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Association Between Plasma Concentrations of Certolizumab
Pegol and Endoscopic Outcomes of Patients With Crohn's Disease
Jean–Frédéric Colombel, William J. Sandborn, Matthieu Allez, Jean–Louis Dupas, Olivier Dewit, Geert D'Haens, Yoram Bouhnik, Gerald Parker,
Bosny Pierre–Louis and Xavier Hébuterne
Clinical Gastroenterology and HepatologyDOI: 10.1016/j.cgh.2013.10.025
Copyright © AGA Institute Terms and Conditions
Stephen B. HanauerStephen B. Hanauer
Potential ConflictsPrometheus, AbbVie, Janssen, UCB
Infliximab AdalimumabGolimumab
IgG1Fc
Fab
Monoclonal antibody
HumanChimeric
Fab′
Certolizumab pegol
PEG
PEGylated humanized
Fab′ fragment2 × 20 kDa
PEG
Anti-TNF Antibodies & PEGylated Fab' fragment for IBD
Anti-TNF Antibodies & PEGylated Fab' fragment for IBD
Background: Certolizumab pegolBackground: Certolizumab pegol
Anti–tumor necrosis factor-α (TNF-α) agent
IgG1 FAB fragment (Fc free) that is pegylated / univalent and ~ 95% humanized
Approved for treatment of moderate- severe active CD in United States, Switzerland, Russia, Mexico, Ecuador, Brazil, Argentina, Chile, Dominican Republic
Fab′ Fab′Certolizumab
pegol
PEG
PEGylated humanized
Fab′ fragment2 × 20 kDa
PEG
Clinical Trials with Anti-TNF Biologics in Refractory Crohn’s disease
Clinical Trials with Anti-TNF Biologics in Refractory Crohn’s disease
Drug
Placebo
Drug
Placebo
Drug
Placebo
Drug
Responder
ResponseMaintenance
Maintenance
Targan/InfliximabClassic I/Adalimumab
ACCENT I/InfliximabCHARM/AdalimumabPRECiSE 2/Certolizumab
CLASSIC II/AdalimumabPRECiSE1/Certolizumab
Recent Anti-TNF Biologic TrialsRecent Anti-TNF Biologic Trials
Step-up/Top-down (Steroid-naïve)
COMMITT(Steroid-induced, IS naive)
SONIC(Steroid-refractory, IS naïve)
SteroidsSteroidsIS
Infliximab + IS
Infliximab
Infliximab + MTX
Infliximab
Infliximab + AZA
AZA
BackgroundBackground
Monitoring plasma concentrations of anti–tumor necrosis factor agents could optimize treatment of patients with Crohn's Disease (CD). In post hoc analysis of data from a clinical trial
in patients with moderate to severe ileocolonic Crohn’s disease (MUSIC) Compared relationship between plasma
concentrations of certolizumab pegol (CZP) and: Endoscopic response Clinical response Clinical Remission
MUSIC TrialMUSIC Trial
After 1 week screening patients entered 52-wk treatment CZP 400 mg s.c at wks 0, 2, 4, then q4wk to wk 52 If no clinical response (CDAI 100)/ remission (CDAI<150) by
wk10 or if clinical resp. lost after wk 10, dose was escalated to 400 mg q2w **(not included in analysis)
CZP plasma concentrations collected at wks 8 (trough) & 54 (mid-2wk) and stratified by quartiles.
Rates of endoscopic response (CDEIS decrease from baseline, >5) and remission (CDEIS, <6) were determined at weeks 10 and 54.
Loss of clinical response was defined as CDAI greater than 150 and an increase in CDAI of 70 points or more at 2 consecutive visits vs week 10.
Analysis SetAnalysis Set
Pts who received loading dose of CZP 400 mg at 0, 2, and 4 weeks, and had an available CZP trough measurement at week 8, and endoscopic and clinical measurements available at week 10 (n = 45).
For wk 54 analyses subset of patients with: (1) availability of CZP plasma measurement at week 54; (2) endoscopic and clinical measurements available at week 54; (3) pts who stayed in every 4 wks dosing group until wk 54.
These criteria limited number of pts with available data at wk 54 to a total of only 18.
Statistical AnalysesStatistical Analyses
CZP plasma concentrations expressed as geometric means with coefficient of variation and related 95% confidence intervals (CIs). Relationship between CZP plasma
concentration quartiles at wk 8 and response or remission at week 10 analyzed using Mantel–Haenszel chi-square test. Logistic regression used to examine
association between plasma CZP levels and outcomes.
Statistical Analyses (cont)Statistical Analyses (cont)
Multivariate analyses conducted to evaluate influence of pt baseline characteristics on CZP trough concentration at week 8.
Effect of each covariate was investigated separately using a univariate linear regression model.
Stepwise multivariate regression subsequently used to identify baseline covariates most likely associated with CZP plasma concentration at week 8.
Covariates included in multivariate model: baseline body weight (kg), CRP, CDEIS, CDAI, gender, immunosuppressant
(azathioprine, 6-mercaptopurine, methotrexate) intake (no/yes), and albumin within normal range (yes/no).
Source: Clinical Gastroenterology and Hepatology (DOI:10.1016/j.cgh.2013.10.025 )Copyright © AGA Institute Terms and Conditions
MUSIC Trial DesignMUSIC Trial Design
Source: Clinical Gastroenterology and Hepatology (DOI:10.1016/j.cgh.2013.10.025 )Copyright © AGA Institute Terms and Conditions
Associations between clinical and endoscopic responses or remission at week 10 and plasma CZP concentrations at
week 8
Associations between clinical and endoscopic responses or remission at week 10 and plasma CZP concentrations at
week 8
Source: Clinical Gastroenterology and Hepatology (DOI:10.1016/j.cgh.2013.10.025 )Copyright © AGA Institute Terms and Conditions
Rates of endoscopic response and remission and clinical response and remission at week 10 by CZP plasma concentration quartiles (μg/mL) at week 8 (trough).
Rates of endoscopic response and remission and clinical response and remission at week 10 by CZP plasma concentration quartiles (μg/mL) at week 8 (trough).
Source: Clinical Gastroenterology and Hepatology (DOI:10.1016/j.cgh.2013.10.025 )Copyright © AGA Institute Terms and Conditions
Rates of endoscopic response and remission and clinical response and remission at week 54 by CZP plasma concentration quartiles (μg/mL) at week 54 (2-week
midpoint).
Rates of endoscopic response and remission and clinical response and remission at week 54 by CZP plasma concentration quartiles (μg/mL) at week 54 (2-week
midpoint).
Relationship Between Baseline Factors and CZP Plasma Concentration at Week 8
Relationship Between Baseline Factors and CZP Plasma Concentration at Week 8
Baseline variable P value
Univariate Stepwise regression regression
CRP level, mg/L .0019 .0014Body weight, kg .0500 .0373Albumin in normal range .1109 _Sex, female vs male .1020 _Immunosuppressants, no vs yes .3268 _CDAI score .5132 _CDEIS score .2446 _
LimitationsLimitations
Small sample sizes (week 10, n = 45; week 54, n = 18) Data showed an association but not causality CZP plasma concentrations not at steady state at week
8 after the loading dose, but rather are at a steady state at 4 weeks after the loading dose. Thus trough concentrations at week 8 cannot be compared with
a maintenance trough concentration. The pharmacokinetic data point from week 54 is 2 weeks after a
CZP 400-mg dose. Thus, the CZP plasma concentration from week 54 is at the midpoint in the dosing cycle and not a trough.
ConclusionsConclusions
Endoscopic response and remission associated with higher concentrations of CZP
The highest CZP plasma concentration quartiles associated with higher rates of endoscopic response and remission at week 10.
At week 54, rates of endoscopic remission correlated with the CZP plasma concentration.
Higher body weight and CRP concentrations were associated with lower CZP concentrations.
ConclusionsConclusions
Significant inverse relationship between CZP plasma concentration and baseline CRP suggests a high inflammatory burden may increase the clearance of the TNF antagonist. The association between endoscopic outcome
and CZP concentrations supports need to consider the PKs of TNF antagonists when optimizing drug treatment. Findings from post hoc analysis should be
evaluated further in a prospective randomized trial.
Chicken vs Egg Chicken vs Egg
It is possible that higher trough concentrations at week 8 may be a consequence of mucosal healing and, thus, higher rates of CDEIS response and remission at week 10.
Therapeutic Monitoring with BiologicsTherapeutic Monitoring with Biologics
Trough Levels of Infliximab May Be a Better Predictor of Continued
Response Than ATI
Trough Levels of Infliximab May Be a Better Predictor of Continued
Response Than ATI
Undetectable 2.0 ug/ml
* P < 0.001
Undetectable 2.0 ug/mlUndetectable 2.0 ug/ml
* P < 0.001 * P < 0.001
CLINICAL REMISSION C- REACTIVE PROTEIN ENDOSCOPIC CHANGE
**
*
Maser EA et al. Clin Gastroenterol Hepatol. 2006;4:1248-54
High Infliximab Levels are Associated with Mucosal Healing in Crohn’s Disease
High Infliximab Levels are Associated with Mucosal Healing in Crohn’s Disease
Serum samples in 210 CD patients undergoing treatment with infliximab
Infliximab trough levels were correlated with endoscopic healing (complete, partial or none)
0
1
2
3
4
5
6
7
Complete Partial None
Trou
gh le
vel (
mcg
/mL)
Van Moerkercke W. et al. DDW 2010. Abs #405
Clinical Remission Without Corticosteroidsby Trough Infliximab Concentration:
Serum Infliximab Trough Levels at Week 30
Clinical Remission Without Corticosteroidsby Trough Infliximab Concentration:
Serum Infliximab Trough Levels at Week 30
59 57
73 74 72
0102030405060708090
100
0 >0-1 >1-3 >3-6 >6
% o
f Pat
ient
s
Serum IFX Concentration* (g/mL)
1.6
3.5
0123456789
10
IFX IFX + AZA
Seru
m IF
X C
once
ntra
tion*
(g/
mL)
P<0.001
Steroid-free Clinical Remission atWeek 26 by IFX Trough Level at Week 30Median IFX Concentration
* IFX- or IFX/AZA-treated patients who had serum samples collected prior to infusion at wk 30 (n=206).
N=97 N=109 19/32 13/23 43/59 36/49 31/43
SONIC
Colombel JF et al. N Engl J Med. 2010;362:1383-1395.
Concentration–effect relationship of IFX in CD: Results of a cohort study
Concentration–effect relationship of IFX in CD: Results of a cohort study
The aim was to study concentration–effect relationships of IFX in a cohort of CD patients.
Relationship between C-reactive protein concentrations and infliximab trough concentration. Observed data are represented by open circles and model predicted data are represented by the curve.
Lamblin et al. ECCO 2012, abstract P334
• 44 pts included (20 in remission)
• IFX concentrations were higher in pts in remission (6.33 mg/L vs 3.39 ug/ml p<0.02)
• Estimated IFX concentration leading to 50% decrease CRP level was 1.1 ug/ml
• CRP below 5mg/L was obtained by > 5.6 ug/ml IFX
• Optimal trough level of IFX is suggested to be 5 ug/ml
Time (days)
Sim
ulat
ed a
nti-T
NF
biol
ogic
con
c
0 20 40 60 80 100 120
0.5
1.0
5.0
10.0
50.0
Time (days)
Sim
ulat
ed a
nti-T
NF
biol
ogic
con
c
0 20 40 60 80 100 120
0.5
1.0
5.0
10.0
50.0
Time (days)
Sim
ulat
ed a
nti-T
NF
biol
ogic
con
c
0 20 40 60 80 100 120
0.5
1.0
5.0
10.0
50.0
Time (days)
Sim
ulat
ed a
nti-T
NF
biol
ogic
con
c
0 20 40 60 80 100 120
0.5
1.0
5.0
10.0
50.0
Time (days)
Sim
ulat
ed a
nti-T
NF
biol
ogic
con
c
0 20 40 60 80 100 120
0.5
1.0
5.0
10.0
50.0
Adalimumab 160 mg (day 1), 80 mg (day8)and 40 mg every two weeks Adalimumab 40 mg every two weeks
Infliximab 5 mg/kg at day 1, day 15, day 43 and every 8 weeksInfliximab 3 mg/kg at day 1, day 15, day 43 and every 8 weeks
Theoretical threshold
Subtherapeutic
Implications of Low Trough LevelsImplications of Low Trough Levels
Disease RecursNo longer maintenance but re-
treatmentDevelopment of anti-drug
antibodiesEventual loss of response
Factors that Influence the PK of TNF Antagonists
Factors that Influence the PK of TNF Antagonists
Impact on TNF antagonist PKPresence of ADAs Decreases drug concentration
Increases clearanceWorse clinical outcomes
Ordas I et. al. Clin Gastroenterol Hepatol.
28
Factors that Influence the PK of TNF Antagonists
Factors that Influence the PK of TNF Antagonists
Impact on TNF antagonist PK
Concomitant use of immunosuppressives
Reduces ADA formationIncreases drug concentrationDecreases drug clearanceBetter clinical outcomes
Ordas I et. al. Clin Gastroenterol Hepatol.
29
Factors that Influence the PK of TNF Antagonists
Factors that Influence the PK of TNF Antagonists
Impact on TNF antagonist PK
Low serum albumin concentration Increases drug clearanceWorse clinical outcome
High baseline CRP concentration Increase drug clearanceHigh baseline TNF concentration May decrease drug concentration by
increasing clearance
Ordas I et. al. Clin Gastroenterol Hepatol.
30
Factors that Influence the PK of TNF Antagonists
Factors that Influence the PK of TNF Antagonists
Impact on TNF antagonist PK
High body size May increase drug clearanceSex Males have higher clearance
Ordas I et. al. Clin Gastroenterol Hepatol.
31
Factors that Influence the PK of TNF Antagonists
Factors that Influence the PK of TNF Antagonists
Impact on TNF antagonist PKPresence of ADAs Decreases drug concentration
Increases clearanceWorse clinical outcomes
Concomitant use of immunosuppressives
Reduces ADA formationIncreases drug concentrationDecreases drug clearanceBetter clinical outcomes
Low serum albumin concentration Increases drug clearanceWorse clinical outcome
High baseline CRP concentration Increase drug clearanceHigh baseline TNF concentration May decrease drug concentration by
increasing clearanceHigh body size May increase drug clearanceSex Males have higher clearance
Ordas I et. al. Clin Gastroenterol Hepatol.
32
What drives loss of response to monoclonalanti 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
Algorithm for loss of response to Anti-TNFAlgorithm for loss of response to Anti-TNF
Is there active disease?
Yes
Measure mAb and ADA Low [mAb]
undetectable ADA
Suboptimal PK
Increase mAb dose or frequency
Undetectable [mAb]Detectable ADA
Loss of response due to ADA
Switch mAb
Therapeutic [mAb]
IBD refractory to anti‐TNF
Alternative MOA(Natalizumab)
No IBS SBBOBile‐acid diarrheaStrictures
Utility of Drug and ADA for Loss of Response
Utility of Drug and ADA for Loss of Response
Afif, Am J Gastoenterol 2010
If Drug Level is Low, Increase the Dose
Afif, Am J Gastoenterol 2010
If Anti-Drug Antibodies, Switch
Utility of Drug and ADA for Loss of Response
Utility of Drug and ADA for Loss of Response
Afif, Am J Gastoenterol 2010
Utility of Drug and ADA for Loss of Response
Utility of Drug and ADA for Loss of Response
No benefit of substituting one mAB for another if adequate concentrations
If Drug is Present, Switch Mechanisms
Preventing Loss of ResponsePreventing Loss of Response
Infliximab trough levels may predict sustained response to infliximab in patients with Crohn's disease: A single cohort
study
Infliximab trough levels may predict sustained response to infliximab in patients with Crohn's disease: A single cohort
study N = 84, responded to 3 dose induction followed by scheduled
maintenance therapy Blood samples: prior to 1st or 2nd maintenance infusion (TLcut-off 3 μg/ml)
Sustained Response (SR) to IFX in 47 (56%) patients after FU of 25 mo
Bortlik et al. ECCO 2012, abstract P360
• After a median follow up of 2 years, SR to IFX was observed in slightly more than half of CD patients. IFX TL >3 μg/ml at the start of maintenance regime was predictive of SR to IFX.
Univariate Analysis Multivariate AnalysisIFX TL TLs >3 μg/ml associated with a
decreased probability of loss of SR
(HR 0.31; 95%CI: 0.16–0.62),
Had impact on SR to IFX
(HR 0.34; 95%CI: 0.16-0.74
Corticosteroids increased the risk of treatment failure (HR 2.34, 95%CI: 1.13–4.84).
No impact
Thiopurines No impact No impact
• Only 43% have optimal ITL. In the others dose adjustment was carried out. • 9% of the patients have undetectable ITL despite staying in remission. •Dose escalation improved outcomes (HBS & CRP)•After initial dose optimization, no benefit of TDM vs clinical and CRP monitoring
Individualized IFX Treatment using Therapeutic Drug Monitoring: a Prospective Controlled Trough Level Adapted InfliXImab Treatment
(TAXIT) Trial
Individualized IFX Treatment using Therapeutic Drug Monitoring: a Prospective Controlled Trough Level Adapted InfliXImab Treatment
(TAXIT) Trial
270 IBD patients on IFX maintenance therapy. All pts had their IFX trough levels adjusted to 3-7 ug/ml.
They were then randomized to dosing based on IFX trough levels (ITL) group 1: ITL kept between 3 and 7 μg/ml group 2: dosing and optimization based on clinical symptoms
Vande Casteele et al. UEGW 2013
Perc
enta
ge o
f pat
ient
s (%
)
Decreased dose
Increased dose
Baseline trough levels
(77%) were ATI positive
Post-induction serum infliximab trough level and
decrease of C-reactive protein level are associated with sustained response to
infliximab: a retrospective analysis of the ACCENT I trial
Post-induction serum infliximab trough level and
decrease of C-reactive protein level are associated with sustained response to
infliximab: a retrospective analysis of the ACCENT I trial
Cornillie F, Hanauer SB, Diamond RH, Wang J,Tang KL, Xu Z, Rutgeerts , Vermiere S
Gut, in Press
MethodsMethods
ACCENT I was a multicentre, randomised,placebo-controlled study. Week 14 trough levels and CRP percentage
decrease from baseline to week 14 compared between patients with/without sustained response through week 54. Sensitivity and specificity determined to predict
sustained response. Receiver operating characteristic (ROC) curves
identified optimal cut-off points; logistic regression determined ORs.
ResultsResults
After induction with 5 mg/kg infliximab, 25%(37/147) and 33% (47/144) of pts sustained week 14response to infliximab 5 or 10 mg/kg without dose-
escalation through week 54.
Median week 14 trough levels of patients with and without sustained response to infliximab 5 mg/kg were 4.0 and 1.9 mg/mL (p=0.0331).
Results (cont)Results (cont)
Optimal predictors of sustained response to maintenance infliximab 5 mg/kg were week 14 trough level ≥3.5 mg/mL and ≥60% CRP decrease [ORs (95% CI), 3.5 (1.1 to 11.4) and 7.3 (1.4 to 36.7)] in patients with raised baseline CRP Area under the ROC curve was 0.75 for both
predictors. A ≥3.5 mg/mL week 14 infliximab serum level did
not predict sustained response to 10 mg/kg maintenance infliximab.
CRP may be surrogate for adequate Drug Trough?
CRP may be surrogate for adequate Drug Trough?
Therapeutic Drug Monitoring with BiologicsTherapeutic Drug Monitoring with Biologics
Assessing loss of response Also cost effective vs. empiric changes
Preventing loss of response Preventing complications Pharmacoeconomics
✔
✔−
??