Testim (Testosterone) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

Testim^® 1% (testosterone gel) delivers physiologic amounts of testosterone, producing circulating testosterone levels that approximate normal levels (e.g., 300 - 1000 ng/dL) seen in healthy men.

Testosterone - General Androgen Effects

Testosterone and dihydrotestosterone (DHT), endogenous androgens, are responsible for normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement; vocal cord thickening; alterations in body musculature; and fat distribution.

Male hypogonadism results from insufficient secretion of testosterone and is characterized by low serum testosterone concentrations. Symptoms associated with male hypogonadism include decreased sexual desire with or without impotence, 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 have been reported to stimulate the production of red blood cells by enhancing erythropoietin production.

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.

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 post-surgical convalescence.

Pharmacokinetics

The pharmacokinetics of Testim^® have been evaluated with administration of doses containing 50 mg and 100 mg of testosterone to adult males with morning testosterone levels ≤300 ng/dL.

Absorption

Testim^® is a topical 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 applied on the skin surface is absorbed into the systemic circulation during a 24-hour period.

Single Dose

In single dose studies, when either Testim^® 50 mg or 100 mg was administered, absorption of testosterone into the blood continued for the entire 24 hour dosing period. Also, mean peak and average serum concentrations within the normal range were achieved within 24 hours.

Multiple Dose

With single daily applications of Testim^® 50 mg and 100 mg, follow-up measurements at 30 and 90 days after starting treatment have confirmed that serum testosterone and DHT concentrations are generally maintained within the normal range.

Figure 1 summarizes the 24-hour pharmacokinetic profile of testosterone for patients maintained on Testim® 50 mg or Testim® 100 mg for 30 days.

Figure 1

Mean Steady-State Serum Testosterone (±SD) (ng/dL) Concentrations on Day 30 in Patients Applying Testim® Once Daily

The average daily testosterone concentration produced by Testim^® 100 mg at Day 30 was 612 (± 286) ng/dL and by Testim^® 50 mg at Day 30 was 365 (± 187) ng/dL.

Figure 2 summarizes the 24-hour pharmacokinetic profile of DHT for patients maintained on Testim^® 50 mg or Testim^® 100 mg for 30 days.

Figure 2

Mean Steady-State Serum Dihydrotestosterone (±SD) (pg/mL) Concentrations on Day 30 in Patients Applying Testim® Once Daily

The average daily DHT concentration produced by Testim^® 100 mg at Day 30 was 555 (± 293) pg/mL and by Testim^® 50 mg at Day 30 was 346 (± 212) pg/mL.

Washing

The effect of showering (with mild soap) at 1, 2 and 6 hours post application of Testim^® 100 mg was evaluated in a clinical trial in 12 men. The study demonstrated that the overall effect of washing was to lessen testosterone levels; however, when washing occurred two or more hours post drug application, serum testosterone levels remained within the normal range.

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. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins. The amount of SHBG in the serum and the total testosterone level will determine the distribution of bioactive and nonbioactive androgen.

Metabolism

There is considerable variation in the half-life of testosterone as reported in the literature, ranging from ten 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. Testosterone is metabolized to DHT by steroid 5α-reductase located in the skin, liver, and the urogenital tract of the male. 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 3α and 3β androstanediol. Inactivation of testosterone occurs primarily in the liver.

DHT concentrations increased in parallel with testosterone concentrations during Testim^® treatment. After 90 days of treatment, mean DHT concentrations remained generally within the normal range for Testim^®-treated subjects.

Excretion

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

Special Population

In patients treated with Testim^® there are no observed differences in the average daily serum testosterone concentration at steady-state based on age or cause of hypogonadism. No formal studies were conducted in a pediatric age population or in patients with renal or hepatic insufficiencies.

Clinical Studies

Testim^® was evaluated in a randomized multicenter, multi-dose, active and placebo controlled 90-day study in 406 adult males with morning testosterone levels ≤300 ng/dL. The study was double-blind for the doses of Testim^® and placebo, but open label for the non-scrotal testosterone transdermal system. During the first 60 days, patients were evenly randomized to Testim^® 50 mg, Testim^® 100 mg, placebo gel, or testosterone transdermal system. At Day 60, patients receiving Testim^® were maintained at the same dose, or were titrated up or down within their treatment group, based on 24-hour averaged serum testosterone concentration levels obtained on Day 30.

Of 192 hypogonadal men who were appropriately titrated with Testim^® and who had sufficient data for analysis, 74% achieved an average serum testosterone level within the normal range on treatment Day 90.

Table 1 summarizes the mean testosterone concentrations on Day 30 for patients receiving Testim^® 50 mg or 100 mg.

Table 1: Mean (± SD) Steady-State Serum Testosterone Concentrations on Day 30

	Testim® 50 mg n=94	Testim® 100 mg n=95	Placebo n=93
Cavg (ng/dL)	365 ± 187	612 ± 286	216 ± 79
Cmax (ng/dL)	538 ± 371	897 ± 565	271 ± 110
Cmin (ng/dL)	223 ± 126	394 ±189	164 ± 64

At Day 30, patients receiving Testim^® 100 mg daily showed significant improvement from baseline in multiple sexual function parameters as measured by patient questionnaires when compared to placebo. These parameters included sexual motivation, sexual desire, sexual activity and spontaneous erections. For Testim^® 100 mg, improvements in sexual motivation, spontaneous erections, and sexual desire were maintained through Day 90. Sexual enjoyment and satisfaction with erection duration were improved compared to baseline but these improvements were not significant compared to the placebo group.

In Testim^®-treated patients, the number of days in which sexual activity was reported to occur increased by 123% from baseline at Day 30 and was still increased from baseline by 59% at Day 90. The number of days with spontaneous erections increased by 137% at Day 30 and was maintained at 78% at Day 90 for Testim^®-treated patients compared to baseline.

Table 2 summarizes the changes in body composition at Day 90 for patients receiving Testim^® 50 mg or 100 mg as measured by standardized whole body DEXA (Dual Energy X-ray Absorptiometry) scanning.

Table 2: Effect of Testim® on Lean Body Mass, Total Fat Mass and % Body Fat

Days of Treatment	Lean Body Mass (Muscle) (kg)	Total Fat Mass(kg)	% Body Fat
Baseline	61.6	29.4	30.9
Day 90	63.3	28.6	29.8
Change from Baseline	↑1.6	↓0.8	↓1.1

At Day 90, mean increases from baseline in lean body mass and mean decreases from baseline in total fat mass and percent body fat in Testim^®-treated patients were significant when compared to placebo-treated patients.

Potential for Testosterone Transfer

The potential for dermal testosterone transfer following Testim^® use was evaluated in two clinical trials with males dosed with Testim^® and their untreated female partners.

In the first trial (AUX-TG-206), 30 couples were evenly randomized to five groups. In the first four groups, 100 mg of Testim^® was applied to the male abdomen and the couples were then asked to rub abdomen-to-abdomen for 15 minutes at 1 hour, 4 hours, 8 hours or 12 hours after dose application, respectively. In these couples, serum testosterone concentrations in female partners increased from baseline by at least 4 times and potential for transfer was seen at all timepoints.

When 6 males used a shirt to cover the abdomen at 15 minutes post-application and partners again rubbed abdomens for 15 minutes at the 1 hour timepoint, the potential for transfer was markedly reduced.

In the second trial (AUX-TG-209), 24 couples were evenly randomized to four groups. Testim^® 100 mg was applied to the male arms and shoulders. In one group, 15 minutes of direct skin-to-skin rubbing began at 4 hours after application. In these six women, all of whom showered immediately after the rubbing activity, mean maximum serum testosterone concentrations increased from baseline by approximately 4 times. When males wore a long-sleeved T-shirt and rubbing was started at 1 and at 4 hours after application, the transfer of testosterone from male to female partners was prevented.