title: Predicting the effects of 8C2, a monoclonal anti-topotecan antibody, on plasma and tissue disposition of topotecan.
abstract: We are investigating an inverse targeting strategy to reduce the dose limiting systemic toxicities resultant from intraperitoneal administration of topotecan, a model chemotherapeutic drug. This approach utilizes systemic co-administration of anti-topotecan antibodies to alter the plasma and tissue disposition kinetics of topotecan. To better predict the effects of 8C2, a high affinity anti-topotecan monoclonal antibody, on the pharmacokinetics of topotecan, two mathematical models have been developed and evaluated. Model 1 is a hybrid physiologically based pharmacokinetic (PBPK) model that was created by merging a PBPK model for topotecan with a simple two compartment model of 8C2 pharmacokinetics. Model 2 is a comprehensive PBPK model developed by merging a PBPK model for IgG with a PBPK model for topotecan. To help validate the simulation results from both the models, a tissue distribution experiment was conducted, in which topotecan and 8C2 were co-administered in mice. Experimental and simulated data were compared by calculating the median percent prediction error (%PE) for all tissues. For both models, the median %PE values for all the tissues were less than 100 %, indicating that the predicted values were, on average, less than twofold the observed plasma and tissue topotecan concentrations values. In general model 2 was found to be more predictive of the data set than model 1, as the overall median %PE value for model 2 (%PE = 63) was less than model 1 (%PE = 73).
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, 452 Kapoor Hall, Buffalo, NY, 14260, USA.
authors.forename: Dhaval K
authors.initials: DK
authors.lastname: Shah
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Balthasar
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D003198:Computer Simulation; D008297:Male; D051379:Mice; D008962:Models, Theoretical; D014018:Tissue Distribution; D019772:Topotecan / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*
chemical_list: D000911:Antibodies, Monoclonal; D019772:Topotecan