Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2015 Publisher: MGI PHARMA LIMITED, Holborn Gate, 1st Floor, 330 High Holborn, London,WC1V 7QT, United Kingdom
Pharmacotherapeutic group: Antineoplastic agents
ATC Code: L01AD01
GLIADEL Implant delivers carmustine directly into the surgical cavity created after tumoural resection. On exposure to the aqueous environment of the cavity the anhydride bonds in the copolymer are hydrolysed, releasing carmustine, carboxyphenoxypropane and sebacic acid. The carmustine released from GLIADEL Implant diffuses into the surrounding brain tissue and produces an antineoplastic effect by alkylating DNA and RNA.
Carmustine is spontaneously both degraded and metabolised. The alkylating moiety thus produced and presumed to be chloroethyl carbonium ion, leads to the formation of irreversible DNA cross-links.
The tumourcidal activity of GLIADEL Implant is dependent on release of carmustine into the tumour 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 predominantly eliminated by the kidney and sebacic acid, an endogenous fatty acid, is metabolised by the liver and expired as CO2 in animals.
In a randomised, double-blind, placebo-controlled clinical trial in 240 adults with newly-diagnosed high grade malignant glioma undergoing initial craniotomy for tumour resection median survival increased from 11.6 months with placebo to 13.9 months with GLIADEL Implant (p-value 0.079, unstratified log-rank test) in the original study phase. The most common tumour type was Glioblastoma Multiforme (GBM) (n=207), followed by anaplastic oligoastrocytoma (n=11), anaplastic oligodendroglioma (n=11), and anaplastic astrocytoma (n=2). The hazard ratio for GLIADEL Implant was 0.77 (95% CI: 0.57 to 1.03). In the long term follow-up phase, patients still alive at the completion of the original phase were followed for up to at least three years or until death. Median survival increased from 11.6 months with placebo to 13.9 months with GLIADEL Implant (p-value <0.05, log-rank test). The hazard ratio for GLIADEL Implant treatment was 0.73 (95% CI: 0.56 to 0.95).
In a randomised, double-blind, placebo-controlled clinical trial in 145 adults with recurrent glioblastoma (GBM), GLIADEL Implant prolonged survival in these patients. Ninety-five percent of the patients treated with GLIADEL Implant received 7 to 8 implants.
The six-month survival rate was 36% (26/73) with placebo compared to 56% (40/72) with GLIADEL Implant treatment. Median survival of GBM patients is 20 weeks with placebo versus 28 weeks with GLIADEL Implant treatment.
The absorption, distribution, metabolism, and excretion of the copolymer in humans is unknown. Carmustine concentrations delivered by GLIADEL Implant in human brain tissue have not been determined. Plasma levels of carmustine after GLIADEL Implant implantation cannot be assayed. In rabbits that had implants containing 3.85% carmustine placed, carmustine is not detected in the blood or cerebrospinal fluid.
Following an intravenous infusion of carmustine at doses ranging from 30 to 170mg/m², the average terminal half-life, clearance, and steady-state volume of distribution are 22 minutes, 56mL/min/kg, and 3.25L/kg, respectively. Approximately 60% of the intravenous 200mg/m² dose of 14C-carmustine is excreted in the urine over 96 hours and 6% is expired as CO2.
GLIADEL Implants are biodegradable in human brain when placed into the cavity after tumour resection. The rate of biodegradation is variable from patient to patient.
During the biodegradation process an implant remnant may be observed on brain imaging scans or at re-operation even though extensive degradation of all components has occurred.
No carcinogenicity, mutagenicity, embryo-foetal toxicity, pre- and post-natal toxicity and impairment of fertility studies have been conducted with GLIADEL Implants.
Carmustine, the active component of GLIADEL Implant, when administered systemically, has embryotoxic, genotoxic and carcinogenic effects and can cause testicular degeneration in several animal models.
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