6-MP and Azathioprine - Advances in Inflammatory Bowel Diseases

Report
6-MP and AZA Applications
and Approaches
Marla Dubinsky, MD
Chief, Pediatric GI and Hepatology
Co-Director, Susan and Leonard
Feinstein IBD Clinical Center
Icahn School of Medicine
Mount Sinai Hospital, New York
Metabolism of AZA/6-MP
6-thiouric acid
XO
HPRT
AZA
6-MP
6-TGNs
TPMT
6-MMP
TPMT Activity Distribution
Wild type
Heterozygous
mutation
Homozygous
mutation
www.nzma.org.nz/
journal/118-1210/1324/
Cies C et al. NZ Med
J 2005;118:1324
Safety of Starting Full Weight-Based Dosing vs. Low-Dose
Thiopurines in Normal Metabolizers (TPMT >25)
•
Retrospective study of 134 adult
CD patients with TPMT > 25
(normal metabolizers) and > 1
year follow-up
Complication Rates in Patients Starting
Full-Dose Thiopurines vs. Controls (Gradual Increase)
 Dose initiation at 2-2.5mg/kg AZA
or 1-1.5 mg/kg 6MP (therapy)
compared with gradual increase
(control)
•
Results
 Overall similar rates of AEs
 90% of complications in both
groups occurred in first 3
months
Benmassauod A, et al. Presented at DDW; May 4, 2014. Abstract Su1416.
Adverse Event Comparison*
Target 6-TGN Level to Optimize Efficacy: >235
Frequency of Response
P< 0.001
78%
100%
80%
60%
Odds Ratio 5.0 for
treatment response
when 6-TGN > 235
41%
40%
20%
0%
n=44
0-173
Dubinsky MC et al. Gastroenterol2000;118:
n=42
174-235
n=43
236-367
6-TGN QUARTILES
n=44
368-1203
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
Weight-Based
Individualised
80
60
p=0.11
60
40
20
40
16
Per Protocol
70
Intention To Treat
100
50
Weight-Based
60
p=0.12
40
30
25
20
10
0
Clinical Remission at 16
weeks(%)
Dassopoulos T, et al. Aliment Pharmacol Ther 2014;39: 163-175
0
Clinical Remission at 16 weeks(%)
6-MP Metabolite Profiles
6-TGN
450
235
6-MMP
5700
Dose Too Low;
Noncompliant
Therapeutic
Range
Toxicity
Preferential
6MMP
AZA/6-MP as Maintenance Therapy in
Crohn’s Disease after Steroid Induction
ADULTS
CHILDREN
1.00
100
AZA 2.5 mg/kg/d (n=33)
Placebo (n=30)
0.75
Fractional Survival
% Patients Not Failing Trial
80
60
40
P=0.001
0.50
6MP
0.25
20
Control
0
0.00
0
1
2
3
4
5
6
7
8
9
10 11 12
13
14 15
Duration of Trial (months)
0
100
200
300
400
Remission Duration (days)
*Remission induced by prednisolone tapered over 12 wk.
9
Candy S et al. Gut. 1995;37(5):674-678.
Markowitz, et al. Gastroenterology. 2000;119(4):895-902.
500
600
Early “top-down” therapy with azathioprine is not
more effective than placebo or conventional therapy
RAPID
Cosnes J et al. Gastroenterology 2013;145: 758-65
AZTEC
Predictors of surgery within 5 years of Crohn’s diagnosis
Chatu S et al Am J Gastroenterol 2014;109:409-16
The Role of Thiopurines in Reducing the Need for Surgical
Resection in Crohn’s disease: Systematic review and meta-analysis
Chatu S et al. Am J Gastroenterol. 2014 Jan;109:23-34
Thiopurines Use and Surgical Rates: UK
Chatu S et al Am J Gastroenterol 2014;109:409-16
Azathioprine and 6-mercaptopurine for maintenance
of surgically-induced remission in Crohn's disease
Gordon M et al Cochrane database syst rev 2014;8:CD010233
Predictors of Thiopurine response
Predictors
OR (95%)
6-TGN > 250 pmol per 8 . 108 RBC
4.14 (1.49-11.46)
Relative Leukopenia
14.01 (3.77-52.10)
Absence of lymphopenia
3.71 (1.26-10.89)
Platelet (K/ul)
0.995 (0.991-0.999)
TPMT activity (nmole/n/ml)
0.89 (0.80-0.98)
AST (UI/L)
1.05 (1.01-1.09)
6MeMPN:6-TGN ratio
0.95 (0.85-1.04)
Nguyen TV, et al R Inflamm Bowel Dis. 2013 Oct;19(:2404-10
Time To Relapse post Thiopurine Withdrawal
Kennedy NA et al APT 2014:40;1313-2013
Predictors of Relapse post Thiopurine Withdrawal
Kennedy NA et al APT 2014:40;1313-2013
Combined Immunosuppressive Therapy versus Conventional
Management in Early Crohn’s Disease Clinical Results at 2 Years
Primary Endpoint:
•
•
•
Proportion of patients in
remission
CDAI < 150
No Steroids, No Surgery
methylprednisolone
Azathioprine/6-MP
infliximab
D’Haens et al. Lancet. 2008(9613);371:660-667.
SONIC: Corticosteroid-free Clinical Remission
in CD at Week 26
Median disease duration 2.4 years
Clinical Remission
100
P<.001
Patients (%)
P=.02
0
P=.006
56.8
44.4
30.0
51/170
75/169
96/169
AZA + PBO
IFX + PBO
IFX + AZA
Colombel JF, et al. N Engl J Med. 2010; 362(15):1383-1395.
Infliximab in Children Study (REACH)
Shorter Disease Duration
Median disease duration 2 years
Response
Remission
100
Patients (%)
90
p=0.002
88
80
70
64
59
60
56
P<0.001
50
40
30
33
n=99
n=66
n=33
n=29
20
n=17
24
n=12
10
0
Week 10
Week 54 q8
Week 54 q12
Overall number of subjects n=112
• Antibodies to infliximab in 3 (2.9%) patients (1 in each maintenance arm and
another not randomized)
Hyams J, et al. Gastroenterology. 2007;132(3):863-873.
SONIC: Infliximab Trough Levels at Week 30
Median Serum Trough Levels
(mg/ml)
10
8
6
3.5
4
2
0
1.6
(n=97)
(n=109)
IFX + placebo
IFX + AZA
Colombel JF, et al. N Engl J Med. 2010;362(15):1383.
SONIC: Immunogenicity Results at Week 30
98
Percent of Patients (%)
100
Positive
Negative
Inconclusive
94
80
68
60
40
20
14
1/89
0
1
15
0/89
87/89
0
15/106
AZA + placebo
Colombel JF, et al. N Engl J Med. 2010;362(15):1383.
16/106
72/106
IFX + placebo
1/120
2/120
1
2
113/120
AZA + IFX
6-Thioguanine Concentrations Are Associated With Higher
Trough Infliximab Concentrations In IBD Patients On Combination Therapy
Cross-sectional study of IBD patients (N=72, 63% CD) receiving IFX in combination with
a thiopurine for ≥4 months
Correlation Between 6-TGN and
IFX Concentrations
Comparison Between Groups With
and Without Detectable Antibodies to IFX (ATI)
Higher 6-TGN levels correlate with higher IFX trough concentrations but levels of 125 may
maximize IFX levels
Patients with detectable IFX antibodies had significantly lower 6TGN levels
Yarur A, et al. Presented at DDW, May 5, 2014 Abstract 788.
Azathioprine Decreases the Risk of Adalimumab Primary NonResponse and Secondary Loss of Response If Adequately Dosed
CD patients on combination immunomodulator (IM) plus adalimumab (n=76) vs.
adalimumab monotherapy (n=46) followed for mean of 21 months
Induction of Remission
Maintenance of Remission
(Semester Analysis)
IM for 3 months prior to starting adalimumab improves response at 12 weeks
Semester analysis showed lower flare and failure rates only if thioguanine (TGN)
levels were therapeutic (>235 pmol/8x108 RBC)
Kariyawasam V, et al. Presented at DDW; May 4, 2014 Abstract 343.
Withdrawal of Immunomodulator and Infliximab Dose Escalation and
Discontinuation
Drobne D. et al CGH 2014 epub ahead of print
Levels Pre and Post IMM withdrawal
Drobne D. et al CGH 2014 epub ahead of print
Trough Levels at Time of IMM Withdrawal Predict Infliximab Dose
Escalation
Drobne D. et al CGH 2014 epub ahead of print
6-MP/AZA Approaches and Applications :Summary
•
Thiopurine Levels are associated with improved efficacy
•
Role of thiopurines as steroid sparing maintenance strategy
questionable
•
Thiopurines protective of surgery but post operative
effectiveness needs further exploration
•
Combination therapy with thiopurine and anti-TNF is more
effective than monotherapy
•
Combination therapy decreased ATI and improves Anti TNF
drug levels
•
Anti-TNF levels remain stable after stopping thiopurine

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