Single-dose and steady-state pharmacokinetics of ospemifene, a selective estrogen receptor modulator, in postmenopausal women

: Koskimies P, Turunen J, Lammintausta R, Scheinin M

Publisher: DUSTRI-VERLAG DR KARL FEISTLE

: 2013

: International Journal of Clinical Pharmacology and Therapeutics

: INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS

: INT J CLIN PHARM TH

: 11

: 51

: 11

: 861

: 867

: 7

: 0946-1965

DOI: https://doi.org/10.5414/CP201925

Objective: To characterize the pharmacokinetics of the oral, non-estrogen agent ospemifene, an estrogen agonist/antagonist with tissue-selective effects (also called a selective estrogen receptor modulator) that was recently approved for the treatment of dyspareunia associated with vulvar and vaginal atrophy in postmenopausal women. Methods: Two open-label, Phase 1 studies were conducted to determine the pharmacokinetics of ospemifene in healthy postmenopausal women. In the single-dose study, 60 mg of [H-3]-ospemifene was orally administered to 6 subjects. Blood, urine, and fecal samples were collected predose and serially up to 240 hours postdose. In the multiple-dose study, 12 subjects received 60 mg of ospemifene once daily for 9 days. Blood samples were collected predose and serially postdose on Day 1, predose on Days 7 and 8, and predose and serially postdose on Day 9. Results: Ospemifene exhibited high plasma protein binding and was extensively metabolized, predominantly to 4-hydroxyospemifene and 4'-hydroxyospemifene. In the single-dose study, ospemifene was rapidly absorbed, with a median t(max) of 1.50 hours and geometric mean C-max of 612 ng/ml. The geometric mean (CV%) t(1/2) was 24.5 (21.3) hours and 29.0 (18.0) hours for ospemifene and 4-hydroxyospemifene, respectively. Fecal elimination accounted for 75% of the administered [H-3]-ospemifene dose in 240 hours. In the multiple-dosing study, steady state was reached by Day 7. The mean t(1/2) at steady state for ospemifene was 29.1 hours. High values for volume of distribution and total clearance suggested extensive tissue distribution and efficient elimination of ospemifene. Conclusions: In healthy postmenopausal women, ospemifene 60 mg/day reached steady-state concentrations by Day 7 and showed minimal accumulation of parent drug or its two main metabolites, indicating that once-daily dosing is appropriate.