Drug Information for Prempro (Physicians Total Care, Inc.): 12 CLINICAL PHARMACOLOGY

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  • 12.1 Mechanism of Action

    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, 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.

    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 gonadotropins seen in postmenopausal women.

    Parenterally administered medroxyprogesterone acetate (MPA) inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation; although available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses. MPA may achieve its beneficial effect on the endometrium in part by decreasing nuclear estrogen receptors and suppression of epithelial DNA synthesis in endometrial tissue. Androgenic and anabolic effects of MPA have been noted, but the drug is apparently devoid of significant estrogenic activity.

    12.2 Pharmacodynamics

    Currently, there are no pharmacodynamic data known for PREMPRO or PREMPHASE tablets.

    12.3 Pharmacokinetics Absorption

    PREMPRO and PREMPHASE contain a formulation of medroxyprogesterone acetate (MPA) that is immediately released and conjugated estrogens that are slowly released over several hours. Conjugated estrogens are water-soluble and are well-absorbed from the gastrointestinal tract after release from the drug formulation. MPA is well absorbed from the gastrointestinal tract. Table 3 and Table 4 summarize the mean pharmacokinetic parameters for select unconjugated and conjugated estrogens and medroxyprogesterone acetate following administration of PREMPRO to healthy, postmenopausal women.

    TABLE 3: PHARMACOKINETIC PARAMETERS FOR UNCONJUGATED AND CONJUGATED ESTROGENS (CE) AND MEDROXYPROGESTERONE ACETATE (MPA)
    DRUGCE/2.5 mg MPA2 x 0.625 mgCombination(N = 54)TabletsCE/5 mg MPA2 x 0.625 mgCombination(N = 51)Tablets
    PK ParameterArithmetic Mean (%CV)Cmax(pg/mL)tmax(h)t1/2(h)AUC(pg•h/mL) Cmax(pg/mL)tmax(h)t1/2(h)AUC(pg•h/mL)
    Unconjugated Estrogens
    Estrone175(23)7.6(24)31.6(23)5358(34)124(43)10(35)62.2(137)6303(40)
    BA * -Estrone159(26)7.6(24)16.9(34)3313(40)104(49)10(35)26.0(100)3136(51)
    Equilin71(31)5.8(34)9.9(35)951(43)54(43)8.9(34)15.5(53)1179(56)
    PK Parameter Arithmetic Mean (%CV)Cmax (pg/mL)tmax (h)t1/2 (h)AUC (pg•h/mL)Cmax (pg/mL)tmax (h)t1/2 (h)AUC (pg•h/mL)
    Conjugated Estrogens
    Total Estrone6.6(38)6.1(28)20.7(34)116(59)6.3(48)9.1(29)23.6(36)151(42)
    BA * -Total Estrone6.4(39)6.1(28)15.4(34)100(57)6.2(48)9.1(29)20.6(35)139(40)
    Total Equilin5.1(45)4.6(35)11.4(25)50(70)4.2(52)7.0(36)17.2(131)72(50)
    PK Parameter Arithmetic Mean (%CV)Cmax (pg/mL)tmax (h)t1/2 (h)AUC (pg•h/mL)Cmax (pg/mL)tmax (h)t1/2 (h)AUC (pg•h/mL)
    Medroxyprogesterone Acetate
    MPA1.5(40)2.8(54)37.6(30)3730)4.8(31)2.4(50)46.339)10228)
    BA* = Baseline adjusted

    Cmax = peak plasma concentration

    tmax = time peak concentration occurs

    t1/2 = apparent terminal-phase disposition half-life (0.693/?z)

    AUC = total area under the concentration-time curve

    TABLE 4. PHARMACOKINETIC PARAMETERS FOR UNCONJUGATED AND CONJUGATED ESTROGENS (CE) AND MEDROXYPROGESTERONE ACETATE (MPA)
    DRUG
    PK Parameter Arithmetic Mean (%CV)Cmax(pg/mL)tmax (h)t1/2 (h)AUC(pg•h/mL)
    Unconjugated Estrogens
    Estrone149(35)8.9(35)37.5(35)6641(39)
    BA * -Estrone130(40)8.9(35)21.2(35)3799(47)
    Equilin83(38)8.3(48)15.9(44)1889(40)
    PK Parameter Arithmetic Mean (%CV)Cmax(pg/mL)tmax (h)t1/2 (h)AUC(pg•h/mL)
    Conjugated Estrogens
    Total Estrone5.4(49)7.9(48)22.4(53)119(48)
    BA * -Total Estrone5.2(48)7.9(48)15.1(29)100(47)
    Total Equilin43.3(42)6.5(45)11.6(31)74(48)
    PK Parameter Arithmetic Mean (%CV)Cmax(pg/mL)tmax (h)t1/2 (h)AUC(pg•h/mL)
    Medroxyprogesterone Acetate
    MPA0.7(66)2.0(52)26.2(35)5.0(61)
    BA* = Baseline adjusted

    Cmax = peak plasma concentration

    tmax = time peak concentration occurs

    t1/2 = apparent terminal-phase disposition half-life (0.693/?z)

    AUC = total area under the concentration-time curve

    Food-Effect: Single dose studies in healthy, postmenopausal women were conducted to investigate any potential drug interaction when PREMPRO or PREMPHASE is administered with a high-fat breakfast. Administration with food decreased the Cmax of total estrone by 18 to 34 percent and increased total equilin Cmax by 38 percent compared to the fasting state, with no other effect on the rate or extent of absorption of other conjugated or unconjugated estrogens. Administration with food approximately doubles MPA Cmax and increases MPA AUC by approximately 20 to 30 percent.

    Dose Proportionality: The Cmax and AUC values for MPA observed in two separate pharmacokinetic studies conducted with 2 PREMPRO 0.625 mg/2.5 mg or 2 PREMPRO or PREMPHASE 0.625 mg/5 mg tablets exhibited nonlinear dose proportionality; doubling the MPA dose from 2 x 2.5 to 2 x 5 mg increased the mean Cmax and AUC by 3.2- and 2.8-folds, respectively.

    The dose proportionality of estrogens and medroxyprogesterone acetate was assessed by combining pharmacokinetic data across another two studies totaling 61 healthy, postmenopausal women. Single conjugated estrogens doses of 2 x 0.3 mg, 2 x 0.45 mg, or 2 x 0.625 mg were administered either alone or in combination with medroxyprogesterone acetate doses of 2 x 1.5 mg or 2 x 2.5 mg. Most of the estrogen components demonstrated dose proportionality; however, several estrogen components did not. Medroxyprogesterone acetate pharmacokinetic parameters increased in a dose-proportional manner.

    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 albumin. MPA is approximately 90 percent bound to plasma proteins, but does not bind to SHBG.

    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 a 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 intestine followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Metabolism and elimination of MPA occur primarily in the liver via hydroxylation, with subsequent conjugation and elimination in the urine.

    Excretion

    Estradiol, estrone, and estriol are excreted in the urine, along with glucuronide and sulfate conjugates. Most metabolites of MPA are excreted as glucuronide conjugates, with only minor amounts excreted as sulfates.

    Specific Populations

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

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