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

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.

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 [3H]-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.

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 tmax of 1.50 hours and geometric mean Cmax of 612 ng/ml. The geometric mean (CV%) t1/2 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 [3H]-ospemifene dose in 240 hours. In the multiple dosing study, steady state was reached by Day 7. The mean t1/2 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.

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.