Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men

Transdermal delivery of testosterone (T) represents an effective alternativ e to injectable androgens. Transdermal T patches normalize serum T levels a nd reverse the symptoms of androgen deficiency in hypogonadal men. However, the acceptance of the closed system T patches has been limited by skin irr itation and/or lack of adherence. T gels have been proposed as delivery mod es that minimize these problems. In this study we examined the pharmacokine tic 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 9-14% of the T applied was bioavailable. After 90 days o f T gel treatment, the dose was titrated up (50 mg to 75 mg) or down (100 m g to 75 mg) if the preapplication serum T levels were outside the normal ad ult male range. Serum T rose rapidly into the normal adult male range on da y 1 with the first T gel or patch application. Our previous study showed th at steady state T levels were achieved 48-72 h after first application of t he 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 da ily application of the T formulations for 180 days, the average serum T lev el over the 24-h sampling period (C-avg) was highest in the 100 mg T gel gr oup (1.4- and 1.9-fold higher than the C-avg in the 50 mg T gel and T patch groups, respectively). Mean serum steady state T levels remained stable ov er the 180 days of T gel application. Upward dose adjustment from T gel 50 to 75 mg/day did not significantly increase the C-avg, whereas downward dos e adjustment from 100 to 75 mg/day reduced serum T levels to the normal ran ge 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. T he serum dihydrotestosterone C-avg rose 1.3-fold above baseline after T pat ch application, but was more significantly increased by 3.6- and 4.6-fold w ith T gel 50 and 100 mg/day, respectively, resulting in a small, but signif icant, increase in the serum dihydrotestosterone/T ratios in the two T gel groups. Serum estradiol rose, and serum LH and FSH levels were suppressed p roportionately with serum T in an study groups; serum sex hormone-binding g lobulin showed small decreases that were significant only in the 100 mg T g el group. We conclude that transdermal T gel application can efficiently an d rapidly increase serum T and free T levels in hypogonadal men to within t he normal range. Transdermal T gel provided flexibility in dosing with litt le skin irritation and a low discontinuation rate.