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
Regranex Pharmacology, Pharmacokinetics, Studies, Metabolism - Becaplermin
Regranex Pharmacology, Pharmacokinetics, Studies, Metabolism - Becaplermin
CLINICAL PHARMACOLOGY
REGRANEX has biological
activity similar to that
of endogenous platelet-derived
growth factor, which includes
promoting the chemotactic
recruitment and proliferation
of cells involved in wound repair and enhancing the formation
of granulation tissue.
Pharmacokinetics
Ten patients with Stage III or IV (as defined in the International Association
of Enterostomal Therapy (IAET) guide
to chronic wound
staging, J. Enterostomal Ther 15:4, 1988 and Decubitis 2:24,
1989) lower extremity diabetic
ulcers received topical applications
of becaplermin gel 0.01% at a dose
range of 0.32-2.95 µg
(7µg/cm2) daily for 14 days. Six patients had non-quantifiable
PDGF levels at baseline and throughout the study, two patients had PDGF
levels at baseline which
did not increase substantially, and two patients had PDGF levels that
increased sporadically above their baseline
values during the 14 day study period.
Systemic bioavailability
of becaplermin was less than 3% in rats with full thickness wounds receiving
single or multiple (5 days) topical
applications of 127 µg/kg (20.1 µg/cm2 of wound
area) of becaplermin gel.
Clinical Studies
The effects of REGRANEX Gel on the incidence
of and time to complete healing
in lower extremity diabetic
ulcers were assessed in four randomized controlled studies. Of 922 patients
studied, 478 received either REGRANEX Gel 0.003% or 0.01%. All study participants
had lower extremity diabetic
neuropathic ulcers that extended into the subcutaneous
tissue or beyond (Stages III
and IV of the IAET
guide to chronic
wound staging). Ninety-three
percent of the patients enrolled in these four trials had foot
ulcers. The remaining 7% of the patients had ankle
or leg ulcers. The diabetic ulcers
were of at least 8 weeks duration
and had an adequate blood supply
(defined as TcpO2 > 30 mm
Hg). In the four trials, ninety-five
percent of the ulcers measured
in area up to 10 cm2,
and the median ulcer
size at baseline ranged from
1.4 cm2 to 3.5 cm2. All treatment
groups received a program
of good ulcer care consisting of initial
complete sharp debridement, a non-weight-bearing regimen, systemic
treatment for wound-related
infection if present, moist
saline dressings changed twice a day, and additional debridement
as necessary. REGRANEX Gel 0.003% or 0.01% or placebo
gel was applied once a day and
covered with a saline moistened
dressing. After approximately 12 hours, the gel
was gently rinsed off and a saline
moistened dressing was then
applied for the remainder of the day. Patients were treated until complete
healing, or for a period of
up to 20 weeks. Patients were considered a treatment failure
if their ulcer did not show
an approximately 30% reduction in initial
ulcer area
after eight to ten weeks of REGRANEX Gel therapy.
The primary endpoint,incidence
of complete ulcer closure
within 20 weeks, for all treatment
arms is shown in Figure 1 . In
each study, REGRANEX Gel in conjunction with good ulcer
care was compared to placebo
gel plus good ulcer
care or good ulcer care alone
.
In Study 1, a multicenter, double-blind, placebo controlled trial of
118 patients, the incidence
of complete ulcer closure for REGRANEX Gel 0.003% (n=61) was 48% versus
25% for placebo gel (n=57;
p=0.02, logistic regression
analysis).
In Study 2, a multicenter, double-blind, placebo controlled trial of
382 patients, the incidence
of complete ulcer closure for REGRANEX Gel 0.01% (n=123), was 50% versus
36% for REGRANEX Gel 0.003% (n=132), and 35% for placebo
gel (n=127). Only REGRANEX Gel
0.01% was significantly different from placebo
gel (p=0.01, logistic regression
analysis).
The primary goal
of Study 3, a multicenter controlled trial of 172 patients, was to assess
the safety of vehicle gel
(placebo; n=70) compared to good ulcer
care alone (n=68). The study included a small (n=34) REGRANEX Gel 0.01%
arm. Incidences of complete ulcer
closure were 44% for REGRANEX Gel, 36% for placebo
gel and 22% for good ulcer
care alone.
In Study 4, a multicenter, evaluator-blind, controlled trial of 250 patients,
the incidences of complete ulcer
closure in the REGRANEX Gel 0.01% arm
(n=128) (36%) and good ulcer
care alone (n=122) (32%) were not statistically different.
In general, where REGRANEX Gel was associated with higher incidences
of complete ulcer closure, differences
in the incidence first became apparent
after approximately 10 weeks and increased with continued treatment (Table
1).
Table 1: Life Table Estimates of the Incidence (%) of
Complete Healing Over Time for Study 2
| |
REGRANEX
Gel 0.01%
(%) |
Placebo Gel
(%) |
| Week 2 |
1 |
0 |
| Week 4 |
6 |
2 |
| Week 6 |
9 |
6 |
| Week 8 |
16 |
14 |
| Week 10 |
23 |
18 |
| Week 12 |
34 |
25 |
| Week 14 |
37 |
28 |
| Week 16 |
43 |
33 |
| Week 18 |
46 |
34 |
| Week 20 |
50 |
37 |
In a 3-month follow-up
period where no standardized
regimen of preventative care
was utilized, the incidence
of ulcer recurrence was
approximately 30% in all treatment
groups, demonstrating that the durability of ulcer
closure was comparable in
all treatment groups. The
efficacy of REGRANEX Gel
for the treatment of nondiabetic
ulcers is under evaluation.
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