IngentaConnect Influence of Immunogenicity on the Pharmacokinetics of BMS-191352...

Abstract:

BMS-191352 is an immunotoxin construct of modified Pseudomonas exotoxin conjugated to a fragment of the BR96 monoclonal antibody. We have investigated the potential for immunogenicity of BMS-191352 and its influence on the pharmacokinetics in rats and dogs.

BMS-191352 was administered intravenously at doses of 0·75, 1·5, and 3 mg m^-2 once every two days for a total of five doses in rats, and 1·2, 2·4, and 4·8 mg m^-2 once every three days for a total of five doses in dogs. Blood samples were collected on days 1 and 9 in rats, and on days 1, 7, and 13 in dogs to monitor pharmacokinetics and anti-BMS-191352 immune response. Plasma concentrations of BMS-191352 and serum anti-BMS-191352 antibody titre were determined using ELISA assays. Pharmacokinetics were assessed using a non-compartmental method.

Anti-BMS-191352 antibodies were not observed in rats within the drug administration interval. In all dogs, except one, markedly higher anti-BMS-191352 antibody titres were observed on day 13 compared with days 1 and 7, and its magnitude was independent of BMS-191352 dose. The single dose kinetics of BMS-191352 in rats and dogs were linear and the drug exposures were generally dose proportional. Mean half-life, total body clearance, and volume of distribution were 1·74 h, 3·35 mL min^-1 m^-2, and 0·27 L m^-2 in rats, respectively, and 4·27 h, 6·28 mL min^-1 m^-2, 1·19 L m^-2 in dogs, respectively. The multiple-dose (day 9) kinetics in rats were similar to the single-dose kinetics. In dogs, the disposition of BMS-191352 on day 7 was similar to that on day 1; however, there was a precipitous reduction in the systemic drug exposure (by 5- to 110-fold) and marked increase in drug clearance on day 13. These changes in the kinetics of BMS-191352 were attributed to the generation of anti-BMS-191352 antibodies. In the one dog that did not develop anti-BMS-191352 antibodies, the pharmacokinetics were unchanged.

The pharmacokinetics of BMS-191352 may be perturbed due to an immune response thus restricting the therapeutic utility of the immunotoxin.

Document Type: Research article

DOI: 10.1211/0022357001774345

Affiliations: 1: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543 2: Department of Toxicology, Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, NY 13057, USA

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Influence of Immunogenicity on the Pharmacokinetics of BMS-191352, a Pseudomonas Exotoxin Immunoconjugate, in Rats and Dogs