Androgel Mechanism of Action

Pharmacotherapeutic class: Androgens. ATC Code: G03B A03.
Pharmacology: Pharmacodynamics: Endogenous androgens, mainly testosterone, secreted by the testes and its main metabolite, DHT, are responsible for the development of external and internal genital organs and for the maintenance of secondary sexual characteristics (hair growth, deepening of the voice, development of libido). Androgens also have an effect on protein anabolism, development of skeletal muscle and body fat distribution, and also reduce urinary excretion of nitrogen, sodium, potassium, chlorides, phosphorus, and water.
Testosterone reduces pituitary gland secretion of gonadotropins.
The effects of testosterone on some target organs occur only after conversion at the peripheral level of the testosterone to estradiol, which then binds to the target cell oestrogen nuclear receptors, for example, in the pituitary gland, the adipose tissue, the brain, the bone, and the Leydig cells in the testicle.
Pharmacokinetics: The percutaneous absorption of testosterone after administration of ANDROGEL 16.2 mg/g, gel varies between 1% and 8.5%. After percutaneous through the skin, testosterone diffuses into the general circulation at relatively constant levels during a diurnal cycle.
Blood testosterone concentration increases from the first hour after application to reach a steady state from the second day. The daily changes in testosterone levels are then similar in amplitude to those observed during the circadian rhythm of the endogenous testosterone. The percutaneous route thus avoids the blood distribution peaks induced by injections. It does not cause any supraphysiological hepatic concentrations of the steroid, unlike oral androgen therapy.
The administration of 5 g of ANDROGEL 16.2 mg/g, gel produces a mean increase in plasma testosterone levels of approximately 2.3 ng/mL (8.0 nmol/L).
When treatment is stopped, testosterone levels start decreasing about 24 hours after the last administration. Levels return to baseline within approximately 72 to 96 hours of the last administration.
The main active metabolites of testosterone are dihydrotestosterone and oestradiol.
Testosterone is primarily excreted in the urine as conjugated metabolites, with a small amount being excreted unchanged in the faeces.
In the phase III double-blind study, at the end of a 112-day treatment period, during which the dose of ANDROGEL 16.2 mg/g gel could be determined based on total testosterone concentrations, 81.6% (CI 75.1-87.0%) of men had total testosterone concentration in the normal range of young eugonadal men (300-1,000 ng/dL). In patients taking a daily dose of ANDROGEL 16.2 mg/g, gel, the mean (±SD) daily testosterone concentration on Day 112 (Cav) was 561 (±259) ng/dL, mean Cmax was 845 (±480) ng/dL, and mean Cmin was 334 (±155) ng/dL. The corresponding concentrations at Day 182 (double-blind period) were Cav 536 (±236) ng/dL, mean Cmax 810 (±497) ng/dL, and mean Cmin 330 (±147) ng/dL.
In the phase III open-label study, at the end of a 264-day treatment period, during which the dose of ANDROGEL 16.2 mg/g gel could be determined based on total testosterone concentrations, 77% (CI 69.8-83.2%) of men had total testosterone concentration in the normal range of young eugonadal men (300-1,000 ng/dL).
In patients taking a daily dose of ANDROGEL 16.2 mg/g, gel, the mean (±SD) daily testosterone concentration on Day 266 (Cav) was 459 (±218) ng/dL, mean Cmax was 689 (±414) ng/dL, and mean Cmin was 305 (±121) ng/dL. The corresponding concentrations on Day 364 (open-label period extension) were Cav 454 (±193) ng/dL, mean Cmax 698 (±382) ng/dL, and mean Cmin 302 (±126) ng/dL.
Toxicology: Pre-clinical safety data: Testosterone was found to be non-mutagenic in vitro, based on the model for reverse mutations (Ames test) or for hamster ovary cells. In studies in laboratory animals, a link was found between treatment with androgens and certain cancers. Experimental data in rats showed an increased incidence of prostate cancer after testosterone treatment.
Sex hormones are known to facilitate the development of certain tumours induced by known carcinogens. The importance of these findings and the real risk to humans is unclear.
It has been reported that the administration of exogenous testosterone suppressed spermatogenesis in rats, dogs and non-human primates, which was reversible upon discontinuation of treatment.