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
Gliadel Pharmacology, Pharmacokinetics, Studies, Metabolism - Polifeprosan 20 With Carmustine Implant
Gliadel Pharmacology, Pharmacokinetics, Studies, Metabolism - Polifeprosan 20 With Carmustine Implant
CLINICAL PHARMACOLOGY
GLIADEL is designed to deliver carmustine directly into the surgical cavity
created when a brain tumor is resected. On exposure to the aqueous environment
of the resection cavity, the anhydride bonds in the copolymer are hydrolyzed,
releasing carmustine, carboxyphenoxypropane, and sebacic acid. The carmustine
released from GLIADEL diffuses into the surrounding brain tissue and produces
an antineoplastic effect by alkylating DNA and RNA.
Carmustine has been shown to degrade both spontaneously and metabolically.
The production of an alkylating moiety, hypothesized to be chloroethyl carbonium
ion, leads to the formation of DNA cross-links.
The tumoricidal activity of GLIADEL is dependent on release of carmustine to
the tumor cavity in concentrations sufficient for effective cytotoxicity.
More than 70% of the copolymer degrades by three weeks. The metabolic disposition
and excretion of the monomers differ. Carboxyphenoxypropane is eliminated by
the kidney and sebacic acid, an endogenous fatty acid, is metabolized by the
liver and expired as CO 2 in animals.
The absorption, distribution, metabolism, and excretion of the copolymer in
humans is unknown. Carmustine concentrations delivered by GLIADEL in human brain
tissue have not been determined. Plasma levels of carmustine after GLIADEL wafer
implant were not determined. In rabbits implanted with wafers containing 3.85%
carmustine, no detectible levels of carmustine were found in the plasma or cerebrospinal
fluid.
Following an intravenous infusion of carmustine at doses ranging from 30 to
170 mg/m 2 , the average terminal half-life, clearance, and steady-state
volume of distribution were 22 minutes, 56 mL/min/kg, and 3.25 L/kg, respectively.
Approximately 60% of the intravenous 200 mg/m 2 dose of 14 C-carmustine
was excreted in the urine over 96 hours and 6% was expired as CO 2 .
GLIADEL wafers are biodegradable in human brain when implanted into the cavity
after tumor resection. The rate of biodegradation is variable from patient to
patient. During the biodegradation process, a wafer remnant may be observed
on brain imaging scans or at re-operation even though extensive degradation
of all components has occurred. Data obtained from review of CT scans obtained
49 days after implantation of GLIADEL demonstrated that images consistent with
wafers were visible to varying degrees in the scans of 11 of 18 patients. Data
obtained at re-operation and autopsies have demonstrated wafer remnants up to
232 days after GLIADEL implantation.
Wafer remnants removed at re-operation from two patients with recurrent malignant
glioma, one at 64 days and the second at 92 days after implantation, were analyzed
for content. The following table presents the results of analyses completed
on these remnants.
COMPOSITION OF WAFER REMNANTS REMOVED FROM
TWO PATIENTS ON RE-OPERATION
|
Component
|
Patient A |
Patient B |
|
Days After GLIADEL
Implantation
|
64 |
92 |
|
Anhydride Bonds
|
None detected |
None detected |
|
Water Content (% of
wafer remnant weight)
|
95-97% |
74-86% |
|
Carmustine Content
(% of initial)
|
<0.0004% |
0.034% |
|
Carboxyphenoxypropane
Content (% of initial)
|
9% |
14% |
|
Sebacic Acid Content
(% of initial)
|
4% |
3% |
The wafer remnants consisted mostly of water and monomeric components with minimal
detectable carmustine present.
CLINICAL STUDIES
In a randomized, double-blind, placebo-controlled clinical trial in adults
with recurrent malignant glioma, GLIADEL prolonged survival in patients with
glioblastoma multiforme (GBM). Ninety-five percent of the patients treated with
GLIADEL had 7-8 wafers implanted.
In 222 patients with recurrent malignant glioma who had failed initial surgery
and radiation therapy, the six-month survival rate after surgery increased from
47% (53/112) for patients receiving placebo to 60% (66/110) for patients treated
with GLIADEL. Median survival increased by 33%, from 24 weeks with placebo to
32 weeks with GLIADEL treatment. In patients with GBM, the six-month survival
rate increased from 36% (26/73) with placebo to 56% (40/72) with GLIADEL treatment.
Median survival of GBM patients increased by 41% from 20 weeks with placebo
to 28 weeks with GLIADEL treatment. In patients with pathologic diagnoses other
than GBM at the time of surgery for tumor recurrence, GLIADEL produced no survival
prolongation.
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