title: PK/TD modeling for prediction of the effects of 8C2, an anti-topotecan mAb, on topotecan-induced toxicity in mice.
abstract: To facilitate the development of an inverse targeting strategy, where anti-topotecan antibodies are administered to prevent systemic toxicity following intraperitoneal topotecan, a pharmacokinetic/toxicodynamic (PK/TD) model was developed and evaluated. The pharmacokinetics of 8C2, a monoclonal anti-topotecan antibody, were assessed following IV and SC administration, and the data were characterized using a two compartmental model with nonlinear absorption and elimination. A hybrid PK model was constructed by combining a PBPK model for topotecan with the two-compartment model for 8C2, and the model was employed to predict the disposition of topotecan, 8C2, and the topotecan-8C2 complex. The model was linked to a toxicodynamic model for topotecan-induced weight-loss, and simulations were conducted to predict the effects of 8C2 on the toxicity of topotecan in mice. Increasing the molar dose ratio of 8C2 to topotecan resulted in a dose-dependent decrease in the unbound (i.e., not bound to 8C2) topotecan exposure in plasma (AUCf) and a decrease in the extent of topotecan-induced weight-loss. Consistent with model predictions, toxicodynamic experiments showed substantial reduction in the percent nadir weight loss observed with 30 mg/kg IP topotecan after co-administration of 8C2 (20 ± 8% vs. 10 ± 8%). The investigation supports the use of anti-topotecan mAb to reduce the systemic toxicity of IP topotecan chemotherapy.
authors: Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, United States.
authors: Dhaval K
authors: DK
authors: Shah
authors: Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, United States. Electronic address: jb@acsu.buffalo.edu.
authors: Joseph P
authors: JP
authors: Balthasar
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008954:Models, Biological; D017711:Nonlinear Dynamics; D018570:Risk Assessment; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity*; D019772:Topotecan / Q000008:administration & dosage / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity*; D015431:Weight Loss / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D059004:Topoisomerase I Inhibitors; D019772:Topotecan
keywords: 8C2; Enzyme linked immunosorbent assay; Immunotoxicotherapy; Intraperitoneal chemotherapy; Inverse targeting; Monoclonal antibody; Pharmacokinetic/toxicodynamic model; Subcutaneous bioavailability; Surface plasmon resonance; Topotecan