Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: progestogens and estrogens, combinations. ATC code: G03FA17 
Oestradiol

Angeliq contains synthetic 17ß-oestradiol, which is chemically and biologically identical to endogenous human oestradiol. It substitutes f or the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms. Oestrogens prevent bone loss f ollowing menopause or ovariectomy.

Drospirenone

Drospirenone is a synthetic progestogen.
As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen reduces, but does not eliminate the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.
Drospirenone displays aldosterone antagonist activity. Theref ore, increases in sodium and water excretion and decreases in potassium excretion may be observed.

In animal studies, drospirenone has no oestrogenic, glucocorticoid or antiglucocorticoid activity.

Clinical trial inf ormation
•     Relief of oestrogen-def iciency symptoms and bleeding patterns 
Relief of menopausal symptoms was achieved during the f irst f ew weeks of treatment.
Amenorrhea was seen in 73% of the women during months 10-12 of treatment.
Breakthrough bleeding and /or spotting appeared in 59% of the women during the f irst three months of treatment and in 27% during months 10-12 of treatment.

•      Prevention of osteoporosis

Oestrogen def iciency at menopause is associated with an increasing bone turnover and decline in bone mass.

The ef f ect of oestrogen on the bone mineral density is dose-dependent. Protection appears to be ef fective as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.

Evidence from WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a progestogen – given to predominantly healthy women – reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence f or that is limited.
Af ter 2 years of treatment with Angeliq, the increase in hip bone mineral density (BMD) was 3.96 +/- 3.15% (mean +/- SD) in osteopenic patients and 2.78 +/- 1.89% (mean +/- SD) in non-osteopenic patients. The percentage of women who maintained or gained BMD in hip zone during treatment was 94.4% in osteopenic patients and 96.4% in non-osteopenic patients.

Angeliq also had an effect on lumbar spine BMD. The increase af ter 2 years was 5.61 +/- 3.34% (mean +/- SD) in osteopenic women and 4.92+/- 3.02% (mean +/- SD) in non- osteopenic women. The percentage of osteopenic women who maintained or gained BMD in lumbar zone during treatment was 100% , whereas this percentage was 96.4% in non- osteopenic women.

•     Antimineralocorticoid activity

DRSP has aldosterone antagonistic properties that can result in a decrease in blood pressure in hypertensive women. In a double-blind placebo-controlled trial hypertensive postmenopausal women treated with Angeliq (n=123) for 8 weeks experienced a signif icant decrease in systolic/diastolic blood pressure values (office cuff versus baseline -12/-9 mm Hg, corrected for placebo ef f ect -3/-4 mm Hg; 24h ambulatory blood pressure measurement versus baseline -5/--3 mm Hg, corrected f or placebo ef f ect -3/-2 mm Hg).

Angeliq should not be used to treat hypertension. Women with hypertension should be treated according to hypertension guidelines.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Drospirenone
•       Absorption

Af ter oral administration drospirenone is rapidly and completely absorbed. With a single administration, peak serum levels of approx. 21.9 ng/ml are reached about 1 hour af ter ingestion. After repeated administration, a maximum steady-state concentration of 35.9 ng/ml is reached af ter about 10 days. The absolute bioavailability is between 76 and 85%. Concomitant ingestion of f ood had no inf luence on the bioavailability.

•       Distribution

Af ter oral administration, serum drospirenone levels decrease in two phases which are characterised by a mean terminal half -lif e of about 35–39 hours. Drospirenone is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). Only 3-5% of the total serum drug concentrations are present as f ree steroid.
The mean apparent volume of distribution of drospirenone is 3.7-4.2 l/kg.

•      Biotransf ormation

Drospirenone is extensively metabolized af ter oral administration. The major metabolites in plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulphate, formed by reduction and subsequent sulf atation. Both major metabolites are pharmacologically inactive. Drospirenone is also subject to oxidative metabolism catalysed by CYP3A4.

•       Elimination

The metabolic clearance rate of drospirenone in serum is 1.2-1.5 ml/min/kg showing an intersubject variability of about 25%. Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with the faeces and urine at an excretion ratio of about 1.2 to 1.4. The half -life of metabolite excretion with the urine and faeces is about 40 hours.


•       Steady-state conditions and linearity

Following daily oral administration of Angeliq, drospirenone concentrations reached a steady- state af ter about 10 days. Serum drospirenone levels accumulated by a f actor of about 2 to 3 as a consequence of the ratio of terminal half-life and dosing interval. At steady-state, mean serum levels of drospirenone f luctuate in the range of 14–36 ng/ml af ter administration of Angeliq. Pharmacokinetics of drospirenone are dose-proportional within the dose range of 1 to 4 mg.

Oestradiol

•   Absorption
Following oral administration, oestradiol is rapidly and completely absorbed. During the absorption and the first liver passage, estradiol undergoes extensive metabolism, thus reducing the absolute bioavailability of oestrogen af ter oral administration to about 5% of the dose.
Maximum concentrations of about 22 pg/ml were reached 6-8 hours af ter single oral administration of Angeliq. The intake of food had no influence on the bioavailability of oestradiol as compared to drug intake on an empty stomach.

•   Distribution

Following oral administration of Angeliq only gradually changing serum levels of oestradiol are observed within an administration interval of 24 hours. Because of the large circulating pool of oestrogen sulphates and glucuronides on the one hand and the enterohepatic recirculation on the other hand, the terminal half-lif e of oestradiol represents a composite parameter that is dependent on all of these processes and is in the range of about 13-20 hours af ter oral administration.
Oestradiol is bound non-specifically to serum albumin and specifically to SHBG. Only about 1- 2% of the circulating oestradiol is present as f ree steroid, 40-45% is bound to SHBG. The apparent volume of distribution of oestradiol af ter single intravenous administration is about 1 l/kg.

•    Biotransf ormation

Oestradiol is rapidly metabolized, and besides oestrone and oestrone sulphate, a large number of other metabolites and conjugates are f ormed. Oestrone and oestriol are known as pharmacologically active metabolites of oestradiol; only oestrone occurs in relevant concentrations in plasma. Oestrone reaches about 6-fold higher serum levels than oestradiol.
The serum levels of the oestrone conjugates are about 26-times higher than the corresponding concentrations of f ree oestrone.

•     Elimination

The metabolic clearance has been f ound to be about 30 ml/min/kg. The metabolites of oestradiol are excreted via urine and bile with a half -lif e of about 1 day.

•    Steady-state conditions and linearity

Following daily oral administration of Angeliq, oestradiol concentrations reached a steady-state af ter about five days. Serum oestradiol levels accumulate approx. 2-f old. Orally administered oestradiol induces the formation of SHBG which influences the distribution with respect to the serum proteins, causing an increase of the SHBG-bound f raction and a decrease in the albumin-bound and unbound f raction indicating non-linearity of the pharmacokinetics of oestradiol after ingestion of Angeliq. With a dosing interval of 24 hours, mean steady-state serum levels of oestradiol f luctuate in the range of 20-43 pg/ml f ollowing administration of Angeliq. Pharmacokinetics of oestradiol are dose-proportional at doses of 1 and 2 mg.


Special populations
•       Hepatic impairment

The pharmacokinetics of a single oral dose of 3 mg DRSP in combination with 1 mg oestradiol (E2) was evaluated in 10 f emale patients with moderate hepatic impairment (Child Pugh B) and 10 healthy f emale subjects matched for age, weight, and smoking history. Mean serum DRSP concentration-time profiles were comparable in both groups of women during the absorption/ distribution phases with similar Cmax and tmax values, suggesting that the rate of absorption was not affected by the hepatic impairment. The mean terminal half -lif e was about 1.8-times greater and an about 50% decrease in apparent oral clearance (CL/f ) was seen in volunteers with moderate hepatic impairment as compared to those with normal liver f unction.

•       Renal Impairment

The ef f ect of renal insufficiency on the pharmacokinetics of DRSP (3 mg daily f or 14 days) were investigated in female subjects with normal renal f unction and mild and moderate renal impairment. At steady-state of DRSP treatment, serum DRSP levels in the group with mild renal impairment (creatinine clearance CLcr, 50-80 ml/min) were comparable to those in the group with normal renal f unction (CLcr, > 80 ml/min). The serum DRSP levels were on average 37% higher in the group with moderate renal impairment (CLcr, 30-50 ml/min) compared to those in the group with normal renal f unction. Linear regression analysis of the DRSP AUC (0- 24 hours) values in relation to the creatinine clearance revealed a 3.5% increase with a 10 ml/min reduction of creatinine clearance. This slight increase is not expected to be of clinical relevance.