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®1 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 CO2, 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.
Similar content being viewed by others
References
Azizi SA, Miyamoto C. Principles of treatment of malignant gliomas in adults: an overview. J Neurovirol 1998; 4(2): 204–16
Donelli MG, Zucchetti M, Dincalci M. Do anticancer agents reach the tumor target in the human brain. Cancer Chemother Pharmacol 1992; 30(4): 251–60
Petersdorf SH, Livingston RB. High-dose chemotherapy for the treatment of malignant brain tumors. J Neurooncol 1994; 20(2): 155–63
Kochi M, Ushio Y. High-dose chemotherapy with autologous hematopoietic stem-cell rescue for patients with malignant brain tumors. Crit Rev Neurosurg 1999; 9(5): 295–302
Zucchetti M, Boiardi A, Silvani A, et al. Distribution of daunorubicin and daunorubicinol in human glioma tumors after administration of liposomal daunorubicin. Cancer Chemother Pharmacol 1999; 44(2): 173–6
Rapoport SI. Osmotic opening of the blood-brain barrier: principles, mechanism, and therapeutic applications. Cell Mol Neurobiol 2000; 20(2): 217–30
Gumerlock MK, Belshe BD, Madsen R, et al. Osmotic blood-brain-barrier disruption and chemotherapy in the treatment of high-grade malignant glioma -patient series and literature review. J Neurooncol 1992; 12(1): 33–46
Giese A, Westphal M. Glioma invasion in the central nervous system. Neurosurgery 1996; 39(2): 235–50
Hochberg FH, Pruitt AA, Beck DO, et al. The rationale and methodology for intra-arterial chemotherapy with BCNU as treatment for glioblastoma. J Neurosurg 1985; 63(6): 876–80
Mahaley MS, Whaley RA, Blue M, et al. Central neurotoxicity following intracarotid BCNU chemotherapy for malignant gliomas. J Neurooncol 1986; 3(4): 297–314
Jacobs A, Clifford P, Kay HEM. The Ommaya reservoir in chemotherapy for malignant disease in the CNS. Clin Oncol 1981; 7(2): 123–9
Bakhshi S, North RB. Implantable pumps for drug delivery to the brain. J Neurooncol 1995; 26(2): 133–9
Brem H. Polymers to treat brain tumors. Biomaterials 1990; 11(9): 699–701
Domb A, Maniar M, Bogdansky S, et al. Drug delivery to the brain using polymers. Crit Rev Ther Drug Carrier Syst 1991; 8(1): 1–17
Brem H, Walter KA, Langer R. Polymers as controlled drug delivery devices for the treatment of malignant brain tumors. Eur J Pharm Biopharm 1993; 39(1): 2–7
Sipos EP, Brem H. New delivery systems for brain-tumor therapy. Neurol Clin 1995; 13(4): 813–25
Walter KA, Tamargo RJ, Olivi A, et al. Intratumoral chemotherapy. Neurosurgery 1995; 37(6): 1129–45
Menei P, Venier-Julienne MC, Benoit JP. Drug delivery into the brain using implantable polymeric systems. STP Pharma Sci 1997; 7(1): 53–61
Englehard HH. The role of interstitial BCNU chemotherapy in the treatment of malignant glioma. Surg Neurol 2000; 53(5): 458–64
Brem H, Gabikian P. Biodegradable polymer implants to treat brain trumors. J Control Release 2001; 74(1–3): 63–7
Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent Gliomas. Lancet 1995; 345(8956): 1008–12
Brem H, Mahaley S, Vick NA, et al. Interstitial chemotherapy with drug polymer implants for the treatment of recurrent Gliomas. J Neurosurg 1991; 74(3): 441–6
Tew K, Colvin OM, Chabner BA. Alkylating agents. In: Chabner BA, Longo DL, editors. Cancer chemotherapy and biotherapy. Chapter 12. Philadelphia (PA): Lippincott-Raven Publishers, 1991: 297–332
Brem H, Kader A, Epstein JI, et al. Biocompatibility of a biodegradable, controlled-release polymer in the rabbit brain. Sel Cancer Ther 1989; 5(2): 55–65
Tamargo RJ, Epstein JI, Reinhard CS, et al. Brain biocompatibility of a biodegradable, controlled-release polymer in rats. J Biomed Mater Res 1989; 23(2): 253–66
Chasin M, Hollenbeck G, Brem H, et al. Interstitial drug therapy for brain tumors -a case study. Drug Dev Ind Pharm 1990; 16(18): 2579–94
Tamargo RJ, Myseros JS, Epstein JI, et al. Interstitial chemotherapy of the 91-gliosarcoma -controlled release polymers for drug delivery in the brain. Cancer Res 1993; 53(2): 329–33
Brem H, Tamargo RJ, Olivi A, et al. Biodegradable polymers for controlled delivery of chemotherapy with and without radiation therapy in the monkey brain. J Neurosurg 1994; 80(2): 283–90
Buahin KG, Brem H. Interstitial chemotherapy of experimental brain tumors: comparison of intratumoral injection versus polymeric controlled release. J Neurooncol 1995; 26(2): 103–10
Sipos EP, Tyler B, Piantadosi S, et al. Optimizing interstitial delivery of BCNU from controlled release polymers for the treatment of brain tumors. Cancer Chemother Pharmacol 1997; 39(5): 383–9
Brem H, Ewend MG, Piantadosi S, et al. The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: Phase I trial. J Neurooncol 1995; 26(2): 111–23
Valtonen S, Timonen U, Toivanen P, et al. Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 1997; 41(1): 44–8
Subach BR, Witham TF, Kondziolka D, et al. Morbidity and survival after 1,3-bis(2-chloroethyl)-1 nitrosourea wafer implantation for recurrent glioblastoma: a retrospective case matched cohort series. Neurosurgery 1999; 45(1): 17–22
Domb AJ, Langer R. Polyanhydrides: 1. Preparation of highmolecular-weight polyanhydrides. J Polym Sci Pol Chem 1987; 25(12): 3373–86
Dang WB, Daviau T, Brem H. Morphological characterization of polyanhydride biodegradable implant GLIADEL® during in vitro and in vivo erosion using scanning electron microscopy. Pharm Res 1996; 13(5): 683–91
Domb AJ, Israel ZH, Elmalak O, et al. Preparation and characterization of carmustine loaded polyanhydride wafers for treating brain tumors. Pharm Res 1999; 16(5): 762–5
Leong KW, Brott BC, Langer R. Bioerodible polyanhydrides as drug-carrier matrices: 1. Characterization, degradation, and release characteristics. J Biomed Mater Res 1985; 19(8): 941–55
Leong KW, Damore P, Marietta M, et al. Bioerodible polyanhydrides as drug-carrier matrices: 2. Biocompatibility and chemical reactivity. J Biomed Mater Res 1986; 20(1): 51–64
Langer R. Biomaterials in drug delivery and tissue engineering: one laboratory’s experience. Acc Chem Res 2000; 33(2): 94–101
Loo TL, Dion RT, Dixon L, et al. The antitumor agent, 1,3-Bis(2-chloroethyl)-1-nitrosourea. J Pharm Sci 1966; 55(5): 492–7
Dang WB, Daviau T, Ying P, et al. Effects of GLIADEL® wafer initial molecular weight on the erosion of wafer and release of BCNU. J Control Release 1996; 42(1): 83–92
Wu MP, Tamada JA, Brem H, et al. In-vivo versus in-vitro degradation of controlled-release polymers for intracranial surgical therapy. J Biomed Mater Res 1994; 28(3): 387–95
Tamada J, Langer R. The development of polyanhydrides for drug delivery applications. J Biomater Sci Polym Ed 1992; 3(4): 315–53
Langer R. Polymeric delivery systems for controlled drug release. Chem Eng Commun 1980; 6(1–3): 1–48
Domb AJ, Rock M, Schwartz J, et al. Metabolic disposition and elimination studies of a radiolabeled biodegradable polymeric implant in the rat brain. Biomaterials 1994; 15(9): 681–8
Domb AJ, Rock M, Perkin C, et al. Excretion of a radiolabeled anticancer biodegradable polymeric implant from the rabbit brain. Biomaterials 1995; 16(14): 1069–72
Grossman SA, Reinhard C, Colvin OM, et al. The intracerebral distribution of BCNU delivered by surgically implanted biodegradable polymers. J Neurosurg 1992; 76(4): 640–7
Fenstermacher JD, Patlack CS, Blasberg RG. Transport of material between brain extracellular fluid, brain cells and blood. Fed Proc 1974; 33(9): 2070–4
Fenstermacher JD, Patlak CS. The movements of water and solutes in the brains of mammals. In: Pappius HM, Feindel W, editors. Dynamics of brain edema. New York: Springer, 1976: 87–94
Fenstermacher J, Kaye T. Drug ‘diffusion’ within the brain. Ann N Y Acad Sci 1988; 531: 29–39
Morrison PF, Dedrick RL. Transport of cisplatin in rat brain following microinfusion: an analysis. J Pharm Sci 1986; 75(2): 120–8
Nicholson C. Interaction between diffusion and Michaelis-Menten uptake of dopamine after ionophoresis in striatum. J Biophys 1995; 68(5): 1699–715
Jain RK. Transport of molecules in the tumor interstitium: a review. Cancer Res 1987; 47(12): 3039–51
Saltzman WM, Radomsky ML. Drugs released from polymers: diffusion and elimination in brain-tissue. Chem Eng Sci 1991; 46(10): 2429–44
Dang WB, Saltzman WM. Dextran retention in the rat brain following release from a polymer implant. Biotechnol Prog 1992; 8(6): 527–32
Mak M, Fung L, Strasser JF, et al. Distribution of drugs following controlled delivery to the brain interstitium. J Neurooncol 1995; 26(2): 91–102
Krewson C, Saltzman WM. Delivery and distribution of recombinant human nerve growth factor in the brain interstitium. Ann Neurol 1995; 38(2): 294–5
Krewson CE, Klarman ML, Saltzman WM. Distribution of nerve growth-factor following direct delivery to brain interstitium. Brain Res 1995; 680(1–2): 196–206
Mahoney MJ, Saltzman WM. Controlled release of proteins to tissue transplants for the treatment of neurodegenerative disorders. J Pharm Sci 1996; 85(12): 1276–81
Krewson CE, Saltzman WM. Transport and elimination of recombinant human NGF during long-term delivery to the brain. Brain Res 1996; 727(1–2): 169–81
Fung LK, Shin M, Tyler B, et al. Chemotherapeutic drugs released from polymers: distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea in the rat brain. Pharm Res 1996; 13(5): 671–82
Strasser JF, Fung LK, Eller S, et al. Distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea and tracers in the rabbit brain after interstitial delivery by biodegradable polymer implants. J Pharmacol Exp Ther 1995; 275(3): 1647–55
Fung LK, Ewend MG, Sills A, et al. Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. Cancer Res 1998; 58(4): 672–84
Reulen HJ, Graham R, Spatz M, et al. Role of pressure gradients and bulk flow in dynamics of vasogenic brain edema. J Neurosurg 1977; 46(1): 24–35
Kalyanasundaram S, Calhoun VD, Leong KW. A finite element model for predicting the distribution of drugs delivered intracranially to the brain. Am J Physiol Regul Integr Comp Physiol 1997; 42(5): R1810–R21
Kalyanasundaram S, Leong KW. Intracranial drug delivery systems. STP Pharma Sci 1997; 7(1): 62–70
Wang CH, Li J, Teo CS, et al. The delivery of BCNU to brain tumors. J Control Release 1999; 61(1–2): 21–41
Jain RK. Vascular and interstitial barriers to delivery of therapeutic agents in tumors. Cancer Metastasis Rev 1990; 9(3): 253–66
Castillo M, Ewend MG, Cush S, et al. Magnetic resonance imaging appearance of carmustine-impregnated implantable wafers. Int J Neurol 1998; 4(5): 380–4
Teicher BA, Holden SA, Eder JP, et al. Influence of schedule on alkylating agent cyto-toxicity in vitro and in vivo. Cancer Res 1989; 49(21): 5994–8
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fleming, A.B., Saltzman, W.M. Pharmacokinetics of the Carmustine Implant. Clin Pharmacokinet 41, 403–419 (2002). https://doi.org/10.2165/00003088-200241060-00002
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-200241060-00002