Effects of Ospemifene on Drug Metabolism Mediated by Cytochrome P450 Enzymes in Humans in Vitro and in Vivo

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.

Effects of cytochrome P450 inhibitors and inducers on the metabolism and pharmacokinetics of ospemifene

“…Additional studies, reported separately, explored the effects of ospemifene, 4‐hydroxyospemifene and 4′‐hydroxyospemifene on CYP‐mediated metabolism of other drugs . In vitro studies demonstrated that ospemifene, 4‐hydroxyospemifene, and 4′‐hydroxyospemifene weakly inhibited CYP2C9, CYP2C19, CYP2C8 and CYP2D6.…”

Physiologically Based Pharmacokinetic Modeling of Bupropion and Its Metabolites in a CYP2B6 Drug-Drug-Gene Interaction Network

“…Clinical studies of bupropion in single-and multiple-dose regimens were gathered and digitized from the literature [ 27 ]. The collected profiles were divided into a training ( n = 19) and a test dataset ( n = 48), used for model building and model evaluation, respectively [ 3 , 17 , 18 , 19 , 20 , 21 , 22 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. Studies in the training dataset were selected to include metabolite concentration-time profiles, a wide dosing range, and different oral formulations.…”

Drug Metabolism – From In Vitro to In Vivo, From Simple to Complex

“…This drug was an original discovery of Hormos Medical, a Finnish drug development company based in Turku, Finland. Together with Novamass, we contributed to the elucidation of in vitro and in vivo metabolic and pharmacokinetic characteristics of ospemifene, and the results were published recently . Ospemifene has been the most visible milestone of our contributions to drug development.…”