Yuvafem (Page 5 of 10)

12.2 Pharmacodynamics

Currently, there are no pharmacodynamic data known for Yuvafem.

12.3 Pharmacokinetics

Absorption

Estrogen drug products are well absorbed through the skin, mucous membranes and the gastrointestinal tract. The vaginal delivery of estrogens circumvents first-pass metabolism.

In a single-center, randomized, open-label, multiple-dose, parallel group study conducted in 58 patients, Yuvafem 10 mcg demonstrated a mean estradiol (E2) C ave at Day 83 of 5.5 pg/mL and 11.59 pg/mL, respectively after 12 weeks of treatment (see Table 3).

Table 3: Arithmetic Means of Estradiol (E2), Estron (E1), and Estrone Sulfate (E1S) PK Parameters Following Multiple Doses a of Yuvafem 10 mcg

Uncorrected for baseline, N=29

E2 E1 E1S

AUC 0-24

(h.pg/mL)

C ave (0-24)

(pg/mL)

%CV b

AUC 0-24

(h.pg/mL)

C ave (0-24)

(pg/mL)

%CV b

AUC 0-24

(h.pg/mL)

C ave (0-24)

(pg/mL)

%CV b
Day 1 242.08 10.09 33.02 485.21 20.22 44.86 5158.32 214.93 53.57
Day 14 176.49 7.35 43.69 496.14 20.67 30.88 6323.41 263.48 50.07
Day 83 132.04 5.50 59.69 411.08 17.13 39.58 3804.65 158.53 49.76
a Patients received vaginal inserts as a once daily intravaginal treatment for the first 2 weeks and a twice weekly intravaginal maintenance for the following 10 weeks.
b CV: Coefficient of Variance for both AUC 0-24 and C ave (0-24)

Table 4: Arithmetic Means of Estradiol (E2), Estron (E1), and Estrone Sulfate (E1S) PK Parameters Following Multiple Doses a of Yuvafem 10 mcg

Uncorrected for baseline, N=29

E2 E1 E1S

AUC 0-24

(h.pg/mL)

C ave (0-24)

(pg/mL)

%CV b

AUC 0-24

(h.pg/mL)

C ave (0-24)

(pg/mL)

%CV b

AUC 0-24

(h.pg/mL)

C ave (0-24)

(pg/mL)

%CV b
Day1 495.27 20.64 25.70 567.07 23.63 28.96 5738.32 239.10 47.72
Day 14 466.63 19.44 33.53 662.94 27.62 24.36 7725.90 321.91 43.67
Day 83 278.27 11.59 61.83 500.06 20.84 34.99 4110.84 171.29 51.38
a Patients received vaginal inserts as a once daily intravaginal treatment for the first 2 weeks and a twice weekly intravaginal maintenance for the following 10 weeks
b CV: Coefficient of Variance for both AUC 0-24 and C ave (0-24)
c N=28 for treatment before Day 14 and N=27 for treatments from Day 14.

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 SHBG and albumin.

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 portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Excretion

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

Use in Specific Populations

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

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