Absorption

In a single-dose, crossover clinical study conducted in 24 hypogonadal males under fasting conditions, the serum testosterone exposure (AUC 0-72) and maximum testosterone concentration (C max) following a topical administration of 100 mg testosterone administered as 2 x 5 g testosterone gel packets (2 packets applied to the shoulder/upper arm) were bioequivalent to those following a topical administration of an approved testosterone gel product. 

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

Testosterone gel provides continuous transdermal delivery of testosterone for 24 hours following a single application to intact, clean, dry skin of the shoulders, upper arms and/or abdomen.

Testosterone gel 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 testosterone gel is absorbed into systemic circulation. In a study with testosterone gel 100 mg, 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 concentration 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 testosterone gel, 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 2 summarizes the 24-hour pharmacokinetic profiles of testosterone for hypogonadal men (< 300 ng/dL) maintained on testosterone gel 50 mg or 100 mg for 30 days. The average (± SD) daily testosterone concentration produced by 100 mg on Day 30 was 792 (± 294) ng/dL and by testosterone gel 50 mg was 566 (± 262) 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 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.

DHT concentrations increased in parallel with testosterone concentrations during testosterone gel treatment. The mean steady-state DHT/T ratio during 180 days of testosterone gel treatment remained within normal limits and ranged from 0.23 to 0.29 (5 g/day) and from 0.27 to 0.33 (10 g/day).

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 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.

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

Testosterone Transfer from Male Patients to Female Partners

The potential for dermal testosterone transfer following testosterone gel use was evaluated in a clinical study between males dosed with testosterone gel and their untreated female partners. Two (2) hours after application of 100 mg of testosterone from 10 g (2 x 5 g packets) of testosterone gel to upper arm and shoulder of one side by the male subjects, the couples (N = 20 couples) engaged in a 15 minute session of vigorous skin-to-skin contact so that the female partners gained maximum exposure to the testosterone gel application sites. Serum concentrations of testosterone were monitored in the female subjects for 24 hours after the transfer procedure. Under these study conditions, unprotected female partners had a mean testosterone AUC 0-24 and C max that were more than 2 times greater than their mean baseline values. When a shirt covered the application site, study results showed a 16% and 48% increase in testosterone AUC 0-24 and C max, respectively, compared to baseline in these females. The potential for dermal testosterone transfer following testosterone gel application on the abdomen has not been evaluated. 

Effect of Hand Washing and Showering

In a separate clinical study conducted to evaluate the effect of hand washing on the residual amount of testosterone, 33 healthy male subjects received 100 mg of testosterone from 10 g (2 x 5 g packets) of testosterone gel on a hand and applied testosterone gel to the upper arm and shoulder of one side. Subjects washed their hands with liquid soap and warm tap water immediately after drug application. Then the hand was wiped with 3 ethanol dampened gauzes which were then combined together and analyzed for testosterone content. A mean (SD) of 0.40 (0.20) mg of residual testosterone (i.e., approximately 0.4% of the theoretical dose of 100 mg testosterone administered) was recovered after washing hands with liquid soap and warm tap water.

The same study also evaluated the effect of showering on the residual amount of testosterone on the application site. Subjects washed the application site by showering two hours after drug application. The application site was then wiped with 3 ethanol dampened gauzes which were then combined together and analyzed for testosterone content. A mean (SD) of 5.80 (2.77) mg of residual testosterone (i.e., approximately 5.8% of the theoretical dose of 100 mg testosterone administered) was recovered after showering.