Androderm - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Androderm - Scientific Information

Manufacture: Actavis
Country: Canada
Condition: Hypogonadism, Male
Class: Androgens and anabolic steroids
Form: Skin patch (transdermal)
Ingredients: Testosterone, Alcohol, Carbomer, Glycerin, Glycerol Monooleate, Methyl Laurate, Purified Water And Sodium Hydroxide

Pharmaceutical information

Drug Substance

Proper name:Testosterone
Chemical name:Androst-4-en-3-one, 17-hydroxy, (17ß)-17ß-Hydroxyandrost-4-en-3-one
Molecular formula and molecular mass:C19H28O2

Structural formula:


Testosterone
Molecular Weight:288.43
Description:Testosterone is a white or creamy white crystalline powder or crystals.
Physicochemical properties:Testosterone has a melting point of 153 - 157oC and gives an optical rotation of +101 - +103o in dioxane. It exhibits strong UV absorption maxima at 238 nm.

When micronized, testosterone is a white or creamy white, crystalline powder. It is odourless, and stable in air. It is only slightly (1%) hygroscopic, soluble in alcohol, acetone, dioxane, chloroform, and other organic solutions. It is practically insoluble in water and only sparingly soluble in vegetable oils.

CAS Registry No: 58-22-0

Clinical trials

Study demographics and trial design

In clinical studies using the Androderm 2.5 mg patch, 93% of patients achieved normal levels of serum testosterone with application of two patches daily, 6% used three daily, and 1% used one patch daily.

The hormonal effects of Androderm as a treatment for male hypogonadism were demonstrated in four open-label trials that included 94 hypogonadal men, ages 15 to 65 years. In these trials, Androderm produced average morning serum testosterone concentrations within the normal reference range in 92% of patients. The mean (SD) serum hormone concentrations and percentage of patients who achieved average concentrations within the normal ranges are shown in Table 1 below.

Table 1: Individual morning serum hormone concentrations (ng/dL) and percent of patients with mean concentrations within the normal range during continuous Androderm treatment (n=94).

TBTDHTE2
Normal
Range*
(306-1031)(93-420)(28-85)(0.9-3.6)
Mean589312472.7
SD209127181.2
% Normal92888577
% High112222
% Low70131

Abbreviations: T = testosterone, BT = bioavailable testosterone,
DHT = dihydrotestosterone, E2 = estradiol
* Lower number is the 2.5 percentile, higher number the 97.5 percentile.
Source: Endocrine Sciences (1991).

A physiological suppression of the pituitary/gonadal axis occurs during continuous Androderm treatment, leading to reduced serum LH concentrations. In clinical trials, 10 out of 21 men (48%) with primary (hypergonadotropic) hypogonadism achieved normal range LH concentrations within 6- 12 months of treatment. LH concentrations may remain elevated in some patients despite serum testosterone concentrations within the normal range.

Comparison with intramuscular testosterone

Sixty-six patients, previously treated with testosterone injections, received Androderm or intramuscular testosterone enanthate (200 mg every 2 weeks) treatment for 6 months. The percent of time that serum concentrations remained within the normal range (throughout the dosing interval) were as follows (Table 2):

Table 2: Comparison of percent of patients receiving Androderm or intramuscular testosterone with serum concentrations within the normal range.

TBTDHTE2
ANDRODERM82%87%76%81%
IM72%39%70%35%
p value0.05< 0.0010.06< 0.001

Sexual function was comparable between groups.

Detailed pharmacology

Following Androderm (testosterone transdermal system) application to non-scrotal skin, testosterone is continuously absorbed during the 24 hour dosing period. Daily application of two, 2.5 mg patches at approximately 10 PM results in a serum testosterone concentration profile which mimics the normal circadian variation observed in healthy young men (Fig. 2 below). Maximum concentrations occur in the early morning hours with minimum concentrations in the evening.

Figure 1: Mean (SD) Serum Testosterone Concentrations


Figure 1: Mean (SD) serum testosterone concentrations during application of Androderm 2.5 mg patches nightly in 29 hypogonadal male patients; 27 patients used 2 patches nightly and 2 patients used 3 patches nightly. Area between dotted lines shows the 95% confidence interval for the circadian variation observed in healthy young men. Patch application (t=0) was at approximately 10 PM.

In a group of 34 hypogonadal men, application of two, Androderm 2.5 mg patches to the back, abdomen, thighs, or upper arms resulted in average testosterone absorption of 4 to 5 mg over 24 hours. Applications to the chest and shins resulted in greater inter- individual variability and average 24 hour absorption of 3 to 4 mg. The serum testosterone concentration profiles during application were similar for all sites.

In a steady-state study of 12 hypogonadal men, nightly application of 1, 2, or 3 Androderm 2.5 mg patches resulted in increases in the mean morning serum testosterone concentrations. These concentrations (including the baseline concentration) averaged 424, 584, and 766 ng/dL with the application of 1, 2 and 3 patches, respectively. The mean baseline serum testosterone concentration was 76 ng/dL.

Normal range morning serum testosterone concentrations are reached during the first day of dosing. There is no accumulation of testosterone during continuous treatment.

In a study of 20 hypogonadal patients, two Androderm 2.5 mg patches and a single Androderm 5 mg patch produced equivalent serum testosterone concentration profiles. Average steady-state concentrations over 24 hours were 613±169 and 621±176 ng/dL for the two, 2.5 mg patches and for the single, 5 mg patch, respectively. Cmax values were 925±340 ng/dL for the two, 2.5 mg patches and 905±254 ng/dL for the single, 5 mg patch.

Upon removal of the Androderm patches, serum testosterone concentrations decrease with an apparent half-life of approximately 70 minutes. Hypogonadal concentrations are reached within 24 hours following patch removal.

Androderm therapy suppresses endogenous testosterone secretion via the pituitary/gonadal axis, resulting in a reduction in baseline serum testosterone concentrations compared to the untreated state.

In serum, testosterone is bound with high affinity to sex hormone binding globulin (SHBG) and with low affinity to albumin. The albumin bound portion easily dissociates and is presumed to be bioactive. The SHBG-bound portion is not considered to be bioactive. The amount of SHBG in serum and the total testosterone concentration determine the distribution of bioactive and non- bioactive androgen.

Bioactive serum testosterone concentrations (BT) measured during Androderm treatment paralleled the serum testosterone profile (Figure 1) and remained within the normal reference range.

Approximately 90% of a testosterone dose given intramuscularly is excreted in the urine as glucuronide and sulfate conjugates of testosterone and its metabolites; about 6% is excreted in the feces, mostly in unconjugated form. Inactivation of testosterone occurs primarily in the liver. Testosterone is metabolized to various 17-keto steroids through two different pathways, and the major active metabolites are estradiol (E2) and dihydrotestosterone (DHT). DHT binds with greater affinity to SHBG than does testosterone. In reproductive tissues, DHT is further metabolized to 3-alpha and 3-beta androstenediol. (See also reference 6)

During steady-state pharmacokinetic studies in 56 hypogonadal men treated with Androderm, DHT:T and E2:T ratios were comparable to those in normal men, approximately 1:10 and 1:200, respectively.

In many tissues, the activity of testosterone appears to depend on reduction to dihydrotestosterone (DHT), which binds to cytosol receptor proteins. The steroid-receptor complex is transported to the nucleus, where it initiates transcription events and cellular changes related to androgen action. (See also reference 4)

Toxicology

The toxicology of testosterone has been summarized for various animal species and for humans in the following publications:

  • National Institute for Occupational Safety and Health RTECS, April 1989 (RTECS no. XA3030000)
  • Shepard, Thomas H., Catalog of Teratogenic Agents, 6th Edition, Johns Hopkins University Press, (p.1755) (1989)
  • IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, vol. 21 (pp.209-217 and 519-547) (1979)