Role of Convective Flow in Carmustine Delivery to a Brain Tumor

• Published in: Pharmaceutical research Vol. 26; no. 10; pp. 2289 - 2302
• Main Authors: Arifin, Davis Yohanes, Lee, Kam Yiu Timothy, Wang, Chi-Hwa, Smith, Kenneth A
• Format: Journal Article
• Language: English
• Published: Boston Boston : Springer US 01.10.2009; Springer US; Springer; Springer Nature B.V
• Subjects: Animals; Antineoplastic agents; Biochemistry; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Carmustine - administration & dosage; Carmustine - pharmacokinetics; Chemotherapy; Computer Simulation; Decanoic Acids - administration & dosage; Decanoic Acids - pharmacokinetics; Drug Delivery Systems - methods; Drug dosages; General pharmacology; Humans; Medical Law; Medical sciences; NMR; Nuclear magnetic resonance; Pharmaceutical technology. Pharmaceutical industry; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Polyesters - administration & dosage; Polyesters - pharmacokinetics; Rats; Research Paper; Simulation; convection; diffusion; computational fluid dynamics; Gliadel® wafer; BCNU; Antineoplastic agent; Intracranial; Nervous system diseases; Pharmaceutical technology; Nitrosoureas; Carmustine; Glioblastoma; Malignant tumor; Route of administration; Intracranial tumor; Cerebral disorder; Malignant glioma; Alkylating agent; Nitrogen mustard; Central nervous system disease; Diffusion; Cancer
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-009-9945-8

Purpose This paper presents a three-dimensional patient-specific simulation of carmustine delivery to brain tumor. The simulation investigates several crucial factors, particularly the role of convective flow, affecting drug delivery efficacy. Methods The simulation utilizes a complete three-dimensional tissue geometry constructed from magnetic resonance images (MRI) of a brain tumor patient in whom commercially available Gliadel® wafers were implanted for sustained delivery of carmustine following excision of the tumor. This method permits an estimation of the convective flow field (in the irregularly shaped anatomical region) which can be used for prediction of drug penetration into the domain of interest, i.e. remnant tumor. A finite volume method is utilized to perform all simulations. Results Drug exposure exceeds its threshold therapeutic concentration (~15 μM) but for only a limited time (i.e. less than a week) and only in the immediately adjacent tissue (i.e. less than 2 mm). A quasi-steady transport process is established within 1 day following treatment, in which the drug is eliminated rapidly by transcapillary exchange, while its penetration into the tumor is mainly by diffusion. Convection appears to be crucial in influencing the drug distribution in the tumor: the remnant tumor near the ventricle is, by one to two orders of magnitude, less exposed to the drug than is the distal remnant tumor. Conclusions Carmustine penetration from Gliadel® wafers implanted in brain is limited by rapid elimination via transcapillary exchange. Therefore, it could be useful to consider other therapeutic agents such as paclitaxel. In addition, local convective flow within the cavity appears to be a crucial factor in distributing the drug so that the tumor domain near the ventricle is prone to minimal drug exposure. Thus, complete removal of the tumor from this region is of particular concern.