Chemical formula: C₂₄H₂₃ClO₂ Molecular mass: 378.891 g/mol PubChem compound: 3036505
Decreases in oestrogen levels that occur after the menopause lead to vulvar and vaginal atrophy (VVA), characterised by decreased maturation of vaginal epithelial cells, a progressive decrease in the vascularity of the vaginal tissues, and decreased lubrication. The glycogen content of vaginal epithelial cells also decreases, resulting in reduced colonisation by lactobacilli and increased vaginal pH. These changes result in clinical signs which include vaginal dryness, redness, petechiae, pallor, and friability in the mucosa. In addition, these changes can result in chronic symptoms associated with VVA, the most common of which are vaginal dryness and dyspareunia.
Ospemifene’s biological actions are mediated through the binding of ospemifene and its major metabolite to oestrogen receptors. The relative contribution of the metabolite to the pharmacological effect is estimated to be approximately 40%. This binding results in activation of some oestrogenic pathways (agonism) and blockade of other oestrogenic pathways (antagonism). The biological activity profile in humans is predominantly due to the parent compound.
Nonclinical findings show that ospemifene and its major metabolite have an oestrogen like effect in the vagina increasing the cellular maturation and mucification of the vaginal epithelium. In the mammary gland, they have a predominantly oestrogen antagonist effect. In bone, ospemifene has agonist-like activity. In the uterus ospemifene and its major metabolite have weak partial agonist/antagonist effects. These non-clinical findings are consistent with findings from clinical trials, in which ospemifene demonstrated benefits on vaginal physiology without apparent oestrogen-like effects on breast tissue.
Ospemifene is absorbed rapidly after oral administration, with a Tmax of approximately 3-4 hours post-dose in the fed state. The absolute bioavailability of ospemifene has not been established. Mean ospemifene Cmax and AUC0-24hr were 785 ng/mL and 5,448 ng•hr/mL, respectively, after repeat doses of 60 mg ospemifene once daily in the fed state.
When ospemifene is administered with a high fat meal, the Cmax and AUC are 2.5-fold and 1.9-fold higher, respectively, with lower variability relative to the fasting state. A low fat meal resulted in approximately a two-fold increase in exposure of ospemifene and a high fat meal resulted in approximately a three-fold increase in exposure of ospemifene in two food effect studies with tablet formulations different from the commercial formulation. It is recommended that ospemifene should be taken with food at the same time each day.
Ospemifene and 4-hydroxyospemifene are highly (both >99%) bound to serum proteins. Plasma/blood cell partitioning of [14C]-Ospemifene (<3%) and [14C]-4-hydroxyospemifene (<2%) is low. The apparent volume of distribution is 448 l.
Ospemifene and its major metabolite, 4-hydroxyospemifene, are metabolised by multiple metabolic pathways, the main enzymes involved are UGT1A3, UGT2B7, UGT1A1 and UGT1A8, and CYP2C9, CYP3A4 and CYP2C19. The major metabolite, 4-hydroxyospemifene, was seen to undergo formation rate-limited elimination (with t1/2 similar to the parent compound) in a human mass balance study. The principal radioactive component in both plasma and faeces was ospemifene and the main metabolite 4-hydroxyospemifene. Ospemifene and 4-hydroxyospemifene accounted for approximately 20% and 14% of the total radioactivity in serum, respectively. The apparent total body clearance is 9.16 l/hr using a population approach.
In vitro, ospemifene and 4-hydroxyospemifene did not inhibit or induce the activity of CYP450 enzymes at clinically relevant concentrations. In vitro, ospemifene and 4-hydroxyospemifene inhibited glucuronidation via UGT1A3 and UGT1A9 at clinically relevant concentrations. In in vitro studies ospemifene is a weak inhibitor for CYP2B6, CYP2C9, CYP2C19, CYP2C8 and CYP2D6. Furthermore in vitro studies have shown that ospemifene is a weak inducer for CYP2B6 and CYP3A4. In in vitro studies, ospemifene and 4-hydroxyospemifene did not inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT2, organic anion transporter (OAT)1, OAT3, or bile salt export pump (BSEP) transporters at clinically relevant concentrations. It is unknown if ospemifene is a substrate for BCRP in the intestine. Therefore care should be taken if ospemifene is administered with a BCRP inhibitor.
The apparent terminal half-life of ospemifene in post-menopausal women is approximately 25 hours. Following oral administration of [3-H]-ospemifene in the fasted state, approximately 75% and 7% of the dose was excreted in faeces and urine respectively. Less than 0.2% of the ospemifene dose was excreted unchanged in urine. Following a single oral administration of 60 mg ospemifene in the fed state, 17.9%, 10.0% and 1.4% of the administered dose was excreted in faeces as ospemifene, 4-hydroxyospemifene and 4'-hydroxyospemifene, respectively. The fate of remaining fraction is unknown but can probably be explained by formation of glucuronide metabolites.
Ospemifene exhibits linear pharmacokinetics in the fed state within the dose range of 60 mg to 240 mg.
No clinically meaningful differences in ospemifene pharmacokinetics have been observed over the age range studied (40-80) years of age. No dose adjustment is necessary in elderly patients.
Pharmacokinetic studies have not been performed with ospemifene in the paediatric population.
Renal clearance of unchanged active substance is a minor pathway of elimination, less than 0.2% of the ospemifene dose is excreted unchanged in urine. In patients with severe renal impairment the ospemifene exposure was increased by approximately 20%, when compared to healthy matched subjects. No clinically important pharmacokinetic differences between subjects with severe renal impairment and healthy subjects were observed. This difference is not considered clinically relevant and no dose adjustment is necessary in patients with renal impairment.
Ospemifene is primarily metabolised by the liver. The pharmacokinetics of ospemifene is only mildly affected by mild and moderate hepatic impairment (Child Pugh scores 5-9) when compared to healthy matched controls. In patients with moderate hepatic impairment the exposure of ospemifene and 4-hydroxyospemifene was approximately 30% and 70% higher. These changes in pharmacokinetics of ospemifene by moderate hepatic impairment are not considered to be clinically significant in consideration of inherent pharmacokinetic variability of ospemifene. No dose adjustment is necessary in patients with mild or moderate hepatic impairment. The pharmacokinetics of ospemifene has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class score >9).
Ospemifene is indicated for use only in postmenopausal women.
Pharmacokinetic differences due to race have been studied in 1,091 postmenopausal women, including 93.1% White, 3.9% Black, 1.8% Asian and 1.1% other in VVA trials. There were no discernible differences in ospemifene plasma concentrations among these groups; however, the influence of race cannot be conclusively determined.
Both CYP2C9 and CYP3A4 are involved in the metabolism of ospemifene. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the AUC of ospemifene by 1.4-fold. In CYP2C9 poor metabolizers, co-administration of CYP3A4 inhibitors may increase systemic concentration of ospemifene to a larger extent. Therefore, co-administration of ospemifene with strong/moderate CYP3A4 inhibitors should be avoided in patients who are known, or suspected to be CYP2C9 poor metabolizers based on genotyping or previous history/experience with other CYP2C9 substrates.
In repeat dose toxicity studies in mouse, rat, dog and the cynomolgus monkey main target organs of toxicity were the ovary, uterus and the liver. Ospemifene-related changes included ovarian follicular cysts, endometrial stromal atrophy and endometrial hypertrophy/hyperplasia which are consistent with the pharmacologic activity of ospemifene in the intact, normally cycling animal. In the liver hepatocyte hypertrophy or increased glycogen storage, increase in alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were observed. Overall, these findings are characteristic for an induction of CYP isoenzymes and are regarded as adaptive responses without any histopathological signs of liver injury. No changes in blood biochemical parameters such as ALT or ALP were determined in postmenopausal women treated with Ospemifene in clinical studies. Taken together, the liver changes observed in experimental animals in repeat dose toxicity studies are regarded as adaptive changes due to enzyme induction and given the lack of any clinical signs are unlikely to represent a safety concern for humans.
Ospemifene was not mutagenic or clastogenic when evaluated in a standard battery of in vitro and in vivo tests.
In a 2-year carcinogenicity study in female mice, ospemifene caused treatment related increases in neoplastic findings in the adrenal gland and ovary. Systemic exposure (AUC) at these doses was 2.1-, 4.0- and 4.7-times the AUC in postmenopausal woman administered 60 mg/day. In the adrenal gland, there was an increased incidence of adrenal subcapsular cell and adrenal cortical tumours in animals dosed at high dose. In the ovary, there was an increase in sex-cord stromal tumours, tubulostromal tumours, granulosa cell tumours and luteomas in all treatment groups.
In a 2-year carcinogenicity study in rats, a clear increase in mostly benign thymic tumours was recorded at all ospemifene dose levels. This effect was likely due to the anti-oestrogenic effect of ospemifene in this target tissue, which was attenuating the physiological thymic involution (atrophy) process induced by oestrogens starting during puberty. In the liver, an increase in hepatocellular tumours were recorded at all ospemifene dose levels. Systemic exposure (AUC) at the administered doses was 0.3-, 1.0- and 1.2-times the AUC in postmenopausal woman administered 60 mg/day.
Overall, tumour development in these studies is believed to be the result of rodent specific hormonal mechanisms when treated during their reproductive lives; these findings are unlikely to have any clinical relevance in postmenopausal women.
Ospemifene was not teratogenic in rats or rabbits. In a two-generation reproductive study on pre-and postnatal development ospemifene induced an increased post-implantation loss, an increased number of dead pups at birth as well as an increased incidence of postnatal loss of pups in the F1 generation. In the F0 maternal generation, a significant prolonged gestation was observed. However, all exposures were far below the intended human exposure. The reproductive effects observed are considered to be related to oestrogen receptor activity of ospemifene. Fertility studies were not conducted.
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