Purpose: Adjuvant chemotherapy with cyclophosphamide (CYC) is used for the treatment of breast cancer. CYC is used as a racemic mixture, although preclinical data have demonstrated differences in the efficacy and toxicity of its enantiomers, with (S)-(-)-CYC exhibiting a higher therapeutic index. The present study investigated the enantioselectivity and influence of CYP2B6, CYP2C9, CYP2C19, and CYP3A on the kinetic disposition of CYC in patients with breast cancer.
Methods: Fifteen patients previously submitted to removal of the tumor and treated with racemic CYC (900 or 1,000 mg/m(2)) and epirubicin were included in the study. The in vivo activity of CYP3A was evaluated using midazolam as a marker drug. Serial blood samples were collected up to 24 h after administration of the first cycle of CYC.
Results: The kinetic disposition of CYC was enantioselective in patients with breast cancer, with plasma accumulation of the (S)-(-)-CYC enantiomer (AUC 195.0 vs. 174.8 μg h/mL) due to the preferential clearance of the (R)-(+)CYC enantiomer (5.1 vs. 5.7 L/h). Clearance of either CYC enantiomer did not differ between the CYP2B6, CYP2C9, and CYP2C19 genotypes or as a function of the in vivo activity of CYP3A evaluated by midazolam clearance.
Conclusions: The pharmacokinetics of CYC is enantioselective in patients with breast cancer concomitantly treated with epirubicin and ondansetron. Genotyping or phenotyping did not contribute to adjustment of the CYC dose regimen in patients included in this study.