Taxoids in combination with anthracyclines and other agents: pharmacokinetic considerations

The combination in clinical trials of taxoids with doxorubicin has focused attention on possible drug interactions. One specific finding requiring explanation is the relative lack of cardiotoxicity of the docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France)/doxorubicin combination compared with that of the paclitaxel/doxorubicin combination. Data in mice demonstrate that epirubicin concentrations in cardiac tissue 24 hours after treatment are approximately doubled by the coadministration of paclitaxel. This effect appears to be less marked with docetaxel administered in its normal polysorbate vehicle or when the drug is given in Cremophor EL (Sigma, St Louis, MO). Both Cremophor EL or polysorbate appear to cause an increase in epirubicin tissue levels, although the levels were less than those seen with paclitaxel. Pharmacokinetic data from women being treated with combination therapy for advanced breast cancer demonstrate that the administration of docetaxel following doxorubicin does not alter doxorubicin's area under the plasma concentration-time, curve, maximum plasma concentration, or time until maximum plasma concentration is reached. However, the area under the curve of docetaxel is significantly increased by the prior administration of doxorubicin. These findings may explain both the low cardiotoxicity and the high clinical efficacy of the docetaxel/doxorubicin combination. Phase I clinical trials of combinations in which docetaxel was used together with vinorelbine, ifosfamide, or 5-fluorouracil have shown no evidence of relevant pharmacokinetic interactions.