Approaches to the problem of individual doxorubicin dosing schedules

Doxorubicin is one of the most commonly used antineoplastic agents today. Dosing schedules are inexact and there remains a need to develop predictive models for its administration. Data from prior work in humans is difficult to interpret because of poor patient selection, poor drug assays, lack of knowledge of metabolite toxicity, concurrent treatment with other hepatically metabolized drugs, and individual pharmacogenetics which are poorly described. We have developed a rabbit model of in vivo drug pharmacokinetics in the setting of enzyme inhibition and sublethal hepatocellular necrosis. Our data suggest that the rabbit may be used as a model of hepatic drug metabolism and that changes in drug pharmacokinetics and pharmacodynamics in isolated hepatic disease may be simulated in the rabbit. The results obtained may be applied in more directed and controlled studies in humans.