title: Mathematical modeling of topotecan pharmacokinetics and toxicodynamics in mice.
abstract: The objective of this study was to investigate the pharmacokinetics and toxicodynamics of topotecan (TPT) in mice and to develop an integrated pharmacokinetic/toxicodynamic (PK/TD) model to characterize the relationship between the time course of TPT disposition and the time course of TPT-induced toxicity. TPT was administered to groups of 3-5 mice via i.v. bolus injection, i.p. bolus injection, and by i.p. infusion over 24, 72 and 168 h. Body weight was monitored to assess TPT-induced toxicity, and serial blood samples were collected and analyzed via HPLC to assess TPT pharmacokinetics. We found that TPT-induced toxicity increased dose-dependently for each mode of dosing investigated. The time course of topotecan-induced body weight-loss was delayed relative to the time course of topotecan disposition; nadir body weight was observed as late as 6 days following i.p. bolus dosing, and 3-5 days following termination of i.p. infusion. TPT exhibited non-linear disposition, which was well-characterized through the use of a two-compartment model with saturable elimination from the central compartment. Toxicodynamic data were characterized with an integrated PK/TD model that incorporated an indirect-effect model and four transit compartments to describe transduction events associated with TPT-induced toxicity. This model will be used to support the development of an inverse-targeting strategy that aims to enhance topotecan safety and efficacy.
authors: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14260, USA.
authors: Jin
authors: J
authors: Chen
authors: Qiang
authors: Q
authors: Lu
authors: Joseph P
authors: JP
authors: Balthasar
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D008433:Mathematics; D051379:Mice; D008954:Models, Biological; D019772:Topotecan / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: D019772:Topotecan