Abstract 3781: Pharmacokinetics of endoxifen and tamoxifen in female mice: Implications for comparative in vivo activity studies

Background: In tamoxifen (TAM) treated patients, both CYP2D6 metabolism and low steady state concentrations of endoxifen (END), the active metabolite of TAM, have been associated with a higher risk of recurrence (Madlensky L, Clin Pharmacol Ther. 2011; 89(5):718-25). END drug development is ongoing at Mayo and NCI, and our previous data demonstrated that 1) END had high oral bioavailability in mice and yielded plasma concentrations and total exposure 20-fold greater as compared to an equivalent oral dose of TAM (MM Ames et al, Cancer Res 2011;70(8 Suppl 1):Abstract nr 3603) and 2) END is superior to TAM in both HER2 (Reinicke AACR 2011) and aromatase expressing (Goetz, SABC 2011) MCF-7 xenograft models. While subcutaneous (SQ) TAM is used by most researchers to study and develop models of TAM resistance, little is known about 1) whether murine and human TAM pharmacokinetics are comparable and 2) whether the route of administration affects concentrations of the active metabolites. Therefore, we conducted murine pharmacokinetic studies evaluating both the oral and SQ administration of TAM and END. Results: Following administration of TAM, concentrations of the active metabolites (END and 4-hydroxy TAM [4HT]) were therapeutic (Cmax- END 35.9 nM, 4HT 62.8 nM) only after a 0.5 mg oral dose of TAM. In contrast, following all doses of SQ TAM, concentrations of the active metabolites (END and 4HT) were sub-therapeutic (Cmax- END 5.2 nM; 4HT 18.7 nM). In contrast to humans, the Cmax of N-desmethyl TAM, the most abundant human TAM metabolite, was < 16.5 nM in mice after oral and SQ TAM. SQ administration of END and TAM resulted in substantially greater bioavailability of the parent drug compared with oral dosing. Following administration of 0.25-5 mg oral END and 0.0625-0.625 mg subcutaneous END, the increase in AUC was greater than dose proportional and active concentrations (>80 nM) were detected in plasma at every dose and both dosing routes. Comparable END and TAM plasma concentrations were achieved with a 0.0625 mg SQ END and a 0.5 mg SQ TAM, respectively. Conclusions: Our data strongly suggest that SQ dosing of TAM results in non-therapeutic concentrations of the active hydroxylated metabolites, and may be a simple pharmacokinetic factor influencing response and resistance in a murine in vivo xenograft model. Given the nonlinear pharmacokinetics and differences in metabolism, the dose and route of END must be carefully selected for comparative studies with TAM