Pharmacokinetic profiles of doxorubicin in combination with taxanes.

Paclitaxel and docetaxel each possess unique chemical and pharmacologic characteristics that account for significant differences in their potencies, toxicologic and pharmacokinetic profiles, and propensity for drug-drug interactions. Results from phase I/II trials of paclitaxel in combination with doxorubicin showed excellent antitumor activity. However, the high incidence of congestive heart failure warranted further investigation. A sophisticated pharmacokinetic study showed that paclitaxel enhances the nonlinearity of doxorubicin pharmacokinetics and significantly decreases the systemic clearance of both doxorubicin and doxorubicinol. The paclitaxel/doxorubicin interaction was found to be paclitaxel-dose dependent, doxorubicin concentration-dependant, and may be the result of competition for elimination mechanisms, possibly competition for hepatic and biliary transporter proteins such as p-glycoprotein, as a result of the formulation vehicle polyethoxylated castor oil (cremophor EL). Phase I/II trials of the docetaxel/doxorubicin combination also show high antitumor activity, but without an increase in anthracycline-induced congestive heart failure. Subsequent pharmacokinetic investigations show minimal alterations in the pharmacokinetic profiles of doxorubicin or docetaxel when used in combination. While both paclitaxel and docetaxel may be effectively combined with doxorubicin in the treatment of metastatic breast cancer, the drug-drug interaction between paclitaxel and doxorubicin (but not of docetaxel and doxorubicin) warrants that certain restrictions be followed for safe use.