Pharmacokinetic analysis of two-step approaches using bifunctional and enzyme-conjugated antibodies.
Bifunctional antibodies (BFA) and enzyme-conjugated antibodies (ECA) can be used to preferentially deliver a hapten or drug to tumor sites for diagnosis and therapy. We present here a simple pharmacokinetic model for the above two systems by considering only two compartments, the plasma and tumor. The models predict that the longer the time delay between the BFA and hapten or between the ECA and prodrug injections, the higher the tumor:plasma concentration ratio of the hapten or drug. In addition, multiple injections of the hapten or prodrug is predicted to give a more uniform concentration of the hapten or drug in both the tumor and plasma than bolus injection. We suggest that, initially, the most effective dose of BFA should be selected and then the hapten concentration chosen accordingly. The decrease of the ECA injection dose would increase the tumor:plasma concentration ratio of the drug and yet decrease the tumor concentration of the drug. In clinical application of the ECA system, consideration of ECA dose should be balanced between the tumor concentration and the tumor:plasma concentration ratio of the drug. The dose of the prodrug injection is suggested to be equal to the required toxic concentration of the drug in the tumor. There are several ways to improve the tumor:plasma concentration ratio of the hapten or drug, such as changing the binding kinetics of the antibody to tumor or the hapten to BFA and removing the antibody from the plasma before the injection of the hapten or prodrug. One notable difference between the BFA and ECA approaches is that there is an upper limit for maximum hapten concentration in the former, and hence, from the point of drug delivery alone the latter approach is presumably superior. The limitations of the models and therapeutic implications are also discussed.
Yuan
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F
Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213-3890.
Baxter
L T
LT
Jain
R K
RK
D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004337:Drug Carriers; D057487:Enzyme Therapy; D004798:Enzymes / Q000493:pharmacokinetics*; D006241:Haptens; D006801:Humans; D007700:Kinetics; D008433:Mathematics; D008954:Models, Biological; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy; D013997:Time Factors
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004337:Drug Carriers; D004798:Enzymes; D006241:Haptens