DISPOSITION OF THE MONOCLONAL ANTIBODY-VINCA ALKALOID CONJUGATE, KS1/4-DAVLB (LY256787), IN FISCHER-344 RATS AND RHESUS-MONKEYS

  • 1 September 1987
    • journal article
    • research article
    • Vol. 15  (5) , 640-647
Abstract
The conjugate, KS1/4-DAVLB, of the murine monoclonal antibody KS1/4 with the vinca alkaloid 4-desacetylvinblastine (DAVLB) was administered intravenously to rats and monkeys. Terminal plasma half-life (t1/2) values were measured as radioequivalents and as functionally immunoreactive antibody conjugate after dosing with KS1/4-[3H]DAVLB. The t1/2 values, determined radiometrically, were 145 hr and 62 hr in male rats after 10 and 100 mg/kg doses and 92 hr and 90 hr in male and female monkeys after a 40 mg/kg dose. Comparable results were obtained when the functionally immunoreactive conjugate concentrations were determined by an enzyme-linked immunosorbent assay technique. The ratio of 35S:3H in the plasma after dosing rats with 100 mg/kg [35S]KS1/4-[3H]DAVLB remained reasonably constant during 336 hr. Less than 1% of the total vinca alkaloid equivalents present in the plasma at any time could be extracted as free vinca species; the major vinca alkaloid metabolites present at early time points were hemisuccinate derivatives of DAVLB, whereas, at later times, DAVLB and its N-oxide were equally as concentrated. The major pathway of elimination was fecal with about one-half of the administered radioactivity cleared in 150-250 hr. After dosing with [35S]KS1/4-[3H]DAVLB, the ratio of 35S:3H radioactivity in the bile was substantially less than that in the plasma. Evaluation of radioactivity eluted from the bile by size-exclusion HPLC showed that almost all of the tritium was associated with material of lower molecular weight than that of KS1/4-DAVLB. These data suggest that the KS1/4-DAVLB conjugate circulated mostly in an intact form in the plasma and was catabolized in the liver with the subsequent excretion of vinca metabolites into the bile. The data are best described by a two-compartment pharmacokinetic model which is consistent with the plasma kinetics and with the tissue distribution studies.