Targeting the systemic exposure of teniposide in the population and the individual using a stochastic therapeutic objective

Abstract

A stochastic control approach for dose regimen design is developed and applied to the problem of targeting the systemic exposure, defined as the area under the blood concentration-time curve (AUC), of the anticancer drug teniposide in both the population and individual patients. The control objective involves maximizing the probability that AUC is within a selected target interval given either the population distribution for the kinetic model parameters (a priori control) or the posterior distribution for an individual patient (feedback control). Results of a detailed simulation study are presented, illustrating the feasibility of applying stochastic control principles to the design of dose regimens. The predictive ability of the calculated distributions of AUC for the population and for individuals is evaluated in part by determining the percentage coverage of the computed 95% uncertainty intervals using the simulation results. For the a priori control phase, 94% of the simulated subjects had values of systemic exposure within the computed 95% uncertainty interval, while 93.4% of the simulated subjects had feedback control phase systemic exposure values within their computed 95% uncertainty intervals. Similar evaluation of the uncertainty intervals calculated for plasma concentrations further document the ability of the proposed stochastic control method to predict the uncertainty associated with future therapy.