title: Pharmacokinetics and disposition of the KS1/4 monoclonal antibody-desacetylvinblastine hydrazide conjugate LY203725 in rats and monkeys.
abstract: The plasma pharmacokinetics of the monoclonal antibody-vinca conjugate KS 1/4-desacetylvinblastine hydrazide (DAVLB-hyd; [3H]LY203725) have been evaluated in rats (17 mg/kg) and monkeys (15 mg/kg) after i.v. dosing. Plasma concentrations of radioactivity 1 hr after dosing were higher in monkeys than in rats. The biphasic elimination of radioactivity in rats was characterized by half-lives (T1/2) of 10 and 143 hr, whereas the elimination of radioactivity in monkeys was characterized by T1/2 values of 11 and 66 hr. Plasma total antibody and radioactivity concentrations were similar within 6 (rat) and 24 (monkey) hr after dosing; however, total antibody concentrations were greater than radioactivity concentrations thereafter, indicating the presence of free antibody in the plasma. Plasma elimination T1/2 values and areas under the curve of total antibody in rats and monkeys were greater than those of radioactivity. The presence of free antibody implies the presence of free DAVLB-hyd; however, plasma concentrations of free DAVLB-hyd were at least 3 orders of magnitude less than those of radioactivity in both species. The T1/2 of free DAVLB-hyd in plasma of LY203725 dosed monkeys was 16 hr. Hydrolysis of the conjugate to yield free DAVLB-hyd was observed upon incubation of conjugate with rat plasma in vitro. Administration of DAVLB-hyd to rats resulted in a rapid initial decrease in plasma DAVLB-hyd followed by a slower (T1/2 = 1.4 hr) elimination rate. Fecal excretion was the predominant mode of elimination of radioactivity in both rats and monkeys dosed with [3H]LY203725.
authors.affiliation: Department of Drug Metabolism and Disposition, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: T D
authors.initials: TD
authors.lastname: Lindstrom
authors.forename: W A
authors.initials: WA
authors.lastname: Althaus
authors.forename: K J
authors.initials: KJ
authors.lastname: Ruterbories
authors.forename: D
authors.initials: D
authors.lastname: Kau
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D000951:Antigens, Neoplasm / Q000032:analysis*; D015815:Cell Adhesion Molecules; D002851:Chromatography, High Pressure Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D000071858:Epithelial Cell Adhesion Molecule; D005243:Feces / Q000032:analysis; D005260:Female; D000922:Immunotoxins / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine
chemical_list: C055183:4-desacetylvinblastine hydrazide-monoclonal antibody KS1-4 conjugate; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D000922:Immunotoxins; C055170:4-desacetylvinblastine hydrazide; D014747:Vinblastine