Abstract
The objective of these investigations was to determine the possible effects of the novel selective estrogen receptor modulator, ospemifene, on cytochrome P450 (CYP)-mediated drug metabolism. Ospemifene underwent testing for possible effects on CYP enzyme activity in human liver microsomes and in isolated human hepatocytes. Based on the results obtained in vitro, three Phase 1 crossover pharmacokinetic studies were conducted in healthy postmenopausal women to assess the in vivo effects of ospemifene on CYP-mediated drug metabolism. Ospemifene and its main metabolites 4-hydroxyospemifene and 4′-hydroxyospemifene weakly inhibited a number of CYPs (CYP2B6, CYP2C9, CYP2C19, CYP2C8, and CYP2D6) in vitro. However, only CYP2C9 activity was inhibited by 4-hydroxyospemifene at clinically relevant concentrations. Induction of CYPs by ospemifene in cultured human hepatocytes was 2.4-fold or less. The in vivo studies showed that ospemifene did not have significant effects on the areas under the plasma concentration-time curves of the tested CYP substrates warfarin (CYP2C9), bupropion (CYP2B6) and omeprazole (CYP2C19), demonstrating that pretreatment with ospemifene did not alter their metabolism. Therefore, the risk that ospemifene will affect the pharmacokinetics of drugs that are substrates for CYP enzymes is low.
Highlights
Ospemifene, a novel selective estrogen receptor modulator (SERM), was recently approved for the treatment of vulvar and vaginal atrophy (VVA) in postmenopausal women [1,2]
Tamoxifen and toremifene are metabolized by cytochrome P450 (CYP) enzymes, whereas raloxifene is metabolized by glucuronide conjugation [7]
Ospemifene inhibition of CYP2C9 was competitive up to 10 μM, but a noncompetitive component emerged at higher concentrations
Summary
Ospemifene, a novel selective estrogen receptor modulator (SERM), was recently approved for the treatment of vulvar and vaginal atrophy (VVA) in postmenopausal women [1,2]. Phase 2 and 3 clinical trials have demonstrated the efficacy and safety of ospemifene in the treatment of VVA [1,3,4,5,6]. Ospemifene is metabolized by the liver into two major metabolites, 4- and 4'-hydroxyospemifene, which represent roughly about 70% and 7% of the total metabolites, respectively, and several minor metabolites [8]. Several CYP enzymes are responsible for the hepatic clearance of ospemifene. The possible effects of ospemifene on CYP-mediated metabolism were investigated as part of its preclinical and clinical development. This report presents the results of several in vitro and in vivo studies that evaluated the interaction potential of ospemifene with regard to CYP-mediated drug metabolism
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