Pharmacokinetics of IgG and IgM Anti-Ganglioside Antibodies in Rats and Monkeys after Intrathecal Administration1
- Ira Bergman1,
- Gilbert J. Burckart3,
- Clifford R. Pohl4,
- Raman Venkataramanan3,
- Mamdouha A. Barmada2,
- Judith A. Griffin1 and
- Nai-Kong V. Cheung5
- Departments of 1Pediatrics (I.B., J.A.G.), 2Pathology (M.A.B.) and3Pharmaceutical Sciences (G.J.B., R.V.), University of Pittsburgh, Pittsburgh, Pennsylvania; 4School of Health Sciences (C.R.P.), Duquesne University, Pittsburgh, Pennsylvania; and 5Department of Pediatrics (N.K.V.C.), Memorial Sloan Kettering Cancer Center, New York, New York
Abstract
Intrathecal (i.t.) administration of monoclonal antibodies (mAbs) represents a new therapeutic approach for the treatment of leptomeningeal cancer, which is rapidly fatal. This study describes the pharmacokinetics of intrathecally administered mAbs in rats and monkeys to optimize their use for regional antineoplastic therapy. We hypothesized that mAbs, which are high-molecular-weight, polar compounds, would be eliminated from the cerebrospinal fluid (CSF) at the same rate as bulk flow of CSF. We found that an IgM mAb was cleared from rat CSF at the rate of CSF bulk flow (0.0041 ml/min), but an IgG mAb was cleared at a faster rate (0.011 ml/min). We attempted to reduce the CSF clearance of an IgG mAb by administration of acetazolamide and furosemide, which inhibit the rate of CSF production and CSF bulk flow. We demonstrated that the administration of acetazolamide and furosemide reduced the clearance of IgG mAb from rat CSF by 58%. These results establish that bulk flow of CSF determines a minimum rate of elimination from the CSF for IgM mAbs and that additional mechanisms operate to clear IgG mAbs from the CSF. Inhibition of CSF production by acetazolamide and furosemide increased the area under the CSF concentration vs. time curve of IgG mAbs in the CSF. The increased area under the CSF concentration vs. time curve is likely to improve the therapeutic index of these agents for i.t. therapy.
Footnotes
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Send reprint requests to: Ira Bergman, MD, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213.
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↵1 This work was supported in part by National Cancer Institute Grant 1-R29-CA58660–01A1, a grant from the Children’s Hospital of Pittsburgh and National Institutes of Health Grant DC01260, which provided the generous gift of rhesus monkeys through the University of Pittsburgh Department of Pediatric Otolaryngology. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the granting institutes.
- Abbreviations:
- CM
- cisterna magna
- CSF
- cerebrospinal fluid
- ELISA
- enzyme-linked immunosorbent assay
- i.t.
- intrathecal
- i.v.
- intravenous
- mAb
- monoclonal antibody
- SAS
- subarachnoid space
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- Received May 8, 1997.
- Accepted September 22, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
