Mechanism of Action
DUAVIVE pairs the SERM, bazedoxifene, with conjugated estrogens. Conjugated estrogens and bazedoxifene function by binding to and activating the two estrogen receptors (α and β). Conjugated estrogens are composed of multiple estrogens that demonstrate tissue selective estrogen receptor agonist activity. Bazedoxifene demonstrates both tissue selective estrogen receptor agonist and antagonist activity. The pairing of a SERM with one or more estrogens (conjugated estrogens/bazedoxifene) is described as a tissue selective estrogen complex (TSEC). For any endpoint measured, the outcome observed is a result of a composite of the components’ effects, which are distinct from conjugated estrogens and bazedoxifene when they are administered alone. The net effect of the TSEC, conjugated estrogens/bazedoxifene, in any particular tissue is specific for that target tissue (i.e., tissue selective activity).
Pharmacodynamics
Pharmacodynamic trials have not been conducted with DUAVIVE.
Pharmacokinetics
The pharmacokinetics of conjugated estrogens/bazedoxifene were evaluated in healthy women who were naturally postmenopausal or who had undergone bilateral oophorectomy.
In a study involving once-daily administration of conjugated estrogens 0.45 mg/bazedoxifene 20 mg for 10 days, the mean steady state pharmacokinetic parameters for conjugated estrogens (baseline adjusted total estrone) and bazedoxifene are summarized in Table 2.
|
|||
Table 2: Mean ± SD Steady-State Pharmacokinetic Parameters (n=24) |
|||
Cmax (ng/mL) |
Tmax (hr) |
AUCss (ng×hr/mL) |
|
Bazedoxifene |
6.9 ± 3.9 |
2.5 ± 2.1 |
71 ± 34 |
Baseline-adjusted total estrone |
2.6 ± 0.8 |
6.5 ± 1.6 |
35 ± 12 |
Absorption
When conjugated estrogens/bazedoxifene were administered with a high-fat meal, the Cmax and AUC of bazedoxifene were increased. The pharmacokinetics of conjugated estrogens were unaffected. No adjustment in dose is recommended; DUAVIVE may be given at any time of the day, without regard to meals (see DOSAGE AND ADMINISTRATION).
Some drugs, such as cholestyramine or other anion exchange resins, have the potential to reduce the absorption and/or enterohepatic recycling of bazedoxifene, therefore, co-administration of these drugs and DUAVIVE is not recommended.
Results from monotherapy trials with conjugated estrogens or bazedoxifene, components of DUAVIVE, are noted below:
Bazedoxifene exhibits a linear increase in plasma concentrations for single doses from 5 mg up to 120 mg and multiple daily doses from 5 mg to 80 mg. The absolute bioavailability of bazedoxifene is approximately 6%.
Conjugated estrogens are soluble in water and are well-absorbed from the gastrointestinal tract after release from the drug formulation.
Distribution
The distribution of conjugated estrogens and bazedoxifene after administration of DUAVIVE has not been studied.
Results from monotherapy trials with conjugated estrogens or bazedoxifene, components of DUAVIVE are noted below:
Following intravenous (IV) administration of a 3 mg dose of bazedoxifene alone, the volume of distribution is 14.7 ± 3.9 L/kg. Bazedoxifene is highly bound (98%-99%) to plasma proteins in vitro, but does not bind to sex hormone binding globulin (SHBG).
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin.
Metabolism
The metabolic disposition of conjugated estrogens and bazedoxifene, after administration of DUAVIVE, has not been studied.
Results from monotherapy trials with conjugated estrogens or bazedoxifene, components of DUAVIVE, are noted below:
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. 17β-estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. In postmenopausal women a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
The metabolic disposition of bazedoxifene has been determined following oral administration of 20 mg of radiolabeled bazedoxifene. Bazedoxifene is extensively metabolized 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 drug in plasma.
Excretion
After administration of a single dose of conjugated estrogens/bazedoxifene, bazedoxifene is eliminated with a half-life of approximately 30 hours. Baseline-adjusted total estrone (representing conjugated estrogens) is eliminated with a half-life of approximately 17 hours. Steady-state concentrations of conjugated estrogens and bazedoxifene are achieved by the second week of once-daily administration.
Results from monotherapy trials with conjugated estrogens or bazedoxifene, components of DUAVIVE, are noted below:
The clearance is 0.4 ± 0.1 L/h/kg based on IV administration. The major route of excretion of radiolabeled bazedoxifene is the feces (>90%), and less than 1% of the dose is eliminated in urine.
Conjugated estrogens components, 17β-estradiol, estrone, and estriol are excreted in the urine, along with glucuronide and sulfate conjugates.
Special Populations and Conditions
Pediatrics
The pharmacokinetics of conjugated estrogens/bazedoxifene have not been evaluated in a pediatric population.
Geriatrics
DUAVIVE has not been studied in women over 75 years of age, therefore DUAVIVE is not recommended for women over 75 years of age. The effect of age on the pharmacokinetics of conjugated estrogens/bazedoxifene tablets has not been evaluated (see CLINICAL TRIALS, Geriatric Use).
No pharmacokinetic trials for conjugated estrogens were conducted in specific populations, including women over 75 years of age.
The pharmacokinetics of a 20 mg single-dose of bazedoxifene were evaluated in 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.
Hepatic Insufficiency
The pharmacokinetics and safety and efficacy of DUAVIVE have not been evaluated in women with impaired liver function or past history of cholestatic jaundice (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS).
Due to the increase in bazedoxifene exposure in women with hepatic impairment, use of DUAVIVE in patients with known liver dysfunction or disease is contraindicated (see CONTRAINDICATIONS).
The disposition of a single 20 mg dose of bazedoxifene was compared in women with hepatic impairment (Child-Pugh Class A (n=6), B (n=6), and C (n=6)) and women with normal hepatic function (n=18). On average, women with hepatic impairment (Child-Pugh Class A, B, and C) showed increases in AUC of 3.6-, 2.1-, and 4.3-fold, respectively, compared with controls.
No pharmacokinetic trials for conjugated estrogens were conducted in specific populations, including women with hepatic impairment.
Renal Insufficiency
The pharmacokinetics of conjugated estrogens/bazedoxifene have not been adequately evaluated in women with renal impairment, therefore use in this population is not recommended (see WARNINGS AND PRECAUTIONS).
Limited clinical data for bazedoxifene are available in women with moderate renal impairment (CrCl <50 mL/min). A single 20 mg dose of bazedoxifene was administered to these women (n=5). Negligible (<1%) amounts of bazedoxifene were eliminated in urine. Impaired renal function showed little or no influence on bazedoxifene pharmacokinetics.
No pharmacokinetic trials for conjugated estrogens were conducted in specific populations, including women with renal impairment.
Bone Mineral Density (BMD)
SMART 1 Study:
In a clinical study, the efficacy of DUAVIVE for the maintenance of bone mineral density (BMD) in postmenopausal women was assessed in two substudies:
Bone Substudy I assessed women >5 years from last menstrual period: n=182 women receiving conjugated estrogens 0.45 mg/bazedoxifene 20 mg and n= 173 women receiving conjugated estrogens 0.625 mg/bazedoxifene 20 mg.
Bone Substudy II and Metabolic Substudy assessed women between 1 and 5 years post menopause, with at least one additional risk factor for osteoporosis: n=111 women receiving conjugated estrogens 0.45 mg/bazedoxifene 20 mg and n=105 women receiving conjugated estrogens 0.625 mg/bazedoxifene 20 mg.
SMART 5 Study:
The efficacy of conjugated estrogens/bazedoxifene for the maintenance of bone mineral density in postmenopausal women was assessed in a substudy in women who were <5 years postmenopausal (n=512).
Body Mass Index (BMI)
Following DUAVIVE administration, the systemic exposures of conjugated estrogens and bazedoxifene were lower in obese subjects, compared to non-obese subjects.
In a clinical study, a single dose of DUAVIVE (conjugated estrogens 0.45 mg/bazedoxifene 20 mg) was administered to 12 obese BMI ≥ 30 [mean (SD) = 32.7 (2.7) kg/m2] and 12 non-obese BMI < 30 [mean (SD) 25.3 (2.6) kg/m2] postmenopausal women. In obese subjects, systemic exposures of baseline-adjusted total estrone, total equilin, and bazedoxifene were 21%, 32%, and 13% lower, respectively, compared to non-obese subjects.
A greater reduction in bazedoxifene exposure compared to conjugated estrogens may be associated with decreased protection from endometrial hyperplasia. Monitor and evaluate women with postmenopausal or unexplained genital bleeding for possible endometrial hyperplasia or malignancy.
Estrogen Pharmacology
Conjugated estrogens function by binding to and activating the two estrogen receptors (α and β). Conjugated estrogens are composed of multiple estrogens that demonstrate tissue selective estrogen receptor agonist activity.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 μg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.
The use of unopposed estrogen therapy has been associated with an increased risk of endometrial hyperplasia, a possible precursor of endometrial adenocarcinoma. The bazedoxifene component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component. The endometrial safety of DUAVIVE was demonstrated in two Phase 3 trials (see CLINICAL TRIALS).