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prothrombin fragments 1
2, reflecting a transient and lim-
ited procoagulant effect of amediplase.
No anti-amediplase antibodies were detected in blood
samples from the three patients analyzed. From the 2K2
study could be concluded:
þ
TABLE 33.4 2K2 Study: TIMI 3 Results Grouped by
Amediplase Dose Expressed as Body Weight-Adjusted Doses
Dose
(mg/kg)
Total Number of
Treated Patients
Number of Patients
with TIMI 3
% TIMI
3
0.2
6
1
17
0.3
3
0
0
The effective dose range of amediplase achieving
0.4
5
0
0
50% TIMI 3 was in the range 70-90mg; when
adjusted by patient's body weight, the effective dose
range corresponded to 1.0-1.2 mg/kg.
Amediplase appeared to be a safe treatment as judged
by the low incidence of adverse events (including
serious class-related adverse events).
The pharmacokinetic profile of amediplase and in
particular its relatively long half-life supports the bolus
intravenous administration.
The effects on coagulation parameters confirmed the
fibrin specificity and the low procoagulant effect of
amediplase.
0.5
9
2
22
0.6
13
3
23
0.7
19
8
42
0.8
23
13
57
0.9
10
4
40
1.0
21
11
52
1.1
11
6
55
1.2
10
6
60
1.3
10
4
40
1.4
1
0
0
range) values for relevant pharmacokinetic parameters are
summarized in Table 33.5. Hemostatic parameters results
referring to the 80-mg dose of amediplase are summarized in
Table 33.6.
Overall, amediplase showed satisfactory fibrin specific-
ity, with a moderate and transient consumption of fibrinogen
and a -2-antiplasmin. The decrease in plasminogen and the
increase of plasmin- a 2-antiplasmin complexes and D-dimer
reflected the fibrinolytic activity of the compound. PAI-1
levels
33.4.3 3K2 Study: A Double-Blind, Randomized,
Parallel Group Study to Compare the Efficacy and
Safety of Two Doses of Amediplase
This Phase II, open label study (coded 3K2) has been carried
out to compare the efficacy and safety of two different doses
of amediplase (1.0 mg/kg vs 1.2 mg/kg), both given as an i.v.
bolus injection, in patients with suspected AMI and further
treated with heparin and aspirin [25,26].
Patients were randomly assigned, in a 1:1 ratio, to receive
1.0mg/kg (Group A) or 1.2 mg/kg (Group B) of amediplase.
The efficacy was evaluated by assessing the infarct-related
appeared not
to be
affected by amediplase
administration.
A modest increase of thrombin-antithrombin III com-
plexes was restricted to the first hour, with no increase in
TABLE 33.5
2K2 Study: Median (Range) Amediplase Pharmacokinetic Parameters by Dose
Dose (mg)
50 (n ¼ 4)
70 (n ¼ 5)
80 (n ¼ 5)
90 (n ¼ 4)
C max ( m g/mL)
9.7 (6.9-12.1)
11.1 (7.5-15.1)
14.2 (6.8-34.4)
20.6 (10.0-33.6)
AUC 0- 1 ( m g min/mL)
222 (152-296)
327 (150-334)
391 (152-987)
455 (356-607)
t 1 = 2 a (min)
8.6 (8.1-10.0)
12.0 (8.0-22)
12.0 (9.0-12.0)
13 (9-17)
t 1 = 2 b (min)
92 (45-125)
85 (79-140)
126 (84-253)
126 (93-195)
CL (mL/min)
236 (169-328)
213 (209-467)
204 (81-526)
203 (148-252)
V c (L)
3.2 (2.4-3.8)
4.7 (4.0-7.7)
2.7 (1.5-10)
3.9 (2.2-6.4)
V area (L/kg)
0.6 (0.3-0.7)
0.4 (0.3-0.7)
0.7 (0.1-1.5)
0.6 (0.4-0.8)
TABLE 33.6
2K2 Study: Mean Coagulation Parameters at 80mg Dose
PAI-1
(ng/mL)
D-Dimer
( m g/L)
Fibrinogen
(mg/dL)
Plasminogen
(%)
a 2-Antiplasmin
(%)
TAT
( m g/L)
F1
2
(nM)
þ
Time
N
PAP ( m g/L)
Predose
9 259.7 39.3
4464.4 2771.4
25.2 11.5
341 32.8
82.5 7.4
95.5 4.4
7.6 2.9
2.4 0.8
1 h
7 258.6 57.8 23933.1 1133.7
308 54.6
189.4 30.8
36.7 5.8
32 5.2
22.4 9.3
3.3 1.1
2 h
6 311.6 55.9 22139.3 1908.3 306.2 72.2
243.3 40.5
60.3 8.8
41 6.2
9.4 2.4
2.5 1.0
24 h
8 346.8 45.3
1387.7 401.4
25.9 9.8
334 31.2
69.1 3.8
74.5 2.0
11 4.3
1.7 0.4
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