Androgel Pharmacology, Pharmacokinetics, Studies, Metabolism - Testosterone Gel

Androgel Pharmacology, Pharmacokinetics, Studies, Metabolism - Testosterone Gel

CLINICAL PHARMACOLOGY

AndroGel® (testosterone gel) delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate normal levels (298 – 1043 ng/dL) seen in healthy men.

General Androgen Effects: Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal chord thickening, alterations in body musculature, and fat distribution. Testosterone and DHT are necessary for the normal development of secondary sex characteristics. Male hypogonadism results from insufficient secretion of testosterone and is characterized by low serum testosterone concentrations. Symptoms associated with male hypogonadism include impotence and decreased sexual desire, fatigue and loss of energy, mood depression, regression of secondary sexual characteristics and osteoporosis. Hypogonadism is a risk factor for osteoporosis in men.

Drugs in the androgen class also promote retention of nitrogen, sodium, potassium, phosphorus, and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein.

Androgens are responsible for the growth spurt of adolescence and for the eventual termination of linear growth brought about by fusion of the epiphyseal growth centers. In children, exogenous androgens accelerate linear growth rates but may cause a disproportionate advancement in bone maturation. Use over long periods may result in fusion of the epiphyseal growth centers and termination of the growth process. Androgens have been reported to stimulate the production of red blood cells by enhancing erythropoietin production.

During exogenous administration of androgens, endogenous testosterone release may be inhibited through feedback inhibition of pituitary luteinizing hormone (LH). At large doses of exogenous androgens, spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH).

There is a lack of substantial evidence that androgens are effective in accelerating fracture healing or in shortening postsurgical convalescence.

Absorption: AndroGel® is a hydroalcoholic formulation that dries quickly when applied to the skin surface. The skin serves as a reservoir for the sustained release of testosterone into the systemic circulation. Approximately 10% of the testosterone dose applied on the skin surface from AndroGel® is absorbed into systemic circulation. Therefore, 5 g and 10 g of AndroGel® systemically delivers approximately 5 mg and 10 mg of testosterone, respectively. In a study with 10 g of AndroGel®, all patients showed an increase in serum testosterone within 30 minutes, and eight of nine patients had a serum testosterone concentration within normal range by 4 hours after the initial application. Absorption of testosterone into the blood continues for the entire 24-hour dosing interval. Serum concentrations approximate the steady-state level by the end of the first 24 hours and are at steady state by the second or third day of dosing.

With single daily applications of AndroGel®, follow-up measurements 30, 90 and 180 days after starting treatment have confirmed that serum testosterone concentrations are generally maintained within the eugonadal range. Figure 1 summarizes the 24-hour pharmacokinetic profiles of testosterone for patients maintained on 5 g or 10 g of AndroGel® for 30 days. The average (± SD) daily testosterone concentration produced by AndroGel® 10 g on Day 30 was 792 (± 294) ng/dL and by AndroGel® 5 g 566 (± 262) ng/dL.

FIGURE 1: Mean (± SD) Steady-State Serum Testosterone Concentrations on Day 30 in Patients Applying AndroGel® Once Daily

When AndroGel® treatment is discontinued after achieving steady state, serum testosterone levels remain in the normal range for 24 to 48 hours but return to their pretreatment levels by the fifth day after the last application.

Distribution: Circulating testosterone is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin. The albumin-bound fraction of testosterone easily dissociates from albumin and is presumed to be bioactive. The portion of testosterone bound to SHBG is not considered biologically active. The amount of SHBG in the serum and the total testosterone level will determine the distribution of bioactive and nonbioactive androgen. SHBG-binding capacity is high in prepubertal children, declines during puberty and adulthood, and increases again during the later decades of life. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins.

Metabolism: There is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes. Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are estradiol and DHT. DHT binds with greater affinity to SHBG than does testosterone. In many tissues, the activity of testosterone depends on its reduction to DHT, which binds to cytosol receptor proteins. The steroid-receptor complex is transported to the nucleus where it initiates transcription and cellular changes related to androgen action. In reproductive tissues, DHT is further metabolized to 3-α and 3-β androstanediol.

DHT concentrations increased in parallel with testosterone concentrations during AndroGel® treatment. After 180 days of treatment, mean DHT concentrations were within the normal range with 5 g AndroGel® and were about 7% above the normal range after a 10 g dose. The mean steady-state DHT/T ratio during 180 days of AndroGel® treatment remained within normal limits (as determined by the analytical laboratory involved with this clinical trial) and ranged from 0.23 to 0.29 (5 g/day) and from 0.27 to 0.33 (10 g/day).

Excretion: About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.

Special Populations: In patients treated with AndroGel®, there are no observed differences in the average daily serum testosterone concentration at steady state based on age, cause of hypogonadism or body mass index. No formal studies were conducted involving patients with renal or hepatic insufficiencies.

AndroGel® 1% was evaluated in a multicenter, randomized, parallel-group, active-controlled, 180-day trial in 227 hypogonadal men. The study was conducted in 2 phases. During the Initial Treatment Period (Days 1-90), 73 patients were randomized to AndroGel® 5 g daily, 78 patients to AndroGel® 10 g daily, and 76 patients to a non-scrotal testosterone transdermal system. The study was double-blind for dose of AndroGel® but open-label for active control. Patients who were originally randomized to AndroGel® and who had single-sample serum testosterone levels above or below the normal range on Day 60 were titrated to 7.5 g daily on Day 91. During the Extended Treatment Period (Days 91-180), 51 patients continued on AndroGel® 5 g daily, 52 patients continued on AndroGel® 10 g daily, 41 patients continued on a non-scrotal testosterone transdermal system (5 mg daily), and 40 patients received AndroGel® 7.5 g daily.

Mean peak, trough and average serum testosterone concentrations within the normal range (298-1043 ng/dL) were achieved on the first day of treatment with doses of 5 g and 10 g. In patients continuing on AndroGel® 5 g and 10 g, these mean testosterone levels were maintained within the normal range for the 180-day duration of the study. Figure 2 summarizes the 24-hour pharmacokinetic profiles of testosterone administered as AndroGel® for 30, 90 and 180 days. Testosterone concentrations were maintained as long as the patient continued to properly apply the prescribed AndroGel® treatment.

Table 1 summarizes the mean testosterone concentrations on Treatment Day 180 for patients receiving 5 g, 7.5 g, or 10 g of AndroGel®. The 7.5 g dose produced mean concentrations intermediate to those produced by 5 g and 10 g of AndroGel®.

Of 129 hypogonadal men who were appropriately titrated with AndroGel® and who had sufficient data for analysis, 87% achieved an average serum testosterone level within the normal range on Treatment Day 180.

AndroGel® 5 g/day and 10 g/day resulted in significant increases over time in total body mass and total body lean mass, while total body fat mass and the percent body fat decreased significantly. These changes were maintained for 180 days of treatment. Changes in the 7.5 g dose group were similar. Bone mineral density in both hip and spine increased significantly from Baseline to Day 180 with 10 g AndroGel®.

AndroGel® treatment at 5 g/day and 10 g/day for 90 days produced significant improvement in libido (measured by sexual motivation, sexual activity and enjoyment of sexual activity as assessed by patient responses to a questionnaire). The degree of penile erection as subjectively estimated by the patients, increased with AndroGel® treatment, as did the subjective score for "satisfactory duration of erection." AndroGel® treatment at 5 g/day and 10 g/day produced positive effects on mood and fatigue. Similar changes were seen after 180 days of treatment and in the group treated with the 7.5 g dose. DHT concentrations increased in parallel with testosterone concentrations at AndroGel® doses of 5 g/day and 10 g/day, but the DHT/T ratio stayed within the normal range, indicating enhanced availability of the major physiologically active androgen. Serum estradiol (E2) concentrations increased significantly within 30 days of starting treatment with AndroGel® 5 or 10 g/day and remained elevated throughout the treatment period but remained within the normal range for eugonadal men. Serum levels of SHBG decreased very slightly (1 to 11%) during AndroGel® treatment. In men with hypergonadotropic hypogonadism, serum levels of LH and FSH fell in a dose- and time-dependent manner during treatment with AndroGel®.

Potential for Testosterone Transfer: The potential for dermal testosterone transfer following AndroGel® use was evaluated in a clinical study between males dosed with AndroGel® and their untreated female partners. Two to 12 hours after AndroGel® (10 g) application by the male subjects, the couples (N=38 couples) engaged in daily, 15-minute sessions of vigorous skin-to-skin contact so that the female partners gained maximum exposure to the AndroGel® application sites. Under these study conditions, all unprotected female partners had a serum testosterone concentration > 2 times the baseline value at some time during the study. When a shirt covered the application site(s), the transfer of testosterone from the males to the female partners was completely prevented.