TY - JOUR T1 - Bioavailability and Pharmacokinetics of Endoxifen in Female Rats and Dogs: Evidence to Support the Use of Endoxifen to Overcome the Limitations of CYP2D6-Mediated Tamoxifen Metabolism JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.122.000929 SP - DMD-AR-2022-000929 AU - Emily J Koubek AU - Sarah A Buhrow AU - Stephanie L Safgren AU - Lee Jia AU - Matthew P Goetz AU - Matthew M Ames AU - Joel M. Reid Y1 - 2022/01/01 UR - http://dmd.aspetjournals.org/content/early/2022/11/09/dmd.122.000929.abstract N2 - Endoxifen (ENDX) is an active metabolite of tamoxifen (TAM) currently undergoing clinical development for estrogen receptor positive breast cancer. Here, we characterized the pharmacokinetics and oral bioavailability of ENDX in female rats and dogs. Additionally, ENDX exposure was compared following equivalent doses of ENDX and TAM. ENDX exposure was 100-fold and 10-fold greater in rats and dogs, respectively, with ENDX administration compared to an equivalent dose of TAM. In single-dose administration studies, the terminal elimination half-life and plasma clearance values were 6.3 hours and 2.4 L/h/kg in rats given 2 mg/kg i.v. ENDX and 9.2 hours and 0.4 L/h/kg in dogs given 0.5 mg/kg i.v. ENDX, respectively. Plasma concentrations above 0.1 µM and 1 µM ENDX were achieved with 20 mg/kg and 200 mg/kg doses in rats and concentrations above 1 µM and 10 µM were achieved with 15 mg/kg and 100 mg/kg doses in dogs. Oral absorption of ENDX was linear in rats and dogs with bioavailability greater than 67% in rats and 50% in dogs. In repeated-dose administration studies, ENDX peak plasma concentrations reached 9 µM in rats and 20 µM in dogs following four daily doses of 200 mg/kg or 30 mg/kg ENDX, respectively. The results indicate that ENDX has high oral bioavailability and therapeutic concentrations were maintained after repeated dosing. Oral dosing of ENDX resulted in substantially higher ENDX concentrations than a similar dose of TAM. These data support the ongoing development of ENDX in humans. Significance Statement Here, we present for the first time the pharmacokinetics and bioavailability of endoxifen and three key tamoxifen metabolites following repeated oral dosing in female rats and dogs. We report that endoxifen has high oral bioavailability and therapeutic concentrations were maintained after repeated dosing. Results of this work will support the ongoing development of endoxifen for ER+ breast cancer and future clinical trials. ER -