Download What to Do When Anti-TNFs Don*t Work

When and How to Use Therapeutic
Drug Monitoring in IBD Patients
Bruce E. Sands, MD, MS
Chief of the Dr. Henry D. Janowitz Division of
Gastroenterology
Dr. Burrill B. Crohn Professor of Medicine
Icahn School of Medicine
at Mount Sinai
New York, NY
Disclosures
•
•
•
•
•
•
•
•
•
•
•
AbbVie
Amgen
Celgene
Forest Research Institute
Janssen Biotech
Luitpold Pharmaceuticals
MedImmune
Millennium Pharmaceuticals
Pfizer
Prometheus Laboratories
Takeda
Overview
• To understand the relationship between pharmacokinetics
(levels and distribution of drug) to pharmacodynamics
(therapeutic and adverse effects)
• To determine the roles for therapeutic drug monitoring in
treating IBD, as well as limitations of current knowledge
TOXICITY
MTC
Duration of action
Therapeutic
Range
Cmax
AUC
MEC
LACK OF EFFICACY
Onset
time
tmax
Time
Association of 6-thioguanine nucleotide levels and IBD
activity: a meta-analysis
·Osterman MT. Gastroenterology 2006;130:1047-53.
Prospective Data Supporting Metabolite-Based Dose
Optimization of Thiopurines are Inconclusive
•Multicenter RCT comparing AZA dosing - weight-based (2.5 mg/kg/day)
versus individualized (stratified by TPMT, then optimized to target
6TGN – 250-400 pmol/8 x 108RBC)
•Powered for 226 subjects, 50 subjects randomized, 27 subjects completed
Individualised
Individualised
70
60
p=0.11
40
16
Per Protocol
Intention To Treat
100
90
80
70
60
50
40
30
20
10
0
Weight-Based
50
40
30
Weight-Based
60
p=0.12
25
20
10
0
Clinical Remission at 16
weeks(%)
Clinical Remission at 16
weeks(%)
Dassopoulos T, et al. Aliment Pharmacol Ther 2014;39: 163-175
Higher 6-TGN Levels are Associated with Higher Infliximab
Trough Levels in Patients on Combination Therapy
• Cross-sectional study of 72 patients on combination therapy
• 6TGN levels (but not thiopurine dose or lymphocyte count) correlated with IFX
levels (rho:0.466, p<0.001)
• 6TGN > 125 pmol/8 x 108 RBC predicted higher IFX levels – ROC: 0.82, p=0.002
• 6TGN < 125 pmol/8 x 108 RBC predicted higher likelihood of ATIs – OR: 1.3, 95% CI
2.3 – 72.5, p<0.01
6TGN level –
pmol/8 x 108RBC
250
200
P=0.02
193
150
117
100
50
ATI -ve
ATI +ve
0
Yarur A et al. DDW 2014, Abstract 788
Thiopurine Metabolites Help Clarify Reasons for
Inefficacy or Intolerance to Thiopurines
•Metabolite measurements are indicated in patients not responding
or experiencing adverse events to adequate weight-bases doses of
thiopurines
Absent 6-TGN/
Absent 6-MMP
Low 6-TGN/
Low 6-MMP
Low 6-TGN/
High 6-MMP
Ther 6-TGN/
Ther 6-MMP
High 6-TGN
High 6-MMP
NonAdherence
Underdosing
Thiopurine
Resistance
Thiopurine
Refractory
Overdosing
Education
Increase
dose
Allopurinol
Another
drug
Decrease
dose
=
=
=
=
=
Adapted from Gearry RB et al J Gastroenterol Hepatol 2005; 20:1149-57
Questions about therapeutic drug monitoring
(TDM) with biologic therapy

What is the relationship of exposure to response?

Can we define a minimum effective concentration?

Can we define a maximum therapeutic concentration above which there is
– no additional benefit?
– increased risk of toxicity?

What is the relationship between drug concentration and anti-drug antibodies, and
how should this affect treatment strategy?

Is TDM cost-effective?

In what clinical situations should TDM be used?
–
–
–
–
–
Induction?
Maintenance?
Loss of response?
Toxicity?
Retreatment after drug holiday?
Higher Serum Infliximab Concentration is Associated
with a Higher Response Rate in CD
– 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
100
Duration of Response (days)
• Study design: prospective,
cohort study
• N=125, 30% Rx for fistula
• Median follow-up: 36 months
• Efficacy
81.5
80
68.5
P<0.01
60
40
20
0
≥12.0 μg/mL
<12.0 μg/mL
Baert F, et al. N Engl J Med. 2003;348:601.
Clinical Remission Without Corticosteroids by
Trough IFX Concentration at Week 26: SONIC
·Proportion of Patients (%)
Primary Endpoint
100
90
80
70
59
60
50
40
30
20
10
19/32
0
0
73
74
72
13/23
43/59
36/49
31/43
>0-1
>1-3
>3-6
>6
57
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. 2010.
Higher Serum Infliximab Level is Associated with Longer
Remission and Better Endoscopy Score in CD
– Infliximab concentrations were
positively correlated with the
interval of clinical remission and
change in endoscopic score
Remission (%)
90
80
70
60
R2= 0.61
P<0.001
50
40
0
Endoscopic Improvement (%)
• Study design: prospective cohort in
moderate-severe CD
• N=105
• Median follow-up: 88 weeks
• Efficacy
100
2
4
6
8
10
Serum Infliximab (µg/ml)
12
100
50
0
50
R2= 0.46
P<0.001
-100
0
2
4
6
8
10
Serum Infliximab (µg/ml)
12
Maser EA, et al. Clin Gastroenterol Hepatol. 2006;4:1248.
High Infliximab Levels are Associated with
Mucosal Healing in Crohn’s Disease
7
Trough level (mcg/mL)
• Serum samples in 210
CD patients
undergoing treatment
with infliximab were
collected
• Infliximab trough
levels were correlated
with endoscopic
healing (complete,
partial or none)
6
5.77
5
3.89
4
3
2
0.95
1
0
Complete
Partial
None
·Van Moerkercke W. et al. DDW 2010. Abs #405
ACCENT I: Week 54 Sustained Clinical Outcome and
Week 14 Serum Infliximab Level in CD
Sustained Clinical Outcome
Subjects included in analysis
<3.5 μg/mL Week 14 ≥3.5 μg/mL Week 14
Serum IFX Level
Serum IFX Level
96
51
Subjects with sustained
response
17 (17.7%)
20 (39.2%)
Subjects without sustained
response
79 (82.3%)
31 (60.8%)
P-value*
0.0042
*Chi-square test
Cornillie F, et al. Presented at the 19th Annual United European Gastroenterology Week (UEGW); October 25, 2011. Stockholm,
Sweden. Abstract P0919.
Prospective cohort study of relationship between
serum infliximab level and efficacy in luminal CD
Levesque BG, et al. Aliment Pharmacol Ther. 2014;39:1126-35.
Detectable Serum Trough Infliximab Associated with Higher
Remission Rate and Endoscopic Improvement in UC
– Detectable serum IFX was
associated with
• Higher remission rates (69%
vs. 15%; P<0.001)
• Endoscopic improvement
(76% vs. 28%; P<0.001)
80
Remission (% of Patients)
• Study design: cohort study
• N=115 patients with moderate
to severe UC
• Follow-up time: median 13.9
months
• Efficacy
69
70
60
50
P<0.001
40
30
20
15
10
0
Undetectable
Detectable
Seow CH, et al. Gut. 2010;59:49-54.
Presence of Detectable Trough Infliximab Levels
Reduces Colectomy Rates in Ulcerative Colitis
Colectomy (% of Patients)
100
P < 0.001
80
60
55
40
20
7
0
Undetectable
Detectable
Seow CH, et al. Gut. 2010;59:49.
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.
1st
Quartile
2nd
Quartile
3rd
Quartile
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%
25.5%
(<0.11μg/mL) (≥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)
79.0%
(≥3.6-<8.1μg/mL)
60.0%
(>8.1μg/mL)
P=0.0066
IFX Conc.
(% patients)
55.0%
(≥1.4-<3.6μg/mL)
Reinisch W et al., Gastro Vol 142, Issue 5, suppl-1, May 2012, page S-114
Increasing dose of infliximab in the presence of ATI
formation is inferior to changing anti-TNF
Clinical outcomes in patients with subtherapeutic concentrations (n=69)*
P<0.004
* 6 discontinued IFX, 3 continued same dose
3, 3 proceeded to surgery, 5 patients could not
be assessed
Complete / partial response (%)
Complete / partial response (%)
Clinical outcomes in patients with
detectable HACA (n=35)*
P<0.016
* 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;105:1133-9.
Proposed algorithm for patients with
loss of response to infliximab
Positive HACA
Change to another
anti-TNF agent
Therapeutic IFX
concentration
Active disease on
endoscopy/radiology?
yes
no
Subtherapeutic IFX
concentration
Increase
infliximab
dose or
frequency
Change to
different
anti-TNF
agent
Change to
different
anti-TNF
agent
Change to
non–
anti-TNF
agent
persistent
disease
Change to non–
anti-TNF agent
Change to
different
anti-TNF
agent
Investigate
alternate
etiologies
Afif W et al. Am J Gastroenterol 2010;105:1133.
Serum Adalimumab (ADA) Levels and Anti-Adalimumab
Antibodies (ATA) Correlate with Endoscopic Inflammation
and Inflammatory Markers
66 patients: 27% with detectable ATA
adalimumab [g/mL]
0
p=0.028
40
Variables associated with positive ATA (≥ 1.7 µg/ml)
30
20
10
0
Ye
s
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)
Ye
s
o
N
ADA level ≥ 5 µg/ml is associated with
lower CRP and healed mucosa



Endoscopic Inflammation
No
•
10
0
adalimumab [g/mL]
•
Undetectable ATA
Mucosal healing
Concomitant use of immunosuppressants
10
20
+



20
30
AT
A
Mean ADA levels were higher in
patients with
30
-
•
59 (89%) CD, 7 (11%) UC
40
AT
A

p=0.016
p=0.002
40
adalimumab [g/mL]
•
Immunosuppresant Use
Yarur, AJ, et al. Presented at DDW; May 21, 2013. Abstract Tu1147.
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.
Higher trough levels of adalimumab are
associated with higher rates of mucosal healing
Roblin X, et al. Clin Gastroenterol Hepatol 2014;12:80-84.
Trough adalimumab levels are higher in
patients with mucosal healing
P<0.005
6.5 μg/mL
4.2 μg/mL
Roblin X, et al. Clin Gastroenterol Hepatol 2014;12:80-84.
Adalimumab Trough Serum Levels < 0.33 µg/mL Predicts
a Lower Rate of Sustained Complete Response in
Patients with Crohn’s Disease
Patients with Sustained
Clinical Response (%)
1.0
LogRank: P=.01
0.8
0.6
0.4
0.2
ADA TR>0.33 µg/mL, n=104
ADA TR<0.33 µg/mL, n=16
0.0
0
30
60
90
120
150
180
210
240
Sustained Clinical Response (weeks)
Karmiris K, et al. Gastroenterology. 2009;137:1628.
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;109:1250-6.
Trough Infliximab >2 µg/ml is Associated with
Clinical Remission in Steroid-Refractory UC
• Standard infliximab
induction/maintenance
100
Patients in
Remission (%)
• Single-center cohort of 125 steroidrefractory acute UC patients
Steroid-free Remission by IFX Trough Status
• Fluid-phase assay for [IFX] and ATI
P<0.001
80
69.4
60
40
20
17.5
0
Serum IFX
≤ 2µg/ml
Serum IFX
> 2µg/ml
Colectomy by IFX Trough Status
100
Patients in Remission (%)
100
Colectomy (%)
Steroid-free Remission by IFX/ATI Status
P<0.001
P=0.073
80
70.0
60
P<0.001
80
60
55.5
40
17.7
20
0
40
28.5
16.6
20
Serum IFX
≤ 2µg/ml
P=0.84
13.0
Serum IFX
> 2µg/ml
Remission aOR
[95%CI]
Colectomy aOR
[95%CI]
10 [3,35]
0.18 [0.07,0.44]
0.64 [0.2,2.4]
1.0 [0.5,2.1]
0
IFX+
ATI-
IFX+
ATI+
IFXATI-
IFXATI+
Trough IFX > 2 µg/ml
(vs. ≤ 2 µg/ml)
ATI (vs. no ATI)
IFX, infliximab
Murthy S, et al. Presented at DDW; May 19, 2012. Abstract Sa2047.
Rapid IFX Clearance: Mechanism of
Non-Response in UC
Kevans D, et al. Presented at DDW; May 19, 2012.
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
1. Brandse JF, et al. Presented at DDW; May 5, 2014 A786.
2. Brandse JF, et al. Presented at DDW; May 18, 2013. A157.
Factors Affecting the Pharmacokinetics
of Monoclonal Antibodies
Impact on Pharmacokinetics
•
•
•
•
•
•
•
•
High baseline CRP
Decreases serum mAbs
Threefold-increased clearance
Worse clinical outcomes
Reduces formation
Increases serum mAbs
Decreases mAb clearance
Better clinical outcomes
May decrease mAbs by increasing
clearance
• Increases clearance
• Worse clinical outcomes
• Increases clearance
Body size
• High BMI may increase clearance
Gender
• Males have higher clearance
Presence of ADAs
Concomitant use of IS
High baseline TNF-α
Low albumin
mAB, monoclonal antibody; ADA, antidrug antibody
Ordas I et al. Clin Pharmacol Ther. 2012;91:635.
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
Prospective Therapeutic Drug Monitoring to Optimize
Infliximab Maintenance Therapy in IBD
•
Retrospective cohort of patients in clinical remission, single physician practice
– IFX dose optimization to trough concentrations 5–10ug/mL (n=48)
– No IFX dose optimization (n=78)
Evaluated probability of remaining on IFX, up to 5 years
Probability on Infliximab
100100
80 80
P < 0.0001*
P =P0.0006*
= 0.0006*
60 60
40 40
20 20
TCM
No TCM
P = 0.6
0 0
0 0 100100200200300300400400500500600600700700
Probability on Infliximab
•
100
80
0.0001*
PPP <<
< 0.0001*
0.0001*
P = 0.0006*
60
40
P = 0.6
0.6
PP == 0.6
20
0
0
100
200
300
400
500
600
700
Dose optimization increases probability of remaining on IFX therapy up to 5 years
P = 0.0006*
400
500
600
700
Vaughn BP, et al. Presented at DDW; May 3, 2014 Abstract 209.
Prospective Controlled Trial of Trough Level Adapted
Infliximab Treatment (TAXIT): Study outline
CB Group
IFX maintenance
therapy –> Stable
clinical response
Dosing based on IFX
TL
(3-7 µg/mL)
IFX TL within
optimal interval
Randomized 1:1
LB Group
IFX dosing based on
IFX TL
(3-7 µg/mL)
Maintenance phase
(52 weeks)
Optimization phase
(n weeks)
Screening
IFX dosing based on
clinical symptoms &
CRP
Randomization
Primary end point
Primary end point = rate of clinical (Harvey-Bradshaw or Partial Mayo score) and biological (C-reactive
protein ≤5 mg/l) remission one year after randomization in each group
CB Group= Clinically Based Group; LB Group= Level Based Group
Vande Casteele N, et al. United European Gastroenterology Journal 2013;1:A1
TAXIT Results: Optimization Phase
Dose escalation (N=76)
CD: Harvey-Bradshaw ≤ 4 / UC: Partial Mayo ≤ 2
P=0.02
100
Patients (%)
80
88.4
After optimization
P=1.0
88.9
88.5
65.1
60
40
20
0
CD (N=43)*
UC (N=28)*
Before optimization
Mean CRP Concentration
(mg/liter)
Before optimization
After optimization
15
P<0.001
P=0.16
CD
UC
10
5
0
Dose escalation in Crohn’s disease patients with subtherapeutic levels
results in a better disease control
*five patients (1 CD and 4 UC) were excluded from analysis because of withdrawal of consent during
optimization phase.
Vande Casteele N, et al. United European Gastroenterology Journal 2013;1:A1
Therapeutic Drug Monitoring of Infliximab (IFX) Predicts
Mucosal Healing Following Dose Intensification in IBD
• Enrolled 52 IBD patients (34 CD and
18 UC) with secondary failure to IFX.
Dose escalation to 10mg/kg in all.
• IFX trough, ATI, CRP, and calprotectin
measured before dose optimization
and at Week 8
• Endpoint – Mucosal healing at Week 8
Multivariate Predictors of Mucosal Healing
Factors
LR
95% CI
P value
Delta IFX >0.5
2.02
1.01-4.06
0.048
IFX<2μg/mL and ATI
<200ng/mL (before)
5.28
0.82-34.3
0.08
UC
3.1
0.41-23.6
0.27
Sex F/M
0.58
0.13-3
0.52
• Conclusion: The change in infliximab
trough levels after dose intensification
(delta IFX) predicts mucosal healing in
IBD patients.
Paul S, et al. Presented at DDW; May 19, 2013. Abstract 495.
TAXIT Results: Maintenance Phase
Primary end point
CB Group (N = 122)
100
P = 0.79
80
Patients (%)
LB Group (N = 126)
62.3
64.3
60
40
20
0
Clinical Remission*
*Harvey-Bradshaw index score ≤4 (CD) or Partial MAYO score ≤2 (UC) and C-reactive protein level ≤5 mg/l. Primary end
point could not be calculated for 3 Patients (1 CD from CB and 1 UC and 1 CD from LB group).
Vande Casteele N, et al. United European Gastroenterology Journal 2013;1:A1
TAXIT Results: Maintenance Phase
Relapse-free survival
Secondary end point (loss of response and need for an intervention)
1.0
0.8
LogRank P=0.0038
Breslow P=0.0058
0.6
0.4
0.2
17.3% of CB Group
vs. 5.5% of LB Group
needed rescue
therapy by the end of
the maintenance
phase
CB Group
LB Group
0.0
0
8
16
24
32
40
48
56
64
Maintenance Phase (Weeks)
127
126
122
122
119
116
65
1
120
118
116
109
105
100
57
1
N at risk
Vande Casteele N, et al. United European Gastroenterology Journal 2013;1:A1
Algorithm-Based Approach Based on PK for Secondary
Non-Responders to Infliximab More Cost-Effective
• Patients with secondary IFX failure
randomized to:
– IFX intensification group: IFX 5mg/kg
every 4 weeks OR
– Algorithm group:
• Low IFX and 0 ATI: IFX q4
• ATI positive and low IFX :adalimumab
• High IFX +/- ATI: stop anti-TNF
Intention to treat
Response
– no. (%)
Costs
– $ mean (SD)
Algorithm
n=33
IFX
intensified
n=36
19
(58)
7,806
(5,360)
P
Difference
[95%CI]
19
(53)
0.810
5%
11,867
(2,661)
<0.001
[-19 – 28]
-4,060
[-5,969;-1,775]
• Endpoints
– Costs related to treatment
– Clinical response: reduction in CDAI≥70 or
≥50% reduction of active fistulas at 12 weeks
• Conclusions: Treatment of IFX failure
using an algorithm significantly reduces
average costs without compromising care
Steenholdt C, et al. Gut 2014;63:919-27.
Trough Levels and Anti-drug Antibodies Predict Safety and
Success of Restarting IFX After Long Drug Holiday
- Consecutive cohort of patients (n=128); 105 CD, 23 UC where IFX was restarted after a median
drug holiday of 15 months (at least >6 months).
- Success at Week 14, 1 year, and end of follow-up (median 4 years); ATI and trough level (TL)
assessed
- Restarting IFX successful in 84.5% (short term), 70% (at 1 year) and in 61% (end of follow-up)
- IFX discontinued in 12% due to infusion reaction. IMM at restart prevents infusion reactions.
Multivariate analysis
Shortterm
Year 1
End of FollowUp
71%
54.8%
38.7%
0.14 (0.026-0.74)
P=0.021
91.6%
74.7%
66.6%
6 (1.3-2.7) P=0.019
Reason for discontinuation
(remission &/or pregnancy)
90%
77.5%
66.6%
2.70 (1.09-6.67) P=0.033
TL (at 2nd infusion) > 2 μg/ml
N=43
93%
74%
70%
2.94 (1.18-7.69) P=0.021
Response (%)
ATI (at 2nd infusion) detectable
N=31
IMM at restart N=84
•
HR (95% CI)
Conclusion: Restarting IFX after a drug holiday is safe, with success predicted by absence of
early ATI formation, IMM at recommencement, and not having had previous infusion reactions
Baert FJ, et al. Clin Gastroenterol Hepatol. 2014;12:1474-1481.
Additional questions
• Should target trough levels differ at different phases of
treatment?
– Rate of early drug clearance seems important early in severe disease
– Is a higher trough required in induction than in maintenance?
– Would rate of early drug clearance be a clinically useful parameter?
• Should TDM be individualized, or do population means work?
-
Can accurate predictive models for individual PK be created?
• Is there a safety benefit to dose reduction for
supratherapeutic levels?
• Questions of timing and frequency of TDM: maximizing the
value
Conclusions
• TDM with biologics more complex than with thiopurines
• Minimum effective concentration roughly defined
– IFX trough ~3 μg/mL
– ADA trough ~5 μg/mL
• Role of TDM in assessing loss of response is best established
• TDM appears to be cost effective when dose-reduction
incorporated into treatment algorithm, but will be highly
dependent upon cost and frequency of assay
• Growing interest in early TDM to dose optimize in severe
disease (especially UC)