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Transdermal delivery of testosterone (T) represents an effective alternative to injectable androgens. Transdermal T patches normalize serum T levels and reverse the symptoms of androgen deficiency in hypogonadal men. However, the acceptance of the closed system T patches has been limited by skin irritation and/or lack of adherence. T gels have been proposed as delivery modes that minimize these problems. In this study we examined the pharmacokinetic profiles after 1, 30, 90, and 180 days of daily application of 2 doses of T gel (50 and 100 mg T in 5 and 10 g gel, delivering 5 and 10 mg T/day, respectively) and a permeation-enhanced T patch (2 patches delivering 5 mg T/day) in 227 hypogonadal men. This new 1% hydroalcoholic T gel formulation when applied to the upper arms, shoulders, and abdomen dried within a few minutes, and about 914% of the T applied was bioavailable. After 90 days of T gel treatment, the dose was titrated up (50 mg to 75 mg) or down (100 mg to 75 mg) if the preapplication serum T levels were outside the normal adult male range. Serum T rose rapidly into the normal adult male range on day 1 with the first T gel or patch application. Our previous study showed that steady state T levels were achieved 4872 h after first application of the gel. The pharmacokinetic parameters for serum total and free T were very similar on days 30, 90, and 180 in all treatment groups. After repeated daily application of the T formulations for 180 days, the average serum T level over the 24-h sampling period (Cavg) was highest in the 100 mg T gel group (1.4- and 1.9-fold higher than the Cavg in the 50 mg T gel and T patch groups, respectively). Mean serum steady state T levels remained stable over the 180 days of T gel application. Upward dose adjustment from T gel 50 to 75 mg/day did not significantly increase the Cavg, whereas downward dose adjustment from 100 to 75 mg/day reduced serum T levels to the normal range for most patients. Serum free T levels paralleled those of serum total T, and the percent free T was not changed with transdermal T preparations. The serum dihydrotestosterone Cavg rose 1.3-fold above baseline after T patch application, but was more significantly increased by 3.6- and 4.6-fold with T gel 50 and 100 mg/day, respectively, resulting in a small, but significant, increase in the serum dihydrotestosterone/T ratios in the two T gel groups. Serum estradiol rose, and serum LH and FSH levels were suppressed proportionately with serum T in all study groups; serum sex hormone-binding globulin showed small decreases that were significant only in the 100 mg T gel group. We conclude that transdermal T gel application can efficiently and rapidly increase serum T and free T levels in hypogonadal men to within the normal range. Transdermal T gel provided flexibility in dosing with little skin irritation and a low discontinuation rate.
THE SKIN IS an attractive route for systemic delivery of steroids. Transdermal preparations of testosterone (T) provide a useful delivery system for normalizing serum T levels in hypogonadal men and preventing the clinical symptoms and long-term effects of androgen deficiency (1, 2, 3, 4, 5). Currently available transdermal patches are applied to the scrotal skin (Testosderm) or to other parts of the body (Androderm and Testoderm TTS). The former requires preparation of the scrotal skin with hair clipping or shaving to optimize adherence of the patches. The permeation-enhanced T patch (Androderm) is associated with skin irritation in about a third of the patients, and 1015% of subjects have been reported to discontinue the treatment because of chronic skin irritation (6, 7). Preapplication of corticosteroid cream at the site of application of the Androderm patch has been reported to decrease the incidence and severity of the skin irritation (8). The most recently approved nonscrotal T patch (Testoderm TTS) causes less skin irritation (itching in about 12% and erythema in 3% of the subjects), but adherence of the patch to the skin poses a problem in some subjects (9, 10). Despite these limitations of local irritation and adherence to skin, the various T patches provide a steady state delivery of T to the circulation that mimics the normal diurnal rhythm of serum T at the low to mid normal adult male range (11, 12, 13, 14, 15, 16, 17). The long-term use of these transdermal androgen delivery patches has been shown to be efficacious in maintaining sexual function, secondary sexual characteristics, and bone and muscle mass in hypogonadal young and elderly men (5, 18, 19, 20, 21).
T and other steroids can also be applied to the skin in open systems. When T is applied to the skin surface as a hydroalcoholic gel, the gel dries rapidly, and the steroid is absorbed into the stratum corneum, which serves as a reservoir. The reservoir in the skin releases T into the circulation slowly over several hours, resulting in steady state serum levels of the hormones (22). Our previous short-term (714 days) pharmacokinetic studies of both T and 5-dihydrotestosterone (DHT) transdermal hydroalcoholic gels showed that the androgens were absorbed, and peak levels of the applied androgens occurred 1824 h after initial application. With continued application of the gel for 714 days, steady serum levels of androgens were maintained (23, 24). About 914% of the T in the gel applied to the skin is bioavailable (24). We also demonstrated that application of the T gel (100 mg/day) at a single site or four separate sites resulted in serum T levels at the upper limit of the normal range, with about 23% higher serum levels when the gel was applied at four sites. In the 7- to 14-day studies, neither T nor DHT gel produced skin irritation in the small number of subjects studied (23, 24). In the present study we investigated the detailed pharmacokinetics and tolerability of T gel (AndroGel) at two dosages (50 and 100 mg/day) and T patch after repeated daily dosing for 180 days in a large number of hypogonadal men (n = 227) recruited from 16 centers across the United States.
Subjects
Two hundred and twenty-seven hypogonadal men were recruited, randomized, and studied in 16 centers in the United States. About one third of the subjects were randomized into each treatment group (Table 1). The patients were between 1968 yr of age and had single morning serum T levels at screening of 10.4 nmol/L (300 ng/dL) or less. The screening serum T concentrations were measured at each centers clinical laboratory. Previously treated hypogonadal men were withdrawn from T ester injection for at least 6 weeks and from oral or transdermal androgens for 4 weeks before the screening visit. Aside from the hypogonadism, the subjects were in good health, as evidenced by medical history, physical examination, complete blood count, urinalysis, and serum biochemistry. If the subjects were taking lipid- lowering agents or tranquilizers, the doses were stabilized for at least 3 months before enrollment. The subjects had no history of chronic medical illness or alcohol or drug abuse. The subjects had a normal rectal examination, a prostate-specific antigen level of less than 4 ng/mL, and a urine flow rate of more than 12 mL/s before enrollment to the study. They were excluded if they had a generalized skin disease that might affect T absorption or a prior history of skin irritability with the nonscrotal T patch (Androderm). Subjects with body weight of less than 80 or more than 140% of ideal body weight and subjects taking medications known to alter the cytochrome P450 enzyme systems were also excluded from this study.
THE SKIN IS an attractive route for systemic delivery of steroids. Transdermal preparations of testosterone (T) provide a useful delivery system for normalizing serum T levels in hypogonadal men and preventing the clinical symptoms and long-term effects of androgen deficiency (1, 2, 3, 4, 5). Currently available transdermal patches are applied to the scrotal skin (Testosderm) or to other parts of the body (Androderm and Testoderm TTS). The former requires preparation of the scrotal skin with hair clipping or shaving to optimize adherence of the patches. The permeation-enhanced T patch (Androderm) is associated with skin irritation in about a third of the patients, and 1015% of subjects have been reported to discontinue the treatment because of chronic skin irritation (6, 7). Preapplication of corticosteroid cream at the site of application of the Androderm patch has been reported to decrease the incidence and severity of the skin irritation (8). The most recently approved nonscrotal T patch (Testoderm TTS) causes less skin irritation (itching in about 12% and erythema in 3% of the subjects), but adherence of the patch to the skin poses a problem in some subjects (9, 10). Despite these limitations of local irritation and adherence to skin, the various T patches provide a steady state delivery of T to the circulation that mimics the normal diurnal rhythm of serum T at the low to mid normal adult male range (11, 12, 13, 14, 15, 16, 17). The long-term use of these transdermal androgen delivery patches has been shown to be efficacious in maintaining sexual function, secondary sexual characteristics, and bone and muscle mass in hypogonadal young and elderly men (5, 18, 19, 20, 21).
T and other steroids can also be applied to the skin in open systems. When T is applied to the skin surface as a hydroalcoholic gel, the gel dries rapidly, and the steroid is absorbed into the stratum corneum, which serves as a reservoir. The reservoir in the skin releases T into the circulation slowly over several hours, resulting in steady state serum levels of the hormones (22). Our previous short-term (714 days) pharmacokinetic studies of both T and 5-dihydrotestosterone (DHT) transdermal hydroalcoholic gels showed that the androgens were absorbed, and peak levels of the applied androgens occurred 1824 h after initial application. With continued application of the gel for 714 days, steady serum levels of androgens were maintained (23, 24). About 914% of the T in the gel applied to the skin is bioavailable (24). We also demonstrated that application of the T gel (100 mg/day) at a single site or four separate sites resulted in serum T levels at the upper limit of the normal range, with about 23% higher serum levels when the gel was applied at four sites. In the 7- to 14-day studies, neither T nor DHT gel produced skin irritation in the small number of subjects studied (23, 24). In the present study we investigated the detailed pharmacokinetics and tolerability of T gel (AndroGel) at two dosages (50 and 100 mg/day) and T patch after repeated daily dosing for 180 days in a large number of hypogonadal men (n = 227) recruited from 16 centers across the United States.
Subjects
Two hundred and twenty-seven hypogonadal men were recruited, randomized, and studied in 16 centers in the United States. About one third of the subjects were randomized into each treatment group (Table 1). The patients were between 1968 yr of age and had single morning serum T levels at screening of 10.4 nmol/L (300 ng/dL) or less. The screening serum T concentrations were measured at each centers clinical laboratory. Previously treated hypogonadal men were withdrawn from T ester injection for at least 6 weeks and from oral or transdermal androgens for 4 weeks before the screening visit. Aside from the hypogonadism, the subjects were in good health, as evidenced by medical history, physical examination, complete blood count, urinalysis, and serum biochemistry. If the subjects were taking lipid- lowering agents or tranquilizers, the doses were stabilized for at least 3 months before enrollment. The subjects had no history of chronic medical illness or alcohol or drug abuse. The subjects had a normal rectal examination, a prostate-specific antigen level of less than 4 ng/mL, and a urine flow rate of more than 12 mL/s before enrollment to the study. They were excluded if they had a generalized skin disease that might affect T absorption or a prior history of skin irritability with the nonscrotal T patch (Androderm). Subjects with body weight of less than 80 or more than 140% of ideal body weight and subjects taking medications known to alter the cytochrome P450 enzyme systems were also excluded from this study.
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