Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1      Pharmacodynamic properties
Pharmacotherapeutic group: urogenital system (including sex hormones), ATC code: G03CX01
Mechanism of action and pharmacodynamic effects
Following oral administration, tibolone is rapidly metabolised into three compounds, which all contribute to the pharmacodynamic profile of Livial. Two of the metabolites (3-OH- tibolone and 3β-OH-tibolone) have oestrogenic-like activities, whereas the third metabolite (4-isomer of tibolone) has progestogenic and androgenic-like activities.
Livial substitutes for the loss of oestrogen production in postmenopausal women and alleviates menopausal symptoms. Livial prevents bone loss following menopause or ovariectomy.
Clinical efficacy and safety
•       Relief of oestrogen-deficiency symptoms - Relief of menopausal symptoms generally occurs during the first few weeks of treatment.
•       Effects on the endometrium and bleeding patterns
-   There have been reports of endometrial hyperplasia and endometrial cancer in patients treated with Livial (see section 4.4 and 4.8).
-   Amenorrhea has been reported in 88% of women using Livial 2.5 mg after 12 months of treatment. Breakthrough bleeding and/or spotting has been reported in 32.6% of women during the first 3 months of treatment, and in 11.6% of women after 11-12 months of use.
•     Prevention of osteoporosis −       Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.
−       In the LIFT study, Livial reduced the number of women (mean age 68 years) with new vertebral fractures compared to placebo during the 3 years of treatment (ITT: Livial to placebo odds ratio 0.57; 95% CI [0.42, 0.78]).
−       After 2 years of treatment with Livial (2.5 mg), the increase in lumbar spine bone mineral density (BMD) was 2.6 ± 3.8%. The percentage of women who maintained or gained BMD in lumbar zone during treatment was 76%. A second study confirmed these results.
−     Livial (2.5 mg) also had an effect on hip BMD. In one study, the increase after 2 years was 0.7 ± 3.9% at the femoral neck and 1.7 ± 3.0% at the total hip.
The percentage of women who maintained or gained BMD in the hip region during treatment was 72.5%. A second study showed that the increase after 2 years was 1.3 ± 5.1% at the femoral neck and 2.9 ± 3.4% at the total hip. The percentage of women who maintained or gained BMD in the hip region during treatment was 84.7%.
•     Effects on the breast
−     In clinical studies mammographic density is not increased in women treated with Livial compared to placebo.

Pharmacokinetic Properties

5.2      Pharmacokinetic properties
Absorption and biotransformation
Following oral administration, tibolone is rapidly and extensively absorbed. The consumption of foods has no significant effects on the extent of absorption.
Due to rapid metabolism, the plasma levels of tibolone are very low. The plasma levels of the 4-isomer of tibolone are also very low. Therefore some of the pharmacokinetic parameters could not be determined. Peak plasma levels of the 3-OH and the 3β-OH metabolites are higher but accumulation does not occur.
Table 5                 Pharmacokinetic parameters of Livial (2.5 mg) tibolone        3-OH metabolite   3β-OH metabolite    4-isomer SD          MD         SD       MD       SD        MD      SD      MD 
Cmax (ng/ml)            1.37        1.72      14.23     14.15     3.43     3.75     0.47    0.43 
Caverage                 --              --     --      1.88       --       --       --      -- 
Tmax (h)                1.08        1.19       1.21     1.15      1.37     1.35     1.64    1.65 
T1/2 (h)                 --              --    5.78     7.71      5.87      --       --      -- 
Cmin (ng/ml)             --              --     --      0.23       --       --       --      -- 
AUC0-24 (ng/ml.h)        --              --   53.23     44.73    16.23     9.20      --      -- SD = single dose; MD = multiple dose


Elimination
Excretion of tibolone is mainly in the form of conjugated (mostly sulfated) metabolites.
Part of the administered compound is excreted in the urine, but most is eliminated via the faeces.
Other special populations
The pharmacokinetic parameters for tibolone and its metabolites were found to be independent of renal function.