Transcript GI Toxicity of MTX

Interactive Hot Topics Series
Managing GI Adverse
Events Due To Oral MTX:
What Are the Options?
MP-RA-0283
How Frequent Are Gastrointestinal (GI)
Adverse Events (AEs) in RA Patients
Taking Oral Methotrexate (MTX)?
GI Toxicity of Oral Methotrexate: Clinical Trial Results


24-month ULTRA trial, of patients with rheumatoid arthritis (RA) 18-75 years of age with active disease for ≥6 months
Treatment:
− Leflunomide (LEF; mean dose 19.7 mg/day during year 1 and 19.6 mg/day in year 2)
− Oral MTX (mean dose 11.7 mg/day during year 1 and 12.6 mg/day in year 2)
− Placebo
First 12 Months
24 Months
LEF
(n=190)
PL
(n=128)
Oral MTX
(n=190)
LEF
(n=190)
PL
(n=128)
Oral MTX
(n=190)
All serious AEs
16.3
8.6
7.4
18.9
9.4
18.9
Treatment-related AEs
1.1
1.6
2.6
1.6
1.6
3.7
AEs leading to withdrawal
3.7
1.6
3.2
4.2
1.6
6.3
Treatment-related AEs leading to withdrawal
0.5
0.8
1.6
1.1
0.8
1.6
Diarrhea
32.6
18.8
19.5
36.8
20.3
21.6
URI
28.9
21.1
31.6
37.4
25.0
38.4
Headache
18.4
16.4
20.5
20.0
17.2
23.2
Nausea
16.3
18.0
17.9
18.4
18.8
20.5
Dyspepsia
16.3
14.8
13.2
18.4
16.4
14.2
Rash
14.2
8.6
8.9
17.4
8.6
11.1
Hypertension
11.6
6.3
3.2
18.4
8.6
4.7
Specific AEs
2.1
0.0
1.6
4.7
0.0
2.6
Alopecia
New onset
10.0
0.8
5.8
10.5
0.8
5.8
Abdominal pain
8.9
3.1
7.9
11.6
3.9
7.9
Dizziness
7.9
7.0
4.7
8.9
7.0
5.8
UTI
6.8
7.8
1.6
8.4
9.4
5.8
Vomiting
5.8
6.3
2.6
7.4
6.3
3.7
Mouth ulcer
5.8
5.5
9.5
6.8
5.5
10.5
Pruritis
4.7
0.8
2.1
4.7
0.8
3.2
*Values are the percentage of patients. URI, upper respiratory tract infection; UTI, urinary tract infection.
Cohen S, et al. Arthritis & Rheumatism. 2001;44:1984-1992.
3
GI Toxicity of Oral Methotrexate: Clinical Trial Results
 958 RA patients randomized to receive 5 mg or 10 mg of tofacitinib twice daily or oral MTX at a dose
that was incrementally increased to 20 mg/week (mean dose = 18.5 mg/week)
Patients with Adverse Event, n (%)
†Event
‡event
Preferred Term
Tofacitinib 5 mg
Twice Daily (N=373)
Tofacitinib 10 mg
Twice Daily (N=397)
Oral Methotrexate
(N=186)
Adverse events
1097
1435
561
Abdominal pain
8 (2.1)†
16 (4.0)†
2 (1.1)
Abdominal pain upper
12 (3.2)
13 (3.3)
5 (2.7)
Constipation
7 (1.9)
10 (2.5)
7 (3.8)‡
Diarrhea
15 (4.0)
24 (6.0)
15 (8.1)‡
Dyspepsia
13 (3.5)
18 (4.5)
9 (4.8)‡
Gastritis
13 (3.5)†
9 (2.3)
4 (2.2)
Gastroesophageal reflux disease
6 (1.6)
6 (1.5)
5 (2.7)
Nausea
27 (7.2)
30 (7.6)
40 (21.5)‡
Vomiting
11 (2.9)
13 (3.3)
11 (5.9)‡
occurred more frequently in patients receiving tofacitinib 5 or 10 mg twice daily compared with MTX.
occurred more frequently in patients receiving methotrexate compared with tofacitinib 5 or 10 mg twice daily.
Lee EB, et al. N Engl J Med. 2014;370:2377-86 (suppl).
4
GI AEs with Oral Methotrexate: Survey Results
Adverse event
 AEs reported by
patients with RA
taking oral MTX
(n=1,034)
 Occurrence of
AEs was not
correlated with
oral MTX dose
Nausea
Headache
Mouth ulcers
Light-headedness
Diarrhea
Event experienced ever
Stomach pains
Event experienced regularly
Of the patients who
experience the event regularly,
event experienced
continuously
Skin rashes
Heart palpitations
Vomiting
Others
No effects
No answer
0
10
20
30
% of patients
Nash P, Nicholls D. Int J Rheumatic Dis. 2013; 16: 652-661.
40
50
5
GI-related AEs Common Reason for Safety-related
Oral MTX Discontinuation
 Retrospective, case review
of patients seen in a private
rheumatology practice
attached to a major teaching
hospital was undertaken
over an 18-year period
 Records for 790 patients
were reviewed and toxicityrelated discontinuation
occurred in 93 patients
(11.8%)
Varatharajan N, et al. Internal Medicine Journal. 2009;39:228-236.
Drug adverse reaction
Hepatic
Liver biopsy
Gastrointestinal
Nausea
Mouth ulcers
Abdominal pain
Diarrhea
Pancreatitis
Central nervous system
Headache
Short-term memory loss
Fatigue
Drowsiness
Dizziness
Irritability
Pulmonary
Cough
Pneumonitis
Dyspnea
Bronchiolitis obliterans
Fibrosis
Bronchiectasis
Hematology
Neutropenia
Thrombocytopenia
Other
Rash/pruritus
Hair loss
Hot flushes
Increased arthralgia
Chest pain
Mastalgia
Recurrent infections
Weight loss
Frequency (93 patients)
18
4
37
26
7
1
2
1
26
9
3
6
3
4
1
10
3
3
1
1
1
1
2
1
1
18
7
4
2
1
1
1
1
1
Percentage of all oral MTX
users
2.2
4.7
3.3
1.1
0.2
2.3
6
Over 25% of Oral MTX Intolerance Is Due to GI Events
 Retrospective electronic database
review was undertaken to identify all
patients who had received oral MTX for
RA or psoriatic arthritis (PsA)
 Patients who had discontinued oral
MTX were then identified, and the
reasons for this were categorized
 A total of 1,257 patients who had
received oral MTX were included [762
(61%) RA and 193 (15%) PsA]
 Oral MTX had been stopped in 260
(34%) patients with RA and 71 (36%)
patients with PsA, most commonly due
to GI intolerability
Nikiphorou E, et al. Clin Rheumatol. 2014;33:609-614. © Clinical Rheumatology 2014.
Reasons for oral MTX withdrawal
in patients with RA
1.3%
0.9%
5.3% 4.8%
7.0%
28.6%
9.3%
10.1%
22.0%
10.6%
GI
Respiratory
LFT
FBC
Non-specific symptoms
Neurological
Fatigue
Skin
Renal
Alopecia
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Mechanisms Underlying GI
Toxicity of Methotrexate
GI Toxicity of MTX: Inhibition of Dihydrofolate
Reductase Synthesis
 MTX-associated GI toxicity is not considered to be a
result of direct action on gastrointestinal tract tissues, but
rather to inhibition in dihydrofolate reductase synthesis:
− This enzyme is required to maintain the intracellular
pool of tetrahydrofolate during purine and thymidine
synthesis
− This adversely affects all rapidly dividing cells, including
those in the GI mucosa
Horie T, et al. J Nutr. 2006;136 (3 Suppl):861S-863S.
Methotrexate Increases Oxidative Stress
 MTX increases levels of reactive oxygen species (ROS) and this may be
involved in the beneficial effects of the drug.1
 MTX is toxic to cultured intestinal epithelial cells (IECs) and this toxicity is
correlated with production of ROS2,3
 Administration of an anti-oxidant, α-lipoic acid, decreases MTX-induced
intestinal damage in a rabbit model:3
Antioxidant enzyme activities, lipid peroxidation level, and
intestinal tissue injury in the intestine of rabbits
Control
Methotrexate
Methotrexate +
Alpha-lipoic Acid
Glutathione peroxidase (U/mg wet weight of tissue)
1.69 (1.56-1.91)
0.80 (0.50-1.10)
1.30 (1.10-1.40)
Superoxide dismutase (U/mg wet weight of tissue)
1.93 (1.90-2.20)
1.10 (0.80-1.30)
1.50 (1.30-1.60)
Malondialdehyde (U/mL)
0.95 (0.83-1.20)
3.70 (3.10-3.90)
2.20 (1.90-2.50)
1.0 (1.0-2.0)
10.0 (8.0-11.0)
7.0 (6.0-9.0)
Intestinal tissue injury index
Values are as median (range). The differences among all three groups were significant (P<0.05)
1. Phillips DC, et al. Br J Pharmacol. 2003;138:501-511.
2. Chang CJ, et al. PLoS One. 2013;8:e72553.
3. Somi MH, et al. Indian J Gastroenterol. 2011;30:38-40.
10
Reducing GI Toxicity:
Folate Administration
Efficacy of Folate/Folinic Acid for Decreasing
GI Toxicity of Oral Methotrexate: Studies Analyzed
409 records
identified through
database searching
326 records
after duplicates
removed
326 records
screened
15 full-text
articles
assessed for
eligibility
311 records
excluded
9 full-text
articles
excluded,
with reasons
12 additional records
identified through
other sources
Shea B, et al. Cochrane Database Syst Rev. 2013;5:CD000951.
6 studies
included in
quantitative
synthesis
(meta-analysis)
12
Efficacy of Folate/Folinic Acid for Decreasing
GI Toxicity of Oral Methotrexate: Results
Study or
subgroup
Treatment (n/N)
Control (n/N)
Buckley 1990
6/20
Morgan 1990
Risk Ratio
M-H, Fixed, 95% CI
Weight
Risk Ratio
M-H, Fixed, 95% CI
9/20
8.0%
0.67 (0.29, 1.52)
6/16
9/16
8.0%
0.67 (0.31, 1.43)
Morgan 1994
2/25
7/28
5.9%
0.32 (0.07, 1.40)
Shiroky 1993
4/44
14/48
11.9%
0.31 (0.11, 0.88)
Van Ede 2001
95/274
55/137
65.3%
0.86 (0.67, 1.12)
Weinblatt 1993
1/8
1/8
0.9%
1.00 (0.07, 13.37)
Total (95% CI)
387
257
100.0%
0.74 (0.59, 0.92)
0.05 0.2
Total events: 114 (Treatment), 95 (Control)
Heterogeneity: Chi2 = 5.50, df = 5 (P = 0.36); I2 = 9%
Test for overall effect: Z = 2.64 (P = 0.0083)
Test for subgroup differences: Not applicable
Shea B, et al. Cochrane Database Syst Rev. 2013;5:CD000951.
1
5
20
Folate Treatment Decreases Oral MTX
Discontinuation Due to AEs
 48-week study of the effect of
folates on discontinuation of oral
MTX due to toxicity
Percentages of patients who did not
permanently discontinue oral MTX
treatment during the study period,
by supplement group
 Patients with active RA (n= 434)
were randomly assigned to receive
oral MTX plus either placebo, folic
acid (1 mg/day), or folinic acid (2.5
mg/week)
 Folate dosages were doubled
once the dosage of oral MTX
reached 15 mg/week
 The primary end point was oral
MTX withdrawal because of AEs
van Ede AE, et al. Arthritis & Rheumatism. 2001;44:1515-1524.
90
Percent
 The initial oral MTX dosage was
7.5 mg/week; dosage increases
were allowed up to a maximum of
25 mg/week
100
80
Folic Acid
Folinic Acid
70
Placebo
60
P<0.001 for folate or folinic acid vs placebo
50
0
50
100
150
200
250
300
350
Days After Start of Oral MTX Treatment
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Reducing GI Toxicity:
Changing Route of MTX
Administration
Safety of SC vs Oral MTX:
Single-dose Crossover Study
 Single-center, open-label, randomized, 2-period, 2-sequence,
single-dose, crossover study
 Enrolled healthy subjects aged 18-55 years into 1 of 4 dose groups
(7.5 mg, 15 mg, 22.5 mg, and 30 mg), where they received a single
dose of SC MTX and of the oral MTX tablets
SC MTX Pen
(n=59)
Oral MTX Tablet
(n=57)
TEAEs
#
n
%
#
n
%
Gastrointestinal disorders
9
9
15.3
19
16
28.1
Diarrhea
5
5
8.5
8
8
14
Nausea
3
3
5.1
3
3
5.3
Abdominal pain upper
—
—
—
3
3
5.3
Pichlmeier U, Heuer KU. Clin Exp Rheumatol. 2014;32:563-571.
Trial Design
 6-month, multicenter, randomized, double-blind, controlled clinical trial
evaluating the efficacy of SC administration of MTX compared with oral
administration of MTX in the treatment of patients with active RA
Weeks
MTX
naive
R
A
N
D
O
M
I
Z
A
T
I
O
N
Braun J, et al. Arthritis & Rheumatism. 2008;58:73-81.
0
16
ACR20 nonresponder
24
MTX SC 15 mg
MTX oral 15 mg
(2 7.5-mg tablets + dummy syringe
MTX SC 15 mg
(10-mg/ml prefilled syringe + dummy syringe
ACR20 nonresponder
MTX SC 20
mg
Safety of SC vs Oral MTX
No. (%) of patients
receiving SC MTX (n=193)
No. (%) of patients receiving
Oral MTX (n=193)
Any adverse event
128 (66)
116 (62)
At least a moderate adverse event
79 (41)
77 (41)
Adverse event possibly related to study drug
102 (53)
90 (48)
Serious adverse event
11 (5.7)
8 (4.3)
Adverse event leading to withdrawal
18 (9.3)
8 (4.3)
Adverse events
At least moderate adverse events reported at a ≥3% incidence
Gastrointestinal
Abdominal pain
17 (8.8)
20 (10.6)
Diarrhea
5 (2.6)
13 (6.9)
Dyspepsia
13 (6.7)
11 (5.9)
Loss of appetite
14 (7.3)
6 (3.2)
Nausea
32 (16.6)
23 (12.2)
Stomatitis
6 (3.1)
7 (3.7)
Vomiting
7 (3.6)
6 (3.2)
Increased alanine aminotransferase
3 (1.6)
8 (4.3)
Bronchitis
4 (2.1)
7 (3.7)
Headache
4 (2.1)
8 (4.3)
Nasopharyngitis
9 (4.7)
10 (5.3)
Braun J, et al. Arthritis & Rheumatism. 2008;58:73-81.
GI Tolerability in Patients Switched from
Oral to SC MTX
45
VAS Score (0-100)
40
Oral MTX
P=0.015
P=0.002
36.5
34.9
35
SC MTX
P=0.047
38.7
N=37
30
25.1
25
25
22.6
20
15
P=0.053
10
5.8
5
1
0
Frequency of
Nausea
Intensity of
Nausea
SC, subcutaneous; VAS, visual analog scale
Adapted from Kromann CB, et al. J Dermatolog Treat. 2014;17:1-3.
Frequency of
Vomiting
Frequency of
Discomfort
19
Retrospective Analysis of Switching
Patients from Oral to SC MTX
 Retrospective analysis of 80 patients with RA who were
switched from oral MTX (mean dose = 15.1 mg/week) to
SC MTX (mean dose = 16.5 mg/week) due to GI side
effects
 After switching:
− 30 patients (37.5%) experienced GI side effects in the
first month
− 27 patients (33.7%) experienced GI side effects during
the second month
− No patients discontinued SC MTX due to intolerability
over 3 months of follow-up
Borman P, et al. Open Rheumatology J. 2014;8:18-19.
20
Intramuscular MTX Also Has Better
Tolerability than Oral Drug
Effects of a switch from IM
to oral MTX in 143 patients
60%
Percent of Patients with
Changes in GI Events
 143 patients were
switched from
intramuscular (IM) to
oral MTX
 A multiple choice
questionnaire was
sent by mail to
evaluate clinical and
biological criteria of
efficacy and tolerance
50%
48%
40%
29%
30%
22%
20%
10%
0%
0%
Increase
Adapted from Wegrzyn J, et al. Ann Rheum Dis. 2004;63:1232-1234.
No Change
Decrease
Not
Answered
21
Why Is GI Toxicity of MTX
Decreased with Parenteral
Administration?
Some Facts and Considerations
 Rapidly proliferating cells have a very high demand for folic acid and are
greatly affected by folic acid deficiency1
 A primary sign of folic acid deficiency is intestinal mucosa deterioration1
 Uptake of folic acid by intestinal cells is mediated by the human proteincoupled folate transporter (hPCFT/SLC46A1)1
 MTX is also taken up by hPCFT2,3
 Uptake of both folic acid and MTX by hPCFT is concentration dependent and
folic acid uptake by this transporter is competitively reduced by MTX1-3
 Oral delivery of MTX may result in higher intestinal drug concentrations vs
parenteral administration leading to:
− Greater inhibition of hPCFT
− Greater folate deficiency
− Increased risk for GI AEs
1. Urquhart BL, et al. Am J Physiol Gastrointest Liver Physiol. 2010;298:G248-254.
2. Inoue K, et al. Am J Physiol Gastrointest Liver Physiol. 2008;294:G660-668.
3. Yokooji T, et al. J Pharm Pharmacol. 2009;61:911-918.
Summary
Summary
 GI AEs occur often in patients receiving oral MTX and are the most
common reason for intolerance-associated discontinuation of the
drug in patients with RA
 These events may be mediated, at least in part, by adverse effects of
oral MTX on the metabolism of intestinal epithelial cells
 Administration of folate significantly decreases the risk for GI AEs in
patients with RA receiving oral MTX
 SC or IM administration of MTX also decreases the risk for GI events
 The decreased risk for for GI AEs with parenteral MTX may be due,
at least in part, to lower levels of drug in the intestine and reduced
competition with folate for hPCFT