Pharmacokinetics and dose estimates following intrathecal administration of 131I-monoclonal antibodies for the treatment of central nervous system malignancies

Papanastassiou, V.; Pizer, Barry; Chandler, Christopher; Zananiri, Tony F.; Kemshead, J. T.; Hopkins, Kirsten

doi:10.1016/0360-3016(94)00396-3

Cited by 25 publications

(16 citation statements)

References 15 publications

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“…The acute toxicity observed in this study mirrored that previously reported for patients receiving intrathecal targeted radiation therapy (Papanastassiou et al, 1995 was heavily pretreated with combination chemotherapy, continued on systemic maintenance chemotherapy for c-ALL throughout his course of targeted radiation therapy. Myelosuppression occurred as a result of each injection of radioimmunoconjugate, this being treated on each occasion with granulocyte-macrophage colonystimulating factor (GM-CSF).…”

Section: Toxicity Acutesupporting

confidence: 78%

“…Dose-limiting toxicity occurs at an activity of approximately 2220 MBq of '311-MAb, although this varies from patient to patient (Moseley et al, 1989;Bigner et al, 1995;Papanastassiou et al, 1995). The amount of combination chemotherapy given to individuals before targeted radiation therapy tends to render them more susceptible to myelosuppression.…”

Section: Discussionmentioning

confidence: 99%

“…Patients were also prescribed dexamethasone and phenytoin to reduce the risks of cerebral oedema and fits respectively (Papanastassiou et al, 1995).…”

Section: Materials and Methods Patient Recruitmentmentioning

confidence: 99%

“…A detailed description of the methods used to determine the dose to these organs as a result of intrathecal targeted radiation has been described previously (Papanastassiou et al, 1995).…”

Section: Dosimetrymentioning

confidence: 99%

“…Patients were selected for study based upon their having either diffuse disseminated disease and/or small tumour nodules no larger than 1.5 cm in diameter, and no blockage in their CSF pathways. As part of these Phase I studies, we identified the primary toxicity of this type of therapy as myelosuppression, which occurred idiosyncratically at doses of 2220 MBq of '3'I-MAb and above (Papanastassiou et al, 1995). Pharmacokinetic data indicate that myelosuppression is brought about through the passage of the radioimmunoconjugate from the CSF into the blood compartment.…”

mentioning

confidence: 99%

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Dose escalation with repeated intrathecal injections of 131I-labelled MAbs for the treatment of central nervous system malignancies

Kemshead

Hopkins²,

Pizer³

et al. 1998

Br J Cancer

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Summary We have previously demonstrated a 33% response rate in patients with primitive neurectodermal tumours after the direct injection of 1311-monoclonal antibodies (MAbs) into the cerebrospinal fluid (CSF). Dose-limiting toxicity is myelosuppression due to the passage of the radioimmunoconjugate from the CSF to the blood compartment. This occurs at doses of 2220 MBq of 131 I-MAb and above, although this is not seen in all patients studied and appears to be related to the degree of prior therapy received. Rather than attempting to improve the efficacy of this approach to the treatment of disseminated disease within the CSF compartment by dose escalation and haemopoietic rescue, we have explored the possibility of repeatedly administering the radioimmunoconjugate. Eight patients were recruited to the study, two of whom received two and six of whom received three injections of 1311-MAb. After repeated administration of '311-MAb pharmacokinetic data revealed that, with one exception, the radioimmunoconjugate cleared from the CSF compartment with similar kinetics, while its residence time in the blood decreased with each injection. This was due to the development of an anti-mouse Ig response in the blood. Clearance of 131I-MAb from the ventricular CSF appears to be independent of the presence of an anti-mouse Ig response in this compartment. The differential clearance of the radioimmunoconjugate from the ventricular CSF and from the blood results in a marked increase in the therapeutic index that can be achieved. Up to 5920 MBq of '311-MAb was administered as the third injection of radioimmunoconjugate and combined doses of up to 12 500 MBq were given without either haematological or neurological toxicity. These data illustrate that dose escalation and thus an increase in the dose rate delivered to tumour cells within the CSF is possible if ways are found to reduce the residence time of the radioimmunoconjugate in the blood compartment. Suggestions as to how this can best be achieved are reviewed in detail.

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Section: Toxicity Acutesupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

“…Patients were also prescribed dexamethasone and phenytoin to reduce the risks of cerebral oedema and fits respectively (Papanastassiou et al, 1995).…”

Section: Materials and Methods Patient Recruitmentmentioning

confidence: 99%

“…A detailed description of the methods used to determine the dose to these organs as a result of intrathecal targeted radiation has been described previously (Papanastassiou et al, 1995).…”

Section: Dosimetrymentioning

confidence: 99%

mentioning

confidence: 99%

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Dose escalation with repeated intrathecal injections of 131I-labelled MAbs for the treatment of central nervous system malignancies

Kemshead

Hopkins²,

Pizer³

et al. 1998

Br J Cancer

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Leptomeningeal Carcinomatosis: Diagnosis and Management

Groves¹

2004

Intracranial Metastases

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Distribution of intraventricularly administered antiamyloid‐beta peptide (Aβ) antibody in the mouse brain

Chauhan

Siegel

Lichtor

2001

J of Neuroscience Research

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There is considerable interest in utilizing the intracerebroventricular (icv) route of administration of antibodies in the brain for various studies and for the therapy of malignancies, but very little is known about the anatomic extent of distribution of the antibody in brain after injection into the third ventricle. To explore the potential for icv administration of antiamyloid-beta peptide (Abeta) in reducing Abeta toxicity in brain in Alzheimer's disease, we first mapped the time course and path of transit of horseradish peroxidase (HRP)-labeled antibody. The results show that, after a single injection into the mouse third venticle, the HRP-labeled antibody is localized within the microvasculature, first that of the corticohippocampal region close to the site of injection at 3 hr. By 24 hr, the antibody is distributed throughout the hippocampus and frontoparietal cortex close to the injection site, as well as in the deep and outer cerebral cortex and cerebellar cortex remote from the injection site. The injected antibody is almost entirely removed by 4 days. Therefore, the antibody had diffused throughout all the brain by 24 hr, showing the feasibility of small quantities of anti-Abeta antibody infused into the third ventricle to reach extracellular epitopes throughout the brain parenchyma rapidly.

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Pharmacokinetics and dose estimates following intrathecal administration of 131I-monoclonal antibodies for the treatment of central nervous system malignancies

Cited by 25 publications

References 15 publications

Dose escalation with repeated intrathecal injections of 131I-labelled MAbs for the treatment of central nervous system malignancies

Dose escalation with repeated intrathecal injections of 131I-labelled MAbs for the treatment of central nervous system malignancies

Leptomeningeal Carcinomatosis: Diagnosis and Management

Distribution of intraventricularly administered antiamyloid‐beta peptide (Aβ) antibody in the mouse brain

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