Sequence effect of epirubicin and paclitaxel treatment on pharmacokineticsand toxicity

Purpose: Sequence-dependent clinical and pharmacokinetic interactions betwe en paclitaxel and doxorubicin have been reported. Some data have shown an i nfluence of paclitaxel on epirubicin metabolism, but no data are available about the effect of diverse sequences of these drugs. We investigated wheth er reversing the sequence of epirubicin and paclitaxel affects the pattern or degree of toxicity and pharmacokinetics. Patients and Methods: Patients receiving epirubicin 90 mg/m(2) by intraveno us bolus followed by paclitaxel 175 mg/m(2) over 3-hour infusion or the opp osite sequence every 3 weeks for four cycles were eligible. Toxicity was re corded at nadir. Pharmacokinetic data were evaluated at the first and the s econd cycle and were correlated with toxicity parameters. Results: Thirty-nine consecutive stage If breast cancer patients were treat ed. Twenty-one patients received epirubicin followed by paclitaxel (ET grou p), and 18 received the opposite sequence (TE group). No significant differ ence in nonhematologic toxicity was seen. A lower neutrophil and platelet n adir and a statistically significant slower neutrophil recovery was observe d in the TE group. Area under the concentration-time curve (AUC) of epirubi cin 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 pharm acokinetics. Conclusion: Our results support a sequence-dependent effect of paclitaxel o ver epirubicin pharmacokinetics that is associated with increased myelotoxi city. Because schedule modifications of anthracyclines and paclitaxel can h ave clinical consequences, the classical way of administration (ie, anthrac yclines followed by paclitaxel) should be maintained in clinical practice. J Clin Oncol 18:2116-2125, (C) 2000 by American Society of Clinical Oncolog y.