Doxorubicin pharmacokinetics: Macromolecule binding, metabolism, and excretion in the context of a physiologic model

The studies described herein were designed to determine whether doxorubicin (DOX) pharmacokinetics (PKs) could be described by a physiologically based PK model that incorporated macromolecule-specific binding and organ-specific metabolism and excretion. Model parameters were determined experimentally, or were gathered from the literature, in a species-specific manner, and were incorporated into a physiologically based description of DOX blood and tissue distribution for mice, dogs, and humans. The resulting model simulation data were compared with experimentally determined data using PK parameters calculated using compartmental or noncompartmental analysis to assess the predictability of the models. The resulting physiologically based PK model that was developed could accurately predict blood and tissue PKs of DOX in mice. When this model was interspecies extrapolated to predict DOX levels in dogs and humans undergoing treatment for cancer, predictions in dog plasma or human serum were also consistent with the actual clinical data. This model has potential utility for predicting the magnitude of PK interactions of DOX with other drugs, and for predicting changes in DOX PKs in any number of clinical situations.