Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Androgens, 3-oxoandrosten (4) derivatives

ATC code: G03BA03

Testosterone undecanoate is an ester of the naturally occurring androgen, testosterone.
The active form, testosterone, is formed by cleavage of the side chain.
Testosterone is the most important androgen of the male, mainly synthesized in the testicles, and to a small extent in the adrenal cortex.

Testosterone is responsible for the expression of masculine characteristics during foetal, early childhood, and pubertal development and thereafter for maintaining the masculine phenotype and androgen-dependent functions (e.g. spermatogenesis, accessory sexual glands). It also performs functions, e.g. in the skin, muscles, skeleton, kidney, liver, bone marrow, and CNS.

Dependent on the target organ, the spectrum of activities of testosterone is mainly androgenic (e.g. prostate, seminal vesicles, epididymis) or protein-anabolic (muscle, bone, haematopoiesis, kidney, liver).

The effects of testosterone in some organs arise after peripheral conversion of testosterone to oestradiol, which then binds to estrogen receptors in the target cell nucleus e.g. the pituitary, fat, brain, bone, and testicular Leydig cells.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
Nebido is an intramuscularly administered depot preparation of testosterone undecanoate and thus circumvents the first-pass effect. Following intramuscular injection of testosterone undecanoate as an oily solution, the compound is gradually released from the depot and is almost completely cleaved by serum esterases into testosterone and undecanoic acid. An increase in serum levels of testosterone above basal values may be seen one day after administration.

Steady-state conditions

After the 1st intramuscular injection of 1000 mg testosterone undecanoate to hypogonadal men, mean Cmax values of 38 nmol/L (11 ng/mL) were obtained after 7 days. The second dose was administered 6 weeks after the 1st injection and maximum testosterone concentrations of about 50 nmol/L (15 ng/mL) were reached. A constant dosing interval of 10 weeks was maintained during the following 3 administrations and steady-state conditions were achieved between the 3rd and the 5th administration. Mean Cmax and Cmin values of testosterone at steady-state were about 37 (11 ng/mL) and 16 nmol/L (5 ng/mL), respectively. The median intra- and inter-individual variability (coefficient of variation, %) of Cmin values was 22 % (range: 9-28%) and 34% (range: 25-48%), respectively.

Distribution

In serum of men, about 98% of the circulating testosterone is bound to sex hormone binding globulin (SHBG) and albumin. Only the free fraction of testosterone is considered as biologically active. Following intravenous infusion of testosterone to elderly men, the elimination half-life of testosterone was approximately one hour and an apparent volume of distribution of about 1.0 l/kg was determined.

Biotransformation

Testosterone which is generated by ester cleavage from testosterone undecanoate is metabolized and excreted the same way as endogenous testosterone. The undecanoic acid is metabolized by ß-oxidation in the same way as other aliphatic carboxylic acids. The major active metabolites of testosterone are oestradiol and dihydrotestosterone.

Elimination

Testosterone undergoes extensive hepatic and extrahepatic metabolism. After the administration of radio-labelled testosterone, about 90% of the radioactivity appears in the urine as glucuronic and sulphuric acid conjugates and 6% appears in the faeces after undergoing enterohepatic circulation. Urinary medicinal products include androsterone and etiocholanolone.
Following intramuscular administration of this depot formulation the release rate is characterised by a half life of 90±40 days.