Mathematical modeling of topotecan pharmacokinetics and toxicodynamics in mice

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.