Striant - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Striant - Scientific Information

Manufacture: Endo Pharmaceuticals Inc.
Country: Italy
Condition: Hypogonadism, Male
Class: Androgens and anabolic steroids
Form: Skin patch (transdermal)
Ingredients: testosterone,anhydrous lactose NF, carbomer 934P, hypromellose USP, magnesium stearate NF, lactose monohydrate NF, polycarbophil USP, colloidal silicon dioxide NF, starch NF, and talc USP.

Description

Striant (testosterone buccal system) mucoadhesive is for buccal administration only. It contains testosterone, an androgen.

Striant is designed to adhere to the gum or inner cheek. It provides a controlled and sustained release of testosterone through the buccal mucosa as the buccal system gradually hydrates. Application of Striant twice a day, in the morning and in the evening, provides continuous systemic delivery of testosterone.

Striant is a white to off-white colored, monoconvex, tablet-like, mucoadhesive buccal system. Striant adheres to the gum tissue above the incisors, with the flat surface facing the cheek mucosa.

The active ingredient in Striant is testosterone (see Figure 1). Each buccal system contains 30 mg of testosterone. Testosterone USP is practically white crystalline powder chemically described as 17-beta hydroxyandrost-4-en-3-one.

Other pharmacologically inactive ingredients in Striant are anhydrous lactose NF, carbomer 934P, hypromellose USP, magnesium stearate NF, lactose monohydrate NF, polycarbophil USP, colloidal silicon dioxide NF, starch NF and talc USP.

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, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter’s syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

Pharmacodynamics

No pharmacodynamic studies were conducted using Striant.

Pharmacokinetics

Absorption

When applied to the buccal mucosa, Striant releases testosterone, allowing for absorption of testosterone through gum and cheek surfaces that are in contact with the buccal system. Since venous drainage from the mouth is to the superior vena cava, trans-buccal delivery of testosterone circumvents first-pass (hepatic) metabolism.

Following the initial application of Striant, the serum testosterone concentration rises to a maximum within 10-12 hours. The mean maximum (Cmax) and mean average serum total testosterone concentrations for the 12 hour dosing period (Cavg(0-12)) are within the normal physiologic range.

Striant is intended for twice daily dosing. Serum concentrations of testosterone reach steady-state levels after the second dose of twice daily Striant dosing. Following removal of Striant, the serum testosterone concentration decreases to a level below the normal range within 2-4 hours.

Although no specific food effect study was conducted, Phase 3 study results showed that consumption of food and beverage did not significantly affect the absorption of testosterone from Striant.

The effects of toothbrushing, mouthwashing, chewing gum and alcoholic beverages on the use and absorption of Striant were not investigated in controlled studies. However, Phase 3 clinical studies permitted patients to do these activities indicating the use of Striant was not significantly affected by these activities.

Distribution

Circulating testosterone is chiefly 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, and the major active metabolites are estradiol and dihydrotestosterone (DHT).

Mean DHT concentrations increased in parallel with testosterone concentrations during Striant treatment. After 24 hours of treatment, mean (SD) DHT serum concentrations was approximately 80 (50) ng/dL. The mean steady-state T/DHT ratio during treatment with Striant ranged approximately 9-12.

Excretion

There is considerable variation in the half-life of testosterone as reported in the literature, ranging from ten 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.

Geriatrics

In patients 65 years of age and older, the total testosterone Cavg(0-24) value was higher by 13% compared to patients < 65 years of age. In addition, the total T to DHT area-under-the curve ratio was lower in the older population compared to the younger population by 16%. These differences may not be clinically significant.

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

Striant was evaluated in a multicenter, open-label Phase 3 trial in 98 hypogonadal men. In this study, 30 mg of Striant was administered buccally twice daily for 12 weeks. The mean age was 53.6 years (range 20 to 75 years). Overall, 69% of patients were Caucasian, 9% were African-American, 15% were Hispanic, 4% were Asian, and 2% were of another ethnic origin. At baseline, 10% of patients reported current use of tobacco and 42% drank alcohol.

Of 82 patients who completed the trial and had sufficient data for full analysis, 86.6% had mean serum testosterone concentration (Cavg(0-24)) values within the physiologic range (300-1050 ng/dL).

The mean (±SD) time-averaged steady-state daily testosterone concentration (Cavg(0-24)) at Day 84 was 520 (±205) ng/dL compared with a mean of 149 (±99) ng/dL at Baseline. The mean (±SD) maximum testosterone concentration (Cmax) at Day 84 was 970 (±442) ng/dL. At Day 84, the mean percentage of time over the 24-hour sampling period that total testosterone concentrations remained within the normal range of 300-1050 ng/dL was 76%.

Figure 3 shows the mean total testosterone serum concentration versus time curves on Day 84 (after 12 weeks of Striant treatment).

Mean DHT concentrations increased in parallel with testosterone concentrations, with the total testosterone/DHT ratio (9-12) indicating no alteration in metabolism of testosterone to DHT in testosterone deficient men treated with Striant.

During continuous treatment there was no accumulation of testosterone, and mean total testosterone, free testosterone, and DHT were maintained within their physiologic ranges.