A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Remicade Pharmacology, Pharmacokinetics, Studies, Metabolism - Infliximab
Remicade Pharmacology, Pharmacokinetics, Studies, Metabolism - Infliximab
CLINICAL PHARMACOLOGY
General
Infliximab neutralizes the biological activity of TNFa
by binding with high affinity to the soluble and transmem-brane forms of TNFa
and inhibits binding of TNFa with its receptors.2,3
Infliximab does not neutralize TNFb (lym-photoxin
a), a related cytokine that utilizes the same receptors
as TNFa. Biological activities attributed to TNFa
include: induction of pro-inflammatory cytokines such as interleukins (IL) 1
and 6, enhancement of leukocyte migration by increasing endothelial layer permeability
and expression of adhesion molecules by endothelial cells and leukocytes, activation
of neutrophil and eosinophil functional activity, induction of acute phase reactants
and other liver proteins, as well as tissue degrading enzymes produced by synoviocytes
and/or chondrocytes. Cells expressing transmembrane TNFa
bound by infliximab can be lysed in vitro3 or in vivo.4
Infliximab inhibits the functional activity of TNFa
in a wide variety of in vitro bioassays utilizing human fibroblasts,
endothelial cells, neutrophils, B and T lymphocytes and epithelial cells. Anti-TNFa
antibodies reduce disease activity in the cotton-top tamarin colitis model,
and decrease synovitis and joint erosions in a murine model of collagen-induced
arthritis. Infliximab prevents disease in transgenic mice that develop polyarthritis
as a result of constitutive expression of human TNFa,
and when administered after disease onset, allows eroded joints to heal.
Pharmacodynamics
Elevated concentrations of TNFa
have been found in the joints of rheumatoid arthritis patients and the
stools of Crohn’s disease patients and correlate with REMICADE reduced
infiltration of inflammatory cells into inflamed areas of the joint as
well as expression of molecules mediating cellular adhesion [E-selectin,
intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion
molecule-1 (VCAM-1)], chemoattraction [IL-8 and monocyte chemotactic protein
(MCP-1)] and tissue degradation [matrix metalloproteinase (MMP) 1 and
3]. In infiltration of inflammatory cells and TNFa
production in inflamed areas of the intestine, and reduced the proportion
of mononuclear cells from the lamina propria able to express TNFa
and interferon. After treatment with REMICADE, patients with rheumatoid
arthritis or Crohn’s C-reactive protein (CRP) compared to baseline. Peripheral
blood lymphocytes from REMICADE-treated patients showed no significant
decrease in number or in proliferative responses to in vitro mitogenic
stimulation when compared to cells from untreated patients.
Pharmacokinetics
Single intravenous (IV) infusions of 3 mg/kg to 20 mg/kg showed
a linear relationship between the dose administered and the maximum serum concentration.
The volume of distribution at steady state was independent of dose and indicated
that infliximab was distributed primarily within the vascular compartment. Median
pharmacokinetic results for doses of 3 mg/kg to 10 mg/kg in rheumatoid arthritis
and 5 mg/kg in terminal half-life of infliximab is 8.0 to 9.5 days.
Following an initial dose of REMICADE, repeated infusions at
2 and 6 weeks resulted in predictable concentration-time profiles following
each treatment. No systemic accumulation of infliximab occurred upon continued
repeated treatment with 3 mg/kg or 10 mg/kg at 4- or 8-week intervals. No major
differences in clearance or volume of distribution were observed in patient
subgroups defined by age, weight, or gender. It is not known if there are differences
in clearance or volume of distribution in patients with marked impairment of
hepatic or renal function.
A pediatric Crohn’s disease pharmacokinetic notable differences
in single-dose pharmacokinetic parameters were observed between pediatric and
adult Crohn’s disease patients (see PRECAUTIONS,
Pediatric Use).
CLINICAL STUDIES
Rheumatoid Arthritis
The safety and efficacy of REMICADE when given in conjunction
with methotrexate (MTX) were assessed in a multicenter, randomized, double-blind,
placebo-controlled study of 428 patients with active rheumatoid arthritis despite
treatment with MTX (the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant
Therapy or ATTRACT). Patients enrolled had a median age of 54 years, median
disease duration of 8.4 years, median swollen and tender joint count of 20 and
31 respectively, and were on a median dose of 15 mg/wk of MTX. Patients received
either placebo + MTX or one of 4 doses/schedules of REMICADE + MTX: 3 mg/kg
or 10 mg/kg of REMICADE by IV infusion at weeks 0, 2 and 6 followed by additional
infusions every 4 or 8 weeks in combination with MTX. Concurrent use of stable
doses of folic acid, oral corticosteroids (£10 mg/day)
and/or nonsteroidal anti-inflammatory drugs was also permitted. Data on use
of REMICADE without concurrent MTX are limited (see ADVERSE
REACTIONS, Immunogenicity).5,6
Clinical response
All doses/schedules of REMICADE + MTX resulted in improvement
in signs and symptoms as measured by the American College of Rheumatology response
criteria (ACR 20) with a higher percentage of patients achieving an ACR 20,
50 and 70 compared to placebo + MTX (Table 1). This improvement was observed
at week 2 and maintained through week 102. Greater effects on each component
of the ACR 20 were observed in all patients treated with REMICADE + MTX compared
to placebo + MTX (Table 2). Approximately 10% of patients treated with REMICADE
achieved a major clinical response, defined as maintenance of an ACR 70 response
over a 6-month period compared to 0% of placebo-treated patients (p£0.018).
|
Table 1 PERCENTAGE OF PATIENTS WHO ACHIEVED AN ACR RESPONSE
AT WEEKS 30 AND 54
|
|
Response
|
Placebo
+ MTX
(n=88)
|
REMICADE + MTX
|
|
3 mg/kga
|
10 mg/kga
|
|
q 8 wks
|
q 4 wks
|
q 8 wks
|
q 4 wks
|
|
(n=86)
|
(n=86)
|
(n=87)
|
(n=81)
|
|
ACR 20
|
|
Week 30
|
20%
|
50%
|
50%
|
52%
|
58%
|
|
Week 54
|
17%
|
42%
|
48%
|
59%
|
59%
|
|
ACR 50
|
|
Week 30
|
5%
|
27%
|
29%
|
31%
|
26%
|
|
Week 54
|
9%
|
21%
|
34%
|
40%
|
38%
|
|
ACR 70
|
|
Week 30
|
0%
|
8%
|
11%
|
18%
|
11%
|
|
Week 54
|
2%
|
11%
|
18%
|
26%
|
19%
|
|
a p<0.05 for each outcome compared to placebo
|
|
Table 2 COMPONENTS OF ACR 20 AT BASELINE AND 54 WEEKS
|
| |
Placebo + MTX(n=88)
|
REMICADE + MTXa(n=340)
|
|
Parameter (medians)
|
Baseline
|
Week 54
|
Baseline
|
Week 54
|
|
No. of Tender Joints
|
24
|
16
|
32
|
8
|
|
No. of Swollen Joints
|
19
|
13
|
20
|
7
|
|
Painb
|
6.7
|
6.1
|
6.8
|
3.3
|
|
Physician’s Global Assessment b
|
6.5
|
5.2
|
6.2
|
2.1
|
|
Patient’s Global Assessment b
|
6.2
|
6.2
|
6.3
|
3.2
|
|
Disability Index (HAQ)c
|
1.8
|
1.5
|
1.8
|
1.3
|
|
CRP (mg/dL)
|
3.0
|
2.3
|
2.4
|
0.6
|
|
a All doses/schedules of REMICADE + MTX
|
|
b Visual Analog Scale (0=best, 10=worst)
|
|
c Health Assessment Questionnaire, measurement of 8 categories:
dressing and grooming, arising, eating, walking, hygiene, reach, grip,
and activities (0=best, 3=worst)
|
Radiographic response
Structural damage in both hands and feet was assessed radiographically
at week 54 by the change from baseline in the van der Heijde-modified Sharp
score, a composite score of structural damage that measures the number and size
of joint erosions and the degree of joint space narrowing in hands/wrists and
feet.7 Approximately 80% of patients had paired x-ray data at 54
weeks and approximately 70% at 102 weeks. The inhibition of progression of structural
damage was observed at 54 weeks (Table 3) and maintained through 102 weeks.
|
Table 3 RADIOGRAPHIC CHANGE FROM BASELINE TO WEEK 54
|
| |
|
REMICADE + MTX
|
|
Median (10, 90 percentiles)
|
Placebo + MTX (n=64)
|
3 mg/kg
|
10 mg/kg
|
p-value a
|
|
q 8 wks (n=71)
|
q 4 wks (n=71)
|
q 8 wks (n=77)
|
q 4 wks (n=66)
|
|
|
Total Score Baseline
|
55 (14, 188)
|
57 (15, 187)
|
45 (8, 162)
|
56 (6, 143)
|
43 (7, 178)
|
|
|
Change from baseline
|
4.0 (-1.0, 19.0)
|
0.5 (-3.0, 5.5)
|
0.1 (-5.2, 9.0)
|
0.5 (-4.8, 5.0)
|
-0.5 (-5.7, 4.0)
|
p<0.001
|
|
Erosion Score Baseline
|
25 (8, 110)
|
29 (9, 100)
|
22 (3, 91)
|
22 (3, 80)
|
26 (4, 104)
|
|
|
Change from baseline
|
2.0 (-1.0, 9.7)
|
0.0 (-3.0, 4.3)
|
-0.3 (-3.1, 2.5)
|
0.5 (-3.0, 2.5)
|
-0.5 (-2.7, 2.5)
|
p<0.001
|
|
JSN Score Baseline
|
26 (3, 88)
|
29 (4, 80)
|
20 (3, 83)
|
24 (1, 79)
|
25 (3, 77)
|
|
|
Change from baseline
|
1.5 (-0.8, 8.0)
|
0.0 (-2.5, 4.5)
|
0.0 (-3.4, 5.0)
|
0.0 (-3.0, 2.5)
|
0.0 (-3.0, 3.5)
|
p<0.001
|
|
a For comparisons of each dose against placebo
|
Physical function response
Physical function and disability were assessed using the Health
Assessment Questionnaire (HAQ) and the general health-related quality of life
questionnaire SF-36. All doses/schedules of REMICADE + MTX showed significantly
greater improvement from baseline in HAQ and SF-36 physical component summary
score aver- was conducted in 21 patients aged 11 to 17 years old. Noaged over
time through week 54 compared to placebo + MTX, and no worsening in the SF-36
mental component summary score.
The median (interquartile range) improvement from baseline
to week 54 in HAQ was 0.1 (-0.1, 0.5) for the placebo + MTX group and 0.4 (0.1,
0.9) for REMICADE + MTX (p<0.001). Both HAQ and SF-36 effects were maintained
through week 102. Approximately 80% of patients in all doses/schedules of REMICADE
+ MTX remained in the trial through 102 weeks.
Active Crohn’s Disease
The safety and efficacy of single and multiple doses of REMICADE
were assessed in two randomized, double-blind, placebo-controlled clinical studies
in 653 patients with moderate to severely active (Crohn’s ³220
and £400) with an inadequate response to prior conventional
Disease Activity Index [CDAI] therapies. Concomitant stable doses of aminosalicylates,
corticosteroids and/or immunomodulatory agents were permitted and 92% of patients
continued to receive at least one of these medications.
In the single-dose trial8 of 108 patients, 16% (4/25)
of placebo patients achieved a clinical response (decrease in CDAI ³70
points) at week 4 vs. 81% (22/27) of patients receiving 5 mg/kg REMICADE (p<0.001,
two-sided, Fisher’s Exact test). Additionally, 4% (1/25) of REMICADE
achieved clinical remission (CDAI <150) at week 4.
In a multidose trial (ACCENT I),9 545 patients received
5 mg/kg at week 0 and were then randomized to one of three treatment groups;
the placebo maintenance group received placebo at weeks 2 and 6, and then every
8 weeks; the 5 mg/kg maintenance group received 5 mg/kg at weeks 2 and 6, and
then every 8 weeks; and the 10 mg/kg maintenance group received 5 mg/kg at weeks
2 and 6, and then 10 mg/kg every 8 weeks. Patients in response at week 2 were
randomized and analyzed separately from those not in response at week 2. Corticosteroid
taper was permitted after week 6.
At week 2, 57% (311/545) of patients were in clinical response.
At week 30, a significantly greater proportion of these patients in the 5 mg/kg
and 10 mg/kg maintenance groups achieved clinical remission compared to patients
in the placebo maintenance group (Table 4).
Additionally, a significantly greater proportion of patients
in the 5 mg/kg and 10 mg/kg infliximab maintenance groups were in clinical remission
and were able to discontinue corticosteroid use compared to patients in the
placebo maintenance group at week 54 (Table 4).
|
Table 4 CLINICAL REMISSION AND STEROID WITHDRAWAL
|
| |
Single 5 mg/kg Dose a Placebo Maintenance
|
Three Dose Inductionb REMICADE Maintenance
q 8 wks
|
|
|
5 mg/kg
|
10 mg/kg
|
|
Week 30
|
25/102
|
41/104
|
48/105
|
|
Clinical remission
|
25%
|
39%
|
46%
|
|
p-valuec
|
|
0.022
|
0.001
|
|
Week 54
|
|
|
|
|
Patients in remission able to
|
6/54
|
14/56
|
18/53
|
|
discontinue corticosteroid used
|
11%
|
25%
|
34%
|
|
p-valuec
|
|
0.059
|
0.005
|
|
a REMICADE at week 0
|
|
b REMICADE 5 mg/kg administered at weeks 0,
2 and 6
|
|
c p-values represent pairwise comparisons
to placebo
|
|
d Of those receiving corticosteroids at baseline
|
Patients in the infliximab maintenance groups (5 mg/kg and
10 mg/kg) had a longer time to loss of response than patients in the placebo
maintenance group. At weeks 30 and 54, significant improvement from baseline
was seen among the 5 mg/kg and 10 mg/kg infliximab-treated groups compared to
the placebo group in the disease specific inflammatory bowel disease questionnaire
(IBDQ), particularly the bowel and systemic components, and in the physical
component summary score of the general health-related quality of life questionnaire
SF-36.
In a subset of 78 patients who had mucosal ulceration at baseline
and who participated in an endoscopic substudy, 13 of 43 patients in the infliximab
maintenance group had endoscopic evidence of mucosal healing compared to 1 of
28 patients in the placebo group at week 10. Of the infliximab-treated patients
showing muco-sal healing at week 10, 9 of 12 patients also showed mucosal healing
at week 54.
Patients who achieved a response and subsequently lost response
were eligible to receive infliximab on an episodic basis at a dose that was
5 mg/kg higher than the dose to which they were randomized. The majority of
such patients responded to the higher dose. Among patients who were not in response
at week 2, 59% (92/157) of infliximab maintenance patients responded by week
14 compared to 51% (39/77) of placebo maintenance patients. Among patients who
did not respond by week 14, additional therapy did not result in significantly
more responses (see DOSAGE AND ADMINISTRATION).
Fistulizing Crohn’s Disease
The safety and efficacy of REMICADE were assessed in 2 randomized,
double-blind, placebo-controlled studies in patients with fistulizing Crohn’s
disease with fistula(s) that were of at least 3 months duration. Concurrent
use of stable doses of corticosteroids, 5-ASA, antibiotics, MTX, 6-MP and/or
AZA was permitted.
In the first trial,10 94 patients received three
doses of either placebo or REMICADE at weeks 0, 2 and 6. Fistula response (³50%
reduction in number of enterocutaneous fistulas draining upon gentle compression
on at least two consecutive visits without an increase in medication or surgery
for 68% (21/31) of patients in the 5 mg/kg REMICADE group (p=0.002) and 56%
(18/32) of patients in the 10 mg/kg REMICADE group (p=0.021) vs. 26% (8/31)
of patients in the placebo arm. The median time to onset of response and median
duration of response in REMICADE-treated patients was 2 and 12 weeks, respectively.
Closure of all fistula was achieved in 52% of REMICADE-treated patients compared
with 13% of placebo-treated patients (p<0.001).
In the second trial (ACCENT II), patients who were enrolled
had to have at least one draining enterocutaneous (perianal, abdominal) fistula.
All patients received 5 mg/kg REMICADE at weeks 0, 2 and 6. Patients were randomized
to placebo or 5 mg/kg REMICADE maintenance at week 14. Patients received maintenance
doses at week 14 and then every eight weeks through week 46. Patients who were
in fistula response (fistula response was defined the same as in the first trial)
at both weeks 10 and 14 were randomized separately from those not in response.
The primary endpoint was time from randomization to loss of response among those
patients who were in fistula response.
Among the randomized patients (273 of the 296 initially enrolled),
87% had perianal fistulas and 14% had abdominal fistulas. Eight percent also
had rectovaginal fistulas. Greater than 90% of the patients had received previous
immunosuppressive and antibiotic therapy.
At week 14, 65% (177/273) of patients were in fistula response.
Patients randomized to REMICADE maintenance had a longer time to loss of fistula
response compared to the placebo maintenance group. At week 54, 38% (33/87)
of REMICADE-treated patients had no draining fistulas compared with 22% (20/90)
of placebo-treated patients (p=0.02). Compared to placebo maintenance, patients
on REMICADE maintenance had a trend toward fewer hospitalizations.
Patients who achieved a fistula response and subsequently lost
response were eligible to receive REMICADE maintenance therapy at a dose that
was 5 mg/kg higher than the dose to which they were randomized. Of the placebo
maintenance patients, 66% (25/38) responded to 5 mg/kg REMICADE, and 57% (12/21)
of REMICADE maintenance patients responded to 10 mg/kg.
Patients who had not achieved a response by week 14 were unlikely
to respond to additional doses of REMICADE.
Similar proportions of patients in either group developed new
fistulas (17% overall) and similar numbers developed abscesses (15% overall).
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