or Review Panels: Abbott, MSD, Ferring, dr. Falk; Speaking and Teaching: GSK
Gijs R. van den Brink - Advisory Committees or Review Panels: AbbVie; Grant/Research Support: Guliani, Crucell, AbbVie; Speaking and Teaching: MSD, AbbVie, Takeda
Geert R. D'Haens - Advisory Committees or Review Panels: Jansen Biologics, Abbvie, TEVA, Glaxo Smith Kline, Shire Pharmaceuticals Inc., Nova Nordisk A/S, Pfizer Inc ; Consulting: MSD, Takeda, AM Pharma, Boehringer Ingelheim, Galapagos, Tillotts, Receptos, Salix , Setpoint, Versant; Grant/Research Support: Falk Pharma, MSD; Speaking and Teaching: MSD, Takeda, Abbvie, Ferring Pharmaceuticals Inc
The following people have nothing to disclose: Desiree van der Kleij, Gert-Jan Wolbink, Irma M. Rigter, Paul A. Baars, M. Lowenberg, Ron A. Mathôt
Brandse JF, et al. Presented at DDW; May 5, 2014 A786.
Brandse JF, et al. Presented at DDW; May 18, A157.

46. 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 formation
Increases serum mAbs
Decreases mAb clearance
Better clinical outcomes
High baseline TNF-α
May decrease mAbs by increasing clearance
Low albumin
Increases clearance
High baseline CRP
Body size
High BMI may increase clearance
Gender
Males have higher clearance
Fact Check:
Table taken from Ordas, table 3, pg 7 (PERMISSION NEEDED)
mAB, monoclonal antibody; ADA, antidrug antibody
Ordas I et al. Clin Pharmacol Ther. 2012;91:635.

47. Do early serial trough and antidrug antibody level measurements predict clinical outcome of infliximab and adalimumab treatment?
Vande Casteele N, et al. Gut 2012;61:321

48. Monitoring Biologics To Guide Treatment Decisions
ADA=anti-drug antibody
Afif W et al. Am J Gastroenterol. 2010;105:

49. What drives loss of response to monoclonal anti TNF Abs?
Neutralizing antibodies/low trough levels
Other immune pathways drive inflammation
Patient has no residual inflammation
Options
Increase dose, switch to other anti-TNF
Biological with other MOA, immunosuppress.
Surgery

50. Utility of IFX and ATI assays
Afif, Am J Gastoenterol 2010

51. Measuring Infliximab and HACA Concentrations in Patients With IBD: Clinical Outcomes** *
**P < 0.004
*P < 0.016
Afif W, et al. Am J Gastroenterol. 2010;105(5):

53. BRIDGe “anti-TNF optimizer”

54. BRIDGe “anti-TNF optimizer”

55. BRIDGe “anti-TNF optimizer”

56. BRIDGe “anti-TNF optimizer”

57. BRIDGe “anti-TNF optimizer”

58. Can you make antibodies go away?
IFX levels closed squares
ATI open squares
Ben-Horin S, et al. Clin Gastroenterol Hepatol. 2013; 11: