Pharmacokinetics of the carmustine implant

Abstract

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.