Pharmacokinetics and dose estimates following intrathecal administration of 131I-monoclonal antibodies for the treatment of central nervous system malignancies.
OBJECTIVE
Treatment of malignant disease in the central nervous system (CNS) with systemic radiolabeled monoclonal antibodies (MoAbs) is compromised by poor penetration into the cerebrospinal fluid (CSF), limited diffusion into solid tumors, and the generation of anti-mouse antibodies. To attempt to avoid these problems we have treated patients with diffuse neoplastic meningitis with radioimmunoconjugates injected directly into the intrathecal space.


METHODS
Tumor-specific MoAbs were conjugated to Iodine-131 (131I) (629-3331 MBq) by the Iodogen technique, and administered via an intraventricular reservoir. A clinical response rate of approximately 33% was achieved, with better results in more radiosensitive tumors. Here, we present detailed pharmacodynamic data on patients receiving this intracompartmental targeted therapy.


RESULTS
Elimination from the ventricular CSF appeared biphasic, with more rapid clearance occurring in the first 24 h. Radioimmunoconjugate entered the subarachnoid space and subsequently the vascular compartment. From this information, the areas under the effective activity curves for ventricular CSF, blood, and subarachnoid CSF were calculated to permit dosimetry. Critical organ doses were calculated using conventional medical internal radiation dose (MIRD) formalism. Where available, S-values were taken from standard tables. To calculate the doses to CSF, brain, and spinal cord, S-values were evaluated using the models described in the text.


CONCLUSIONS
A marked advantage could be demonstrated for the dose delivered to tumor cells within the CSF as compared to other neural elements.
Papanastassiou
V
V
Imperial Cancer Research Fund, Frenchay Hospital, Bristol, UK.
Pizer
B L
BL
Chandler
C L
CL
Zananiri
T F
TF
Kemshead
J T
JT
Hopkins
K I
KI
D000911:Antibodies, Monoclonal / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D001853:Bone Marrow / Q000528:radiation effects; D001921:Brain / Q000528:radiation effects; D001932:Brain Neoplasms / Q000532:radiotherapy*; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D016499:Radioimmunotherapy / Q000009:adverse effects; D011879:Radiotherapy Dosage
D000911:Antibodies, Monoclonal; D007457:Iodine Radioisotopes