TY - JOUR
T1 - Bioavailability and Pharmacokinetics of Endoxifen in Female Rats and Dogs
T2 - Evidence to Support the Use of Endoxifen to Overcome the Limitations of CYP2D6-Mediated Tamoxifen Metabolism
AU - Koubek, Emily J.
AU - Buhrow, Sarah A.
AU - Safgren, Stephanie L.
AU - Jia, Lee
AU - Goetz, Matthew P.
AU - Ames, Matthew M.
AU - Reid, Joel M.
N1 - Funding Information:
This project was funded in part with federal funds from National Institutes of Health National Cancer Institute [Contracts HHSN261200800001E and N01-CM52206] and the Mayo Clinic Cancer Center Support [Grant P30 CA15083].
Funding Information:
M.P.G. is the Erivan K. Haub Family Professor of Cancer Research Honoring Richard F. Emslander, M.D., and reports personal fees CME activities from Research to Practice and Clinical Education Alliance; consulting fees to Mayo Clinic from Eagle Pharmaceuticals, Lilly, Biovica, Novartis, Pfizer, Sermonix, AstraZeneca, Blueprint Medicines, and Biotheranostics; and grant funding to Mayo Clinic from Pfizer, Lilly, and Sermonix. The other authors have nothing to disclose.
Publisher Copyright:
© 2023 American Society for Pharmacology and Experimental Therapy. All rights reserved.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - Endoxifen (ENDX) is an active metabolite of tamoxifen (TAM), a drug commonly used for the treatment of estrogen receptor–positive breast cancer and metabolized by CYP2D6. Genetic or drug-induced reductions in CYP2D6 activity decrease plasma ENDX concentrations and TAM efficacy. It was proposed that direct oral administration of ENDX would circumvent the issues related to metabolic activation of TAM by CYP2D6 and increase patient response. 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 with 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 per 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 mM and 1 mM ENDX were achieved with 20-mg/kg and 200-mg/kg doses in rats, and concentrations above 1 mM and 10 mM 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 greater than 50% in dogs. In repeated-dose administration studies, ENDX peak plasma concentrations reached 9 mM in rats and 20 mM 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 to overcome the limitations associated with CYP2D6-mediated metabolism of TAM in humans.
AB - Endoxifen (ENDX) is an active metabolite of tamoxifen (TAM), a drug commonly used for the treatment of estrogen receptor–positive breast cancer and metabolized by CYP2D6. Genetic or drug-induced reductions in CYP2D6 activity decrease plasma ENDX concentrations and TAM efficacy. It was proposed that direct oral administration of ENDX would circumvent the issues related to metabolic activation of TAM by CYP2D6 and increase patient response. 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 with 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 per 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 mM and 1 mM ENDX were achieved with 20-mg/kg and 200-mg/kg doses in rats, and concentrations above 1 mM and 10 mM 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 greater than 50% in dogs. In repeated-dose administration studies, ENDX peak plasma concentrations reached 9 mM in rats and 20 mM 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 to overcome the limitations associated with CYP2D6-mediated metabolism of TAM in humans.
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U2 - 10.1124/dmd.122.000929
DO - 10.1124/dmd.122.000929
M3 - Article
C2 - 36351835
AN - SCOPUS:85147046829
SN - 0090-9556
VL - 51
SP - 183
EP - 192
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 2
ER -