Chemical formula: C₃₀H₃₄N₂O₃ Molecular mass: 470.613 g/mol PubChem compound: 154257
Bazedoxifene belongs to a class of compounds known as selective estrogen receptor modulators (SERMs). Bazedoxifene acts as both an oestrogen-receptor agonist and/or antagonist, depending upon the cell and tissue type and target genes. Bazedoxifene decreases bone resorption and reduces biochemical markers of bone turnover to the premenopausal range. These effects on bone remodeling lead to an increase in bone mineral density (BMD), which in turn contributes to a reduction in the risk of fractures. Bazedoxifene functions primarily as an oestrogen-receptor antagonist in uterine and breast tissues.
The mean pharmacokinetic parameters of bazedoxifene after multiple doses in healthy postmenopausal ambulatory women who were naturally postmenopausal or who had undergone bilateral oophorectomy are summarized in the following table.
Mean ± SD pharmacokinetic parameters of bazedoxifene (n=23):
| Cmax (ng/ml) | tmax (h) | t½ (h) | AUC (ng.h/ml) | Cl/F (l/h/kg) | |
|---|---|---|---|---|---|
| Multiple dose 20 mg/day | 6.2 ± 2.2 | 1.7 ± 1.8 | 28 ± 11 | 82 ± 37 | 4.1 ± 1.7 |
Bazedoxifene is rapidly absorbed with a tmax of approximately 2 hours and exhibits a linear increase in plasma concentrations for single doses from 0.5 mg up to 120 mg and multiple daily doses from 1 mg to 80 mg. The absolute bioavailability of bazedoxifene is approximately 6%.
When single doses of 20 mg bazedoxifene were administered with a high-fat meal, Cmax and AUC increased by 28% and 22%, respectively. An additional study evaluating the effects of a standardized medium-fat meal on the pharmacokinetics of bazedoxifene at steady-state showed a 42% and 35% increase in Cmax and AUC, respectively, when 20 mg bazedoxifene was administered with food. Because these changes are not considered clinically relevant, bazedoxifene can be administered without regard to meals.
Following intravenous administration of a 3 mg dose of bazedoxifene, the volume of distribution is 14.7 ± 3.9 l/kg. Bazedoxifene is highly bound (98%-99%) to plasma proteins in vitro.
The metabolic disposition of bazedoxifene in postmenopausal women has been determined following oral administration of 20 mg of radio-labelled bazedoxifene. Bazedoxifene is extensively metabolised in women. Glucuronidation is the major metabolic pathway. Little or no cytochrome P450-mediated metabolism is evident. Bazedoxifene-5-glucuronide is the major circulating metabolite. The concentrations of this glucuronide are approximately 10-fold higher than those of unchanged active substance in plasma.
Bazedoxifene is eliminated with a half-life of approximately 30 hours. Steady-state concentrations are achieved by the second week of once-daily administration. The apparent oral clearance of bazedoxifene is approximately 4 to 5 l/h/kg. The major route of excretion of radio-labelled bazedoxifene is the faeces, and less than 1% of the dose is eliminated in urine.
The disposition of a single 20 mg dose of bazedoxifene was compared in patients with hepatic impairment [Child-Pugh Class A (n=6), B (n=6), and C (n=6)] and subjects with normal hepatic function (n=18). On average, patients with hepatic impairment showed a 4.3-fold increase in AUC compared with controls. Safety and efficacy have not been evaluated further in patients with hepatic insufficiency. Use in this patient population is not recommended.
Limited clinical data (n=5) are available in subjects with moderate renal impairment (CrCl <50 ml/min). A single 20 mg dose of bazedoxifene was administered to these subjects. Negligible amounts of bazedoxifene were eliminated in urine. Impaired renal function showed little or no influence on bazedoxifene pharmacokinetics, and no dosing adjustment is required.
The pharmacokinetics of a 20 mg single-dose of bazedoxifene were evaluated in a study in 26 healthy postmenopausal women. On average, compared to women 51 to 64 years of age (n=8), women 65 to 74 years of age (n=8) showed a 1.5-fold increase in AUC, and women 75 years of age (n=8) showed a 2.3-fold increase in AUC. This increase was most likely attributed to age-related changes in hepatic function. No dose adjustment is necessary based on age.
The pharmacokinetics of bazedoxifene have not been studied in the paediatric population.
No pharmacokinetic differences based on ethnic group were observed.
In rabbit studies, abortion and an increased incidence of heart (ventricular septal defect) and skeletal system (ossification delays, misshapen or misaligned bones, primarily of the spine and skull) anomalies in the foetuses were present at maternally toxic doses of ≥0.5 mg/kg/day (1.5 times the human exposure). Treatment of rats at maternally toxic doses ≥1 mg/kg/day (≥0.3 times the human exposure) resulted in reduced numbers of live foetuses and/or reductions in foetal body weights. No foetal developmental anomalies were observed.
Female rats were administered daily doses of 0.3 to 30 mg/kg (0.03 to 8 times the human exposure) prior to and during mating with untreated males. Oestrous cycles and fertility were adversely affected in all bazedoxifene-treated female groups.
The effects of bazedoxifene treatment on bone, uterus, and mammary gland were assessed in ovariectomized rats (0.15 to 1.5 mg/kg/day) and non-human primates [Cynomolgus macaques] (0.2 to 25.0 mg/kg/day). In rats, treatment with bazedoxifene for approximately one year partially prevented the effects of ovariectomy on numerous skeletal parameters (bone mineral content, bone mineral density, and architecture). Additionally, uterine wet weights were reduced compared with untreated animals and histologic evaluation demonstrated little to no difference from the untreated controls. In monkeys, treatment with bazedoxifene for 18 months resulted in the partial preservation of cortical and cancellous bone mass as determined by BMD measurements. The partial preservation of bone mass was achieved by reductions in the ovariectomy-induced increases in bone turnover, evaluated by biochemical markers of bone turnover and histomorphometric indices measured in cancellous and cortical bone. Importantly, in both species, the administration of bazedoxifene had no deleterious effects on bone quality. Like the rodent results, bazedoxifene treatment in non-human primates resulted in uterine and mammary gland atrophy without other histological differentiation from untreated animals.
Repeated-dose studies in normally cycling rodents and cynomolgus monkeys revealed a marked stimulation of ovarian follicle growth without ovulation, leading to partly haemorrhagic-ovarian cysts and markedly elevated estradiol levels. This pharmacological effect of bazedoxifene can also be expected in pre-menopausal women, but is considered clinically irrelevant in post-menopausal women.
In 6-month carcinogenicity studies in transgenic mice, there was an increased incidence of benign, ovarian granulosa-cell tumours in female mice given 150 or 500 mg/kg/day. Systemic exposure (AUC) to bazedoxifene in these groups was 35 and 69 times that in postmenopausal women administered 20 mg/day for 14 days.
In a 2-year carcinogenicity study in rats, an increased incidence of benign, ovarian granulosa-cell tumours was observed in female rats at dietary concentrations of 0.03 and 0.1%. Systemic exposure (AUC) of bazedoxifene in these groups was 2.6 and 6.6 times that observed in postmenopausal women administered 20 mg/day for 14 days.
The observation of benign, ovarian granulosa-cell tumours in female mice and rats administered bazedoxifene is a class effect of SERMs, related to its pharmacology in rodents when treated during their reproductive lives, when their ovaries are functional and responsive to hormonal stimulation.
Bazedoxifene was not genotoxic or mutagenic in a battery of tests, including in vitro bacterial reverse mutation assay, in vitro mammalian cell forward mutation assay at the thymidine kinase (TK±) locus in L5178Y mouse lymphoma cells, in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells, and in vivo mouse micronucleus assay.
Bazedoxifene caused corticomedullar nephrocalcinosis and enhanced spontaneous chronic progressive nephropathy (CPN) in male rats. Urine parameters were pathologically changed. In long-term studies renal tumours (adenomas and carcinomas) were observed at all doses tested, most likely as a consequence of this chronic renal damage. In the 2-year carcinogenicity study, bazedoxifene, administered orally in the diet to rats at dosages of 0, 0.003%, 0.01%, 0.03%, or 0.1%, resulted in exposures, based on surface area (mg/m²) of approximately 0.6 to 23 times and 0.9 to 31 times in males and females, respectively, the clinical dose of 20 mg. Since chronic progressive nephropathy and corticomedullar nephrocalcinosis are most likely rat-specific nephropathies, these findings are presumably not relevant for humans.
In an 18-month bone efficacy study in aged ovariectomized cynomolgus monkeys, bazedoxifene, administered orally to monkeys at dosages of 0, 0.2, 0.5, 1, 5, or 25 mg/kg/day, resulted in exposures, based on surface area (mg/m²) of approximately 0.2 to 24 times the clinical dose of 20 mg. Renal cell carcinomas were observed in this study. These tumours are considered as spontaneous renal cell carcinomas that are known to occur in nonhuman primates and are unlikely to be relevant to humans.
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