Utilization of antidrug antibody fragments for the optimization of intraperitoneal drug therapy: studies using digoxin as a model drug.
The direct administration of chemotherapeutic agents into the peritoneal cavity has been investigated as a method to treat cancers residing within the peritoneum. The benefits of i.p. drug administration are limited, however, by the systemic toxicity of antineoplastic drugs which diffuse out of the peritoneum and into the general circulation. We propose that antidrug antibody fragments may be useful in binding chemotherapeutics in the general circulation, thereby reducing the systemic tissue exposure and toxicity resulting from such i.p. therapy. Inasmuch as antibody fragments directed against antineoplastic agents are not available, we tested our hypothesis by using i.v. administered ovine antidigoxin Fab fragments and determined their ability to limit digoxin tissue exposure and toxicity in mice after an i.p. digoxin injection. The rate of digoxin disappearance from the peritoneal cavity and the fraction of digoxin unbound in the peritoneal cavity were also assessed to determine the effect of the antibody fragments on peritoneal exposure. Our results showed that the antidigoxin antibody fragments can greatly decrease digoxin tissue exposure and toxicity without affecting peritoneal exposure, unbound fraction of digoxin in the peritoneum or peritoneal digoxin disappearance rate. Although the utility of drug-binding antibodies and antibody fragments for the treatment of drug intoxication is well known, these results demonstrated the potential ability of antidrug antibody fragments to improve the site-specificity of drug therapy.
Balthasar
J
J
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo.
Fung
H L
HL
D000818:Animals; D004077:Digoxin / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D008297:Male; D008433:Mathematics; D051379:Mice; D008807:Mice, Inbred BALB C
D007140:Immunoglobulin Fab Fragments; D004077:Digoxin