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Testosterone (Testosterone Cypionate) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Testosterone gel is a clear, colorless hydroalcoholic gel containing testosterone.

The active pharmacologic ingredient in testosterone gel is testosterone, an androgen. Testosterone USP is a white to practically white crystalline powder chemically described as 17-beta hydroxyandrost-4-en-3-one. The structural formula is:

Inactive ingredients in testosterone gel are carbomer 980, ethanol 67.0%, isostearic acid, purified water, and sodium hydroxide. These ingredients are not pharmacologically active.

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 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. 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 is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

Pharmacodynamics

No specific pharmacodynamic studies were conducted using testosterone gel.

Pharmacokinetics

Absorption

In a single-dose, crossover clinical study conducted in 24 hypogonadal males under fasting conditions, the serum testosterone exposure (AUC0-72) and maximum testosterone concentration (Cmax) 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.

Figure 2: Mean (± SD) Steady-State Serum Testosterone Concentrations on Day 30 in Patients Applying Testosterone Gel Once Daily

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 AUC0-24 and Cmax 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 AUC0-24 and Cmax, 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.

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

Testosterone gel was evaluated in a multi-center, 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 to 90), 73 patients were randomized to testosterone gel 50 mg daily, 78 patients to testosterone gel 100 mg daily, and 76 patients to a non-scrotal testosterone transdermal system. The study was double-blind for dose of testosterone gel but open-label for active control. Patients who were originally randomized to testosterone gel and who had single-sample serum testosterone levels above or below the normal range on Day 60 were titrated to 75 mg daily on Day 91. During the Extended Treatment Period (Days 91 to 180), 51 patients continued on testosterone gel 50 mg daily, 52 patients continued on testosterone gel 100 mg daily, 41 patients continued on a non-scrotal testosterone transdermal system (5 mg daily), and 40 patients received testosterone gel 75 mg daily. Upon completion of the initial study, 163 enrolled and 162 patients received treatment in an open-label extension study of testosterone gel for an additional period of up to 3 years.

Mean peak, trough and average serum testosterone concentrations within the normal range (298 to 1043 ng/dL) were achieved on the first day of treatment with doses of 50 mg and 100 mg of testosterone gel. In patients continuing on testosterone gel 50 mg and 100 mg, these mean testosterone levels were maintained within the normal range for the 180-day duration of the original study.

Figure 3 summarizes the 24 hour pharmacokinetic profiles of testosterone administered as testosterone gel for 30, 90 and 180 days. Testosterone concentrations were maintained as long as the patient continued to properly apply the prescribed testosterone gel treatment.

Figure 3: Mean Steady-State Testosterone Concentrations in Patients with Once-Daily Testosterone Gel Therapy

Table 5 summarizes the mean testosterone concentrations on Treatment Day 180 for patients receiving 50 mg, 75 mg, or 100 mg, of testosterone. The 75 mg dose produced mean concentrations intermediate to those produced by 50 mg and 100 mg of testosterone.

Table 5: Mean (± SD) Steady-State Serum Testosterone Concentrations During Therapy (Day 180)

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

In patients treated with testosterone gel, there were no observed differences in the average daily serum testosterone concentrations at steady-state based on age, cause of hypogonadism, or body mass index.

Skin Irritation Study

Testosterone gel was evaluated in a randomized, five-treatment, single-center, controlled, within-subject comparison study with healthy subjects using a cumulative irritation patch test design. Thirty-three (33) subjects completed the study involving testosterone gel, a comparator control product, vehicle, and positive and negative controls. All five treatments were applied to the skin separately with an occlusive patch. Each subject received a set of 5 patches, once daily for 21 consecutive days. Evaluation of dermal reactions at the application sites were assessed every day at the time of removal of each patch using an established ordinal (6-point) scoring system. Testosterone gel showed no evidence of significant irritation and was statistically significantly less irritating than the positive control (P<0.001).

Skin Sensitization Study

Testosterone gel was evaluated in a randomized, five-treatment, single-center, controlled, within-subject study to evaluate the sensitizing potential on healthy volunteers, using a Repeat Insult Patch Test design. Two hundred three (203) subjects completed the study involving Testosterone Gel, a comparator control product, vehicle, and positive and negative controls. All five treatments were applied to the skin separately with an occlusive patch. Each subject received a set of 5 patches, every 48-72 hours for 21 consecutive days. Evaluation of dermal reactions at the application sites were assessed clinically every day at the time of removal of each patch using an established ordinal (6-point) scoring system. Observations at the naïve site during challenge and the pattern of reactivity during induction provided bases for an interpretation of contact sensitizations. Under these conditions there was no evidence of sensitization to testosterone gel, In the cumulative irritancy analysis, testosterone gel was statistically significantly less irritating than the positive control (P<0.001).

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