| 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 rhAbs, 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. |
