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Predicting the Toxicity of Adjuvant Breast Cancer Drug Combination Therapy

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Revised annual summary rept. 1 Sep 2011-31 Aug 2012

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Combination therapy is increasingly utilized for the treatment of metastatic breast cancer. However, co-administration of drugs, particularly agents that are substrates for or inhibitors of p-glycoprotein, can result in increased toxicity. As adverse tissue drug concentrations are not always exposed by plasma drug concentrations, we performed studies in mice to assess both the plasma and tissue levels of the cytotoxics docetaxel and doxorubicin when administered concomitantly with the pglycoprotein substrateinhibitor lapatinib. Both combinations are currently being investigated in clinical trials. Materials and Methods Time course plasma and tissue distribution studies of concomitant lapatinib and docetaxel or doxorubicin were conducted in mice. Intravenous chemotherapy was administered one hour after the first intraperitoneal lapatinib dose. Both single and multiple dose lapatinib were evaluated. Samples were collected up to 12 and 48 hrs post docetaxel and doxorubicin administration, respectively, and drug concentrations were determined. Results In toxicologically significant tissues, combination lapatinib and docetaxel resulted in a 32.8 and 44.6 increase in intestinal docetaxel exposure after single and multiple dose lapatinib, respectively. The causative drug-drug interaction was likely mediated more by competitive inhibition of CYP3A4 metabolism than p-glycoprotein efflux. Conclusion Our mouse studies of combination dosing demonstrate that lapatinib, when dosed to achieve human equivalent plasma exposure in mice, did not significantly alter the plasma or tissue pharmacokinetics of doxorubicin but did increase exposure to docetaxel in the intestine, likely leading to enhanced toxicity. Thus, caution should be taken when docetaxel and lapatinib are administered together, particularly to patients with compromised CYP3A activity.

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  • Medicine and Medical Research
  • Toxicology
  • Pharmacology

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