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.

Rapid regression of glioblastoma following carmustine wafer implantation: A case report

“…Previous pharmacokinetic studies on animals and associated modelling demonstrated the ability of carmustine wafers to produce high-dose delivery (millimolar concentrations) within millimeters of the polymer implant, with a limited penetration distance of carmustine from the site of delivery (13). In addition, the presence of significant doses of carmustine in more distant regions of the brain (centimeters away from the carmustine wafer implant) has been shown to persist over the course of 1 week in non-human primates (13).…”

“…In addition, the presence of significant doses of carmustine in more distant regions of the brain (centimeters away from the carmustine wafer implant) has been shown to persist over the course of 1 week in non-human primates (13). However, Fung et al (12) revealed that a significant concentration of carmustine (0.4 µM) was detected at up to 5 cm from the implant as late as 30 days after implantation, although a high drug concentration (0.5-3.5 mM) was measured within 3 mm.…”

Image-Guided Convection-Enhanced Delivery Platform in the Treatment of Neurological Diseases

“…13,14 Biopolymer tech-nology has allowed chemotherapeutic agents to be placed and gradually released at the brain surface subsequent to tumor resection, providing higher local concentrations than possible via systemic delivery, without the associated systemic toxicity. [15][16][17] Depending on the biopolymer composition, drugs can be delivered in a controlled manner for a finite period of time. Unfortunately, reoperation is required for re-dosing of the patient with these biopolymers, and controversy remains over cost and associated morbidities.…”

Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues

“…During brain tumor excision, gel wafers embedded with chemotherapeutics are inserted into the space previously occupied by tumor, resulting in slow release of drug precisely in the region of persisting malignant cells (31). Ongoing studies are focused on the development of a cytochrome c mimetic that could be delivered in such a manner to eliminate brain tumor cells without harming surrounding neural tissue.…”