PHARMACOKINETICS AND TOXICOLOGY OF IMMUNOTOXINS ADMINISTERED INTO THESUBARACHNOID SPACE IN NONHUMAN-PRIMATES AND RODENTS

Immunotoxins have been suggested as possible therapeutic agents in pat ients with leptomeningeal carcinomatosis. The pharmacokinetics, stabil ity, and toxicity of immunotoxins injected into the i.t. space were ex amined in rats and rhesus monkeys. Monoclonal antibodies specific for the human (454A12 and J1) and rat (OX26) transferrin receptors were co upled to recombinant ricin A chain. In monkeys, the maximally tolerate d dose of the anti-human transferrin receptor immunotoxin (454A12-rRA) was a dose that yielded a nominal cerebrospinal fluid (CSF) concentra tion of approximately 1.2 x 10(-7)M. In rats, the 10% lethal dose (LD1 0) of the anti-human transferrin receptor immunotoxin was a dose yield ing a nominal CSF concentration of 8.8 x 10(-7) M whereas the LD10 of the anti-rat transferrin receptor immunotoxin (OX26-rRA) was a dose yi elding a nominal CSF concentration of 1.2 X 10(-7) M. Thus, the specie s-relevant antibody resulted in toxicity at a concentration one-sevent h that of the immunotoxin with the irrelevant antibody. A comparison o f the area under the concentration curve at the LD10 for rats with the area under the concentration curve at the maximally tolerated dose in monkeys and humans shows that the species-relevant immunotoxin was a better predictor of the toxic dose of the anti-transferrin receptor im munotoxin in humans than the irrelevant immunotoxin. The pharmacokinet ics of the 454A12-rRA immunotoxin within the CSF of monkeys showed a b iphasic clearance with an early-phase half-life of 1.4 h and a late ph ase half-life of 10.9 h. The clearance was 4.4 ml/h or approximately t wice the estimated clearance due to bulk flow of CSF. Loss by degradat ion was ruled out because immunoblot analysis showed that the immunoto xin was stable for up to 24 h after administration. Possible losses in addition to sampling include diffusion into brain tissue and transcap illary permeation. The apparent volume of distribution was 10.1 ml or approximately three-fourths the total CSF volume of the monkey. Dose l imiting toxicity corresponded with the selective elimination of Purkin je cells in both rats and monkeys and was manifested clinically as ata xia and lack of coordination. The onset of ataxia in monkeys occurred within 5 days and, in the more mild form, was reversible with time. Th ere was evidence of only minimal inflammation within the CSF, and ther e were no signs of systemic toxicity. Immunotoxins injected into the s ubarachnoid space may have potential for treatment of leptomeningeal c arcinomatosis.