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Sequence Effect of Epirubicin and Paclitaxel Treatment on Pharmacokinetics and Toxicity

From the Department of Medical Oncology I and Pharmacotoxicology Laboratory, Istituto Nazionale per la Ricerca sul Cancro, Genova; and Department of Medical Oncology, Ospedale S. Croce e Carle, Cuneo, Italy.

Address reprint requests to Marco Venturini, MD, Divisione di Oncologia Medica, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132, Genova, Italy; email mventur{at}hp380 .ist.unige.it.

PURPOSE: Sequence-dependent clinical and pharmacokinetic interactions between paclitaxel and doxorubicin have been reported. Some data have shown an influence of paclitaxel on epirubicin metabolism, but no data are available about the effect of diverse sequences of these drugs. We investigated whether reversing the sequence of epirubicin and paclitaxel affects the pattern or degree of toxicity and pharmacokinetics.

PATIENTS AND METHODS: Patients receiving epirubicin 90 mg/m² by intravenous bolus followed by paclitaxel 175 mg/m² over 3-hour infusion or the opposite sequence every 3 weeks for four cycles were eligible. Toxicity was recorded at nadir. Pharmacokinetic data were evaluated at the first and the second cycle and were correlated with toxicity parameters.

RESULTS: Thirty-nine consecutive stage II breast cancer patients were treated. Twenty-one patients received epirubicin followed by paclitaxel (ET group), and 18 received the opposite sequence (TE group). No significant difference in nonhematologic toxicity was seen. A lower neutrophil and platelet nadir and a statistically significant slower neutrophil recovery was observed in the TE group. Area under the concentration-time curve (AUC) of epirubicin was higher in the TE group (2,346 ng/mL · h v 1,717 ng/mL · h; P = .002). An inverse linear correlation between epirubicin AUC and neutrophil recovery was also observed (P = .012). No difference was detected in paclitaxel pharmacokinetics.

CONCLUSION: Our results support a sequence-dependent effect of paclitaxel over epirubicin pharmacokinetics that is associated with increased myelotoxicity. Because schedule modifications of anthracyclines and paclitaxel can have clinical consequences, the classical way of administration (ie, anthracyclines followed by paclitaxel) should be maintained in clinical practice.

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