Drug interactions with the taxanes: Clinical implications

Background: The taxanes paclitaxel and docetaxel are among the most active antitumor agents. Clinically important pharmacodynamic interactions have been reported to occur with these agents that are sequence or schedule dependent. Because the taxanes undergo hepatic oxidation via the cytochrome P450 system, pharmacokinetic interactions due to enzyme induction or inhibition can also occur. Methods: A comprehensive literature search was conducted using Medline to identify clinically important drug-interactions with the taxanes. Results: Clinically significant taxane interactions were identified for carboplatin, cisplatin, doxorubicin, docetaxel, epirubicin and anticonvulsants. Doxorubicin and epirubicin should be administered 24 h before paclitaxel, and the cumulative anthracycline dose limited to 360 mg/m². This will prevent the enhanced toxicities due to sequence and schedule dependent interactions between anthracyclines and paclitaxel. Conversely, paclitaxel should be administered at least 24 h before cisplatin to avoid a decrease in clearance and increase in myelosuppression. With concurrent anticonvulsant therapy, cytochrome p450 enzyme induction results in decreased paclitaxel plasma steady state concentrations, possibly requiring an increased dose of paclitaxel. A number of other drug interactions have been reported in preliminary studies for which clinical significance has yet to be established. Conclusion: Clinically significant drug interactions have been reported to occur when paclitaxel is administered with doxorubicin, cisplatin, or anticonvulsants (phenytoin, carbamazepine, and phenobarbital).