Human pharmacokinetics of a new Vinca alkaloid S 12363 with use of a monoclonal antibody-based radio- or enzyme immunoassay.
S 12363 is a new Vinca alkaloid derivative, characterized by the grafting of an alpha-aminophosphonate, onto the Vinca nucleus, facilitating drug penetration and increasing intracellular drug retention. As a high cytotoxic activity had been demonstrated in in vitro and in vivo models recommended by the National Cancer Institute, a phase I trial was initiated in cancer patients. In order to quantify S 12363 systemic levels in humans, two monoclonal antibody-based immunoassays, RIA (radio-) and EIA (enzyme immunoassay) were developed. The gamma-emitting probe used in the RIA, 125I-(deacetyl-O4-vinblastine)-tyramine, bound very tightly to the monoclonal antibody (dissociation constant, Kd = 2.5 x 10(-11) M), demonstrating a high affinity mainly directed toward the catharantine nucleus (vindesine, vincristine, vinblastine, 100% cross-reactivity; vinorelbine, 0.3% cross-reactivity). In the EIA, a deacetyl O4-vinblastine/ovalbumine conjugate was used as the competing antigen. Its binding to the monoclonal antibody was revealed by an anti-mouse immunoglobulin G conjugated to biotin which interacts with streptavidin labeled with alkaline phosphatase. This method permitted obtaining nearly the same sensitivity and reproducibility with EIA as with RIA, their respective minimum quantitation limits being 0.100 and 0.040 ng/ml (106 and 42 pM) of S 12363 in plasma. These assays allowed the study of S 12363 systemic pharmacokinetics in cancer patients during a phase I trial up to 72 h after dosing. As determined by RIA, the S 12363 plasma profile was triphasic with a terminal half-life; t1/2 gamma = 49 +/- 16 h, a plasma clearance, CL = 0.14 +/- 0.04 liter/h/kg, and a volume of distribution at steady state, Vdss = 5.0 +/- 2.8 liter/kg. The pharmacokinetics of S 12363 is linearly related to dose when increased from 0.08 up to 0.84 mg/m2 in humans. Its plasma profile and pharmacokinetic parameters are close to those of other Vinca alkaloids with clearance and terminal half-life being intermediate between those of vinblastine and vincristine. Therapeutic doses are 4 to 10 times lower and should be a direct consequence of the higher uptake and retention by the cells of this new aminophosphonate Vinca alkaloid derivative.
Lelievre
E
E
Bio-Pharmacie Servier, Orleans, France.
Guillaudeux
J
J
Cardona
H
H
Bourguignat
A
A
Lokiec
F
F
Solere
P
P
Lucas
C
C
Sauveur
C
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D011863:Radioimmunoassay; D014748:Vinca Alkaloids / Q000276:immunology / Q000493:pharmacokinetics*
D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D014748:Vinca Alkaloids; C064005:S 12363