Testim (Testosterone) - Description and Clinical Pharmacology

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DESCRIPTION

Testim^® (testosterone gel) is a clear to translucent hydroalcoholic topical gel containing testosterone, an androgen.  Testim provides continuous transdermal delivery of testosterone for 24 hours, following a single application to intact, clean, dry skin of the shoulders and/or upper arms.

One 5-g or two 5-g tubes of Testim contains 50 mg or 100 mg of testosterone, respectively, to be applied daily to the skin’s surface.  Approximately 10% of the applied testosterone dose is absorbed across skin of average permeability during a 24-hour period.

The active pharmacological ingredient in Testim is testosterone. Testosterone USP is a white to practically white crystalline powder chemically described as 17-β hydroxyandrost-4-en-3-one. The structural formula is shown in the following figure:

Inactive ingredients in Testim are purified water, pentadecalactone, carbopol, acrylates, propylene glycol, glycerin, polyethylene glycol, ethanol (74%), and tromethamine.

CLINICAL PHARMACOLOGY

Mechanism of Action

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 cord thickening; and 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. Signs/symptoms associated with male hypogonadism include erectile dysfunction and decreased sexual desire, fatigue and loss of energy, mood depression, regression of secondary sexual characteristics and osteoporosis.

Male hypogonadism can present as primary hypogonadism caused by defects of the gonads, such as Klinefelter's Syndrome or Leydig cell aplasia, while secondary hypogonadism (hypogonadotropic hypogonadism) is the failure of the hypothalamus or pituitary to produce sufficient gonadotropins (FSH, LH).

Pharmacodynamics

No specific pharmacodynamic studies were conducted using Testim.

Pharmacokinetics

Absorption

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

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.

Distribution

Circulating testosterone is primarily bound in the serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is loosely bound to albumin and other proteins.

Metabolism

Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are estradiol and DHT. 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.

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

Excretion

There is considerable variation in the half-life of testosterone concentration as reported in the literature, ranging from 10 to 100 minutes. About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic acid 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.

Potential for Testosterone Transfer from Male Patients to Female Partners

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, 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 6 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, serum testosterone concentrations in female partners increased from baseline by approximately 3 times.

In the second trial, 24 couples were evenly randomized to four groups. Testim 100 mg was applied to the male upper 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.  

Effect of showering

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 decrease testosterone concentrations; however, when washing occurred two or more hours post drug application, serum testosterone concentrations remained within the normal range.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Testosterone has been tested by subcutaneous injection and implantation in mice and rats.  In mice, the implant induced cervical-uterine tumors, which metastasized in some cases.  There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma.  Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.

Mutagenesis

Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays.

Impairment of Fertility

The administration of exogenous testosterone has been reported to suppress spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment.

CLINICAL STUDIES

Clinical Trials in Adult Hypogonadal Males

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 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 concentration within the normal range (300 to 1,000 ng/dL) on treatment Day 90.

Table 2 summarizes the mean testosterone concentrations on Day 30 for patients receiving Testim 50 mg or 100 mg.

Table 2:  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 3 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 3:  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.