Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

10.2   Pharmacodynamics
Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to DUAVIVE® nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

Pharmacokinetic Properties

10.3   Pharmacokinetics
Absorption
Following administration of multiple doses of conjugated estrogens 0.45 mg/bazedoxifene 20 mg to healthy women who were naturally postmenopausal or who had undergone bilateral oophorectomy, the mean steady state pharmacokinetic parameters at Day 10 for conjugated estrogens (baseline adjusted for total estrone) and bazedoxifene are summarized in Table 2.

Table 2: Mean ± SD Steady-State Pharmacokinetic Parameters (n=24)

Cmax          Tmax          AUCss
(ng/mL)         (hr)        (nghr/mL)
Baseline-Adjusted Total Estrone       2.6 ± 0.8     6.5 ± 1.6       35 ± 12 Bazedoxifene                          6.9 ± 3.9     2.5 ± 2.1       71 ± 34 
Results from monotherapy studies with conjugated estrogens or bazedoxifene components of DUAVIVE®, are noted below:

Conjugated estrogens are soluble in water and are well-absorbed from the gastrointestinal tract after release from the drug formulation.

Bazedoxifene 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%.

Food Effect
In a single-dose, crossover study in 23 postmenopausal women given conjugated estrogens 0.625 mg/bazedoxifene 20 mg with a high fat/high calorie meal, food increased AUC0-inf of bazedoxifene by 25%. The Cmax of bazedoxifene was unchanged.
Distribution
The distribution of conjugated estrogens and bazedoxifene after administration of DUAVIVE® has not been studied.

Results from monotherapy studies with conjugated estrogens or bazedoxifene, components of DUAVIVE®, are noted below:

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 sex hormone binding globulin (SHBG) and albumin.


Following intravenous (IV) 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, but does not bind to SHBG.

Metabolism
The metabolic disposition of conjugated estrogens and bazedoxifene, after administration of DUAVIVE®, has not been studied.

Results from monotherapy studies 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. 17-β 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 exists 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, baseline-adjusted total estrone (representing conjugated estrogens) is eliminated with a half-life of approximately 17 hours. Bazedoxifene is eliminated with a half-life of approximately 30 hours. Steady-state concentrations are achieved by the second week of once-daily administration.

Results from monotherapy studies with conjugated estrogens or bazedoxifene, components of DUAVIVE®, are noted below:

The conjugated estrogens components, 17β-estradiol, estrone, and estriol are excreted in the urine, along with glucuronide and sulfate conjugates.

The clearance of bazedoxifene is 0.4 ± 0.1 L/h/kg based on intravenous administration. The major route of excretion after oral administration of 20 mg of radiolabeled bazedoxifene is via biliary excretion, followed by elimination in the feces (~85%), with < 1% of the radioactive dose eliminated in the urine. Based on these results, it is expected that bazedoxifene undergoes entero- hepatic recycling from the gut back to the systemic circulation, therefore, some drugs may potentially interfere with bazedoxifene recycling process in the gut by various mechanisms resulting in a decrease in its systemic exposure.


Use in Specific Populations
Pediatric
The pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated in a pediatric population [see Use in Specific Populations (7.4)].

Geriatric
The effect of age on the pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated [see Use in Specific Populations (7.5)].

No pharmacokinetic studies with 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 2.6-fold increase in AUC.

Renal Impairment
The pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated in women with renal impairment [see Dosage and Administration (2.6) and Use in Specific Populations 7.6)].

Hepatic Impairment
The pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated in women with hepatic impairment [see Contraindications (3), Warnings and Precautions (4.5), and Use in Specific Populations (7.7)].

No pharmacokinetic studies with conjugated estrogens were conducted in specific populations, including women with hepatic impairment.

A single dose of bazedoxifene 20 mg was given to fasted, healthy (N=18) and hepatically impaired postmenopausal women. In six mild hepatic impairment patients (Child Pugh Class A), Cmax and AUC of bazedoxifene increased 67% and 143%, respectively, compared to healthy subjects. In six moderate hepatic impairment patients (Child Pugh Class B), Cmax and AUC of bazedoxifene increased 32% and 109%, respectively, compared to healthy subjects. In six severe hepatic impairment patients (Child Pugh Class C), Cmax and AUC of bazedoxifene increased 20% and 268%, respectively, compared to healthy subjects. Half-life was prolonged from 32 to
50 hrs in patients with severe hepatic impairment, compared to healthy subjects.

Body Mass Index

In a clinical study, a single dose of DUAVIVE® (conjugated estrogens 0.45 mg/bazedoxifene 20 mg) was administered to 12 obese [mean (SD) BMI = 32.7 (2.7) kg/m2] and 12 non-obese
[mean (SD) BMI = 25.3 (2.6) kg/m2] postmenopausal women. In obese subjects, systemic exposure (AUC0-72) of total estrone was 2% lower and systemic exposures (AUC0-inf) of total 

equilin and bazedoxifene were 32% and 13% lower, respectively, compared to non-obese subjects.

Drug Interactions

Effect of Co-Administered Drugs on the Pharmacokinetics of Conjugated Estrogens/Bazedoxifene

In a drug-drug interaction study, itraconazole 200 mg, a strong CYP3A4 inhibitor, was administered with breakfast to 24 postmenopausal women for 4 days, followed by a fifth dose of itraconazole 200 mg with breakfast and DUAVIVE® on Day 5 (3 hours after itraconazole).
Itraconazole 200 mg was continued for 2 additional days after the co-administration of itraconazole 200 mg and DUAVIVE®. Following co-administration of DUAVIVE® and itraconazole, baseline-adjusted total estrone Cmax and AUC0-72 increased 9% and 9%, respectively, total equilin Cmax and AUC0-72 increased 11% and 5%, respectively, and bazedoxifene Cmax and AUC0-inf increased 11% and 40%, respectively, compared to subjects treated with DUAVIVE® alone.

Effect of Co-Administered Drugs on the Pharmacokinetics of Bazedoxifene 
Conjugated Estrogens
Conjugated estrogens 0.625 mg were administered alone for 6 consecutive days prior to the co- administration of a single dose of 20 mg bazedoxifene and conjugated estrogens 0.625 mg in thirty postmenopausal women. Conjugated estrogens 0.625 mg were continued for 2 additional days after the co-administration of bazedoxifene and conjugated estrogens. The Cmax of bazedoxifene increased by 3% and AUC of bazedoxifene decreased by 6%.

Ibuprofen
A single dose of ibuprofen 600 mg was given with a bazedoxifene 20 mg capsule in twelve postmenopausal women after an overnight fast. Co-administration of ibuprofen and bazedoxifene increased Cmax and AUC of bazedoxifene by 18% and 7%, respectively.

Atorvastatin
Atorvastatin 20 mg was given once with bazedoxifene 40 mg in thirty postmenopausal women.
Co-administration of atorvastatin and bazedoxifene decreased Cmax of bazedoxifene by 3% and increased AUC of bazedoxifene by 6%.

Azithromycin
Azithromycin 500 mg was given once daily for 8 consecutive days in thirty postmenopausal women. Azithromycin 500 mg and a bazedoxifene 40 mg tablet were co-administered on Day 9.
Azithromycin 250 mg administration once daily continued on Days 10 to 13. Co-administration of azithromycin and bazedoxifene increased Cmax of bazedoxifene by 6% and decreased AUC of bazedoxifene by 15%.

Aluminum and Magnesium Hydroxide

A single dose of 460 mg aluminum hydroxide and 400 mg magnesium hydroxide was given with a bazedoxifene 40 mg tablet in thirty postmenopausal women after an overnight fast. Co- administration of aluminum/magnesium hydroxide and bazedoxifene decreased Cmax of bazedoxifene by 8% and increased AUC of bazedoxifene by 7%.

Effect of Bazedoxifene on the Pharmacokinetics of Co-Administered Drugs 
Conjugated Estrogens
Bazedoxifene 20 mg was administered alone for 8 consecutive days prior to co-administration of a single dose of conjugated estrogens 0.625 mg and bazedoxifene 20 mg in twenty-six postmenopausal women. Bazedoxifene 20 mg was continued for 2 additional days after co-administration of bazedoxifene and conjugated estrogens. The Cmax and AUC of unconjugated estrone increased by 11% and 3%, respectively. The Cmax and AUC of unconjugated equilin increased by 17% and 14%, respectively.

Ibuprofen
A single dose of bazedoxifene 20 mg capsule was given with a single dose of ibuprofen 600 mg in twelve fasted, postmenopausal women. Co-administration of bazedoxifene and ibuprofen increased the Cmax of ibuprofen by 6%. The AUC of ibuprofen was unchanged.

Atorvastatin
Bazedoxifene 40 mg was given for 8 consecutive days prior to co-administration of bazedoxifene 40 mg and atorvastatin 20 mg. Co-administration of bazedoxifene and atorvastatin decreased
Cmax of atorvastatin by 14%. The AUC of atorvastatin was unchanged. The Cmax and AUC of 2-OH atorvastatin were decreased by 18% and 8%, respectively.