GLIADEL (polifeprosan 20 with carmustine implant) wafer
[Eisai Inc.]
DESCRIPTION
GLIADEL® Wafer (polifeprosan 20 with carmustine implant) is a sterile, off-white to pale yellow wafer approximately 1.45 cm in diameter and 1 mm thick. Each wafer contains 192.3 mg of a biodegradable polyanhydride copolymer and 7.7 mg of carmustine [1,3-bis (2-chloroethyl)-1-nitrosourea, or BCNU]. Carmustine is a nitrosourea oncolytic agent. The copolymer, polifeprosan 20, consists of poly[bis(p-carboxyphenoxy) propane: sebacic acid] in a 20:80 molar ratio and is used to control the local delivery of carmustine. Carmustine is homogeneously distributed in the copolymer matrix.
The structural formula for polifeprosan 20 is:

The structural formula for carmustine is:

CLINICAL PHARMACOLOGY
GLIADEL® Wafer 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® Wafer 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® Wafer 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 CO2 in animals.

The absorption, distribution, metabolism, and excretion of the copolymer in humans is unknown. Carmustine concentrations delivered by GLIADEL® Wafer 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/m2, 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/m2 dose of 14C-carmustine was excreted in the urine over 96 hours and 6% was expired as CO2.

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® Wafer 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® Wafer implantation.

Wafer remnants removed at re-operation from two pa