CLINICAL PHARMACOLOGY
Striant® delivers physiologic amounts of testosterone to the systemic circulation, thereby producing circulating testosterone concentrations in hypogonadal males that approximate physiologic levels seen in healthy young men (300 - 1050 ng/dL).
Testosterone - General Androgen Effects
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, 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 production of testosterone and is characterized by low serum testosterone concentrations. Symptoms associated with male hypogonadism include impotence and decreased sexual desire, fatigue and loss of energy, mood depression, regression of secondary sexual characteristics and osteoporosis. Hypogonadism is a risk factor for osteoporosis in men.
Drugs in the androgen class also promote retention of nitrogen, sodium, potassium, phosphorus, and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein.
Androgens are responsible for the growth spurt of adolescence and for the eventual termination of linear growth brought about by fusion of the epiphyseal growth centers. In children, exogenous androgens accelerate linear growth rates but may cause a disproportionate advancement in bone maturation. Use by children and adolescents over long periods may result in fusion of the epiphyseal growth centers and termination of the growth process. Androgens have been reported to stimulate the production of red blood cells by enhancing the production of erythropoietin.
During exogenous administration of androgens, endogenous testosterone release may be inhibited through feedback inhibition of pituitary luteinizing hormone (LH). At large doses of exogenous androgens, spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH).
Pharmacokinetics
Absorption
When applied to the buccal mucosa, Striant® slowly 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 (C max ) and mean average serum total testosterone concentrations for the 12 hour dosing period (C avg(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.
With twice-daily repeated dosing, mean pharmacokinetic parameters at steady-state for total testosterone serum concentration were very similar between studies of 7-day and 12-week dosing durations. Mean C avg(0-24) across the studies ranged from 520 to 550 ng/dL and these mean values were within the physiologic range (see Table 1).
Table 1. Mean (±SD) Steady-State Serum Total Testosterone Concentrations During Treatment with Striant® (on Final Day of Treatment)
|
Study 1 |
Study 2 |
12-weeks
(N=82) |
7-days
(N=29) |
| C avg(0-24) (ng/dL) |
520 (±205) |
550 (±169) |
| C max(0-24) (ng/dL) |
970 (±442) |
910 (±319) |
| C min(0-24) (ng/dL) |
290 (±130) |
320 (±131) |
Although no specific food effect study was conducted, pivotal 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. The albumin-bound fraction of testosterone easily dissociates from albumin and is presumed to be bioactive. The portion of testosterone bound to SHBG is not considered biologically active. The amount of SHBG in the serum and the total testosterone level will determine the distribution of bioactive and nonbioactive androgen. SHBG-binding capacity is high in prepubertal children, declines during puberty and adulthood, and increases again during the later decades of life. 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
There is considerable variation in the half-life of testosterone as reported in the literature, ranging from ten to 100 minutes. Testosterone is metabolized to various 17-keto steroids through two different pathways, and the major active metabolites are estradiol and dihydrotestosterone (DHT). DHT binds with greater affinity to SHBG than does testosterone. In many tissues the activity of testosterone appears to depend on reduction to DHT, which binds to cytosol receptor proteins. The steroid-receptor complex is transported to the nucleus where it initiates transcription and cellular changes related to androgen action. In reproductive tissues, DHT is further metabolized to 3-alpha and 3-beta androstanediol.
Mean DHT concentrations increase in parallel with testosterone concentrations during Striant® treatment. After 24 hours of treatment, mean DHT serum concentrations are within normal range. The mean steady-state T/DHT ratio during treatment with Striant® remained within normal limits as determined by the analytical laboratory involved with the clinical trials. These ratios ranged from approximately 9-12.
Excretion
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.
Special Populations
No formal studies were conducted comparing the pharmacokinetics of testosterone in different racial groups or in compromised patients with renal or hepatic insufficiencies.
Clinical Studies
Striant® was evaluated in a multicenter, open-label, single arm, Phase 3 trial in 98 hypogonadal men (Study 1). In this study, Striant® was administered twice daily for 12 weeks. The mean age was 53.6 years (range 20 to 75 years). Overall, 68 (69.4%) patients were Caucasian, 9 (9.2%) were African-American, 15 (15.3%) were Hispanic, 4 (4.1%) were Asian, and 2 (2.0%) were of another ethnic origin. At baseline, ten patients (10.2%) reported current use of tobacco and forty-one (41.8%) drank alcohol. Of 82 patients who completed the trial and had sufficient data for full analysis, 86.6% had mean serum testosterone concentration (C avg(0-24) ) values within the physiologic range.
The mean (±SD) time-averaged steady-state daily testosterone concentration (C avg(0-24) ) at Week 12 was 520 (±205) ng/dL compared with a mean of 149 (±99) ng/dL at Baseline. At Week 12, 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%. Table 1 above provides the steady-state serum testosterone concentrations in greater detail.
Striant® was also evaluated in a 7-day multicenter, open-label, parallel study comparing Striant® and an approved testosterone transdermal system (Study 2). In this study, Striant® was again administered twice daily. On Day 7, the mean C avg(0-24) for the 29 patients who received Striant® was 550 (±169) ng/dL compared with a mean of 119 (±78) ng/dL at Baseline. At Day 7, the mean percentage of time for Striant® over the 24-hour sampling period that testosterone concentrations remained within the physiologic range of 300-1050 ng/dL was 84%. Additional pharmacokinetic data for this study are presented in Table 1 above.
Figure 1
below shows the mean total testosterone serum concentration versus time at steady-state for two representative consecutive dosing intervals from both the 7-day and 12 week studies. The figure shows that the concentration-time curves for the different duration studies are consistent.
 Figure 1: Mean (SD) total testosterone concentration-time curves for two consecutive dosing intervals at steady-state for both the 12- week study (Study 1) and the 7-day study (Study 2) of Striant®. (The horizontal dotted lines represent the upper and lower limit of normal for the normal physiologic range in healthy adult males).
In both clinical trials, 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® as compared with young, healthy eugonadal men.
During continuous treatment there was no accumulation of testosterone, and mean total testosterone, free testosterone, and DHT were maintained within their physiologic ranges.
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