Predicting the Toxicity of Adjuvant Breast Cancer Drug Combination Therapy.

摘要

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 doxorubicinorubicin when administered concomitantly with the p-glycoprotein substrate/inhibitor lapatinibatinib. Both combinations are currently being investigated in clinical trials. First, we determined the tissue distribution of LAPATINIB in mice after an oral gavage dose of 60 mg/kg, which results in an exposure in mice that is equivalent to the exposure in humans when dosed at the recommended dose of 1,250 mg p.o. once daily. Next, we determined the PKs of LAPATINIB after oral gavage doses of 30 and 90 mg/kg. This completed the thorough pharmacokinetic analysis of the biodistribution of single dose LAPATINIB in mice. Following the elucidation of the pharmacokinetics of LAPATINIB in mice, we conducted time course plasma and tissue distribution studies of concomitant lapatinibatinib and docetaxel or doxorubicinorubicin. Both single and multiple dose lapatinibatinib were evaluated. These studies illustrated that lapatinibatinib, when dosed to achieve human equivalent plasma exposure in mice, did not significantly alter the plasma or tissue pharmacokinetics of doxorubicinorubicin but did increase exposure to docetaxel in the intestine, likely leading to enhanced toxicity. Thus, caution should be taken when docetaxel and lapatinibatinib are administered together, particularly to patients with compromised CYP3A activity. Finally, we developed a PBPK model of docetaxel in mice that incorporated PGP transport studying docetaxel pharmacokinetics in wild-type FVB and Mdr1a/b constitutive knockout (KO) mice.