Controlled release delivery of carmustine from biodegradable polymer wafers was 
approved as an adjunct to surgical resection in the treatment of recurrent 
glioblastoma multiforme after it was shown in clinical trials to be well 
tolerated and effective. Given the localised nature of the drug in the brain 
tissue, no direct pharmacokinetic measurements have been made in humans after 
implantation of a carmustine wafer. However, drug distribution and clearance 
have been extensively studied in both rodent and non-human primate brains at 
various times after implantation. In addition, studies to characterise the 
degradation of the polymer matrix, the release kinetics of carmustine and the 
metabolic fate of the drug and polymer degradation products have been conducted 
both in vitro and in vivo. GLIADEL wafers have been shown to release carmustine 
in vivo over a period of approximately 5 days; when in continuous contact with 
interstitial fluid, wafers should degrade completely over a period of 6 to 8 
weeks. Metabolic elimination studies of the polymer degradation products have 
demonstrated that sebacic acid monomers are excreted from the body in the form 
of expired CO(2), whereas 1,3-bis-(p-carboxyphenoxy)propane monomers are 
excreted primarily through the urine. Carmustine degradation products are also 
excreted primarily through the urine. Pharmacokinetic studies in animals and 
associated modelling have demonstrated the capability of this modality to 
produce high dose-delivery (millimolar concentrations) within millimetres of the 
polymer implant, with a limited penetration distance of carmustine from the site 
of delivery. The limited spread of drug is presumably due to the high 
transcapillary permeability of this lipophilic molecule. However, the presence 
of significant convective flows due to postsurgical oedema may augment the 
diffusive transport of drug in the hours immediately after wafer implantation, 
leading to a larger short-term spread of drug. Additionally, in non-human 
primates, the presence of significant doses in more distant regions of the brain 
(centimetres away from the implant) has been shown to persist over the course of 
a week. The drug in this region was presumed to be transported from the implant 
site by either cerebral blood flow or cerebrospinal fluid flow, suggesting that 
although drug is able to penetrate the blood-brain barrier at the site of 
delivery, it may re-enter within the confines of the brain tissue.