Información de la droga para Femring (estradiol acetate vaginal ring) (Warner Chilcott (US), LLC): CLINICAL PHARMACOLOGY

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  • Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

    The primary source of estrogen in normally cycling adult women is the ovarian follicle which secretes 70 to 500 mcg of estradiol daily depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

    Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

    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 hormones seen in postmenopausal women.

  • A. Absorption

  • Drug delivery from Femring is rapid for the first hour and then declines to a relatively constant rate for the remainder of the 3-month dosing interval. In vitro studies have shown that this initial release is higher as the rings age upon storage. Estradiol acetate is rapidly hydrolyzed to estradiol which is absorbed through the vaginal mucosa as evidenced by the mean time to maximum concentration (tmax) for estradiol of about 1 hour (range 0.25 to 1.5 hrs). Following the maximum concentration (Cmax), serum estradiol decreases rapidly such that by 24 to 48 hours postdose, serum estradiol concentrations are relatively constant through the end of the 3-month dosing interval, see Figure 1 for results from rings stored for 16 months.

    Following administration of Femring (0.05 mg/day estradiol), average serum estradiol concentration was 40.6 pg/mL; the corresponding apparent in vivo estradiol delivery rate was 0.052 mg/day. Following administration of Femring (0.10 mg/day estradiol), average serum estradiol concentration was 76 pg/mL; apparent in vivo delivery rate was 0.097 mg/day. Results are summarized in Table 1 below.

    Table 1. Summary of Mean (%RSD) Relative Standard Deviation Pharmacokinetic Parameters for Femring

    Dose

    (as estradiol)

    Number

    of

    subjects

    Cmax

    (pg/mL)

    Tmax

    (hour)

    Cavg

    (pg/mL)

    0.05 mg/day

    EstradiolStudy 1251129 (25)0.9 (41)40.6 (26)
    Estrone25 141 (25)6.2 (84)35.9 (21)
    Estrone sulfate252365 (44)9.3 (39) 494.6 (48)

    0.10 mg/day

    EstradiolStudy 2121665 (23)0.7 (90)--Not determined
    EstradiolStudy 311----76.0 (24)
    Estrone11----45.7 (25)

    Consistent with the avoidance of first pass metabolism achieved by vaginal estradiol administration, serum estradiol concentrations were slightly higher than estrone concentrations.

  • B. Distribution

  • 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 to albumin.

  • C. Metabolism

  • Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. 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.

  • D. Excretion

  • Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

  • E. Special Populations

  • No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

  • F. Drug Interactions

  • In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

  • Drug Information Provided by National Library of Medicine (NLM).
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