Pharmacokinetics and metabolism of a permeation-enhanced testosterone transdermal system in hypogonadal men: Influence of application site - A clinical research center study

As part of a phase III multicenter study, the pharmacokinetics and metabolism of a permeation-enhanced testosterone (T) transdermal (TTD) system and the influence of application site were investigated in 34 hypogonadal men (21-65 yr of age). After an 8-week androgen washout period, two TTD systems were applied to the back for 24 h. Serum concentrations of total T, bioavailable testosterone (BT), dihydrotestosterone (DHT), and estradiol (E₂) increased from hypogonadal levels into the respective normal physiological ranges and declined to baseline levels within 24 h after system removal. Peak concentrations occurred approximately 8 h after application for T and BT and at 13 h for DHT and E₂. The baseline-subtracted time-average steady state concentrations (C'(ss)) for T and BT were 18.1 ± 7.49 (±SD) and 9.08 ± 3.99 nmol/L, respectively. DHT/T and E₂/T ratios, derived from the C'(ss) values, were 0.063 ± 0.018 and 0.0033 ± 0.0018, comparable to the precursor-product conversion ratios reported in healthy men. The estimated half-lives of each hormone were: T, 1.29 ± 0.71 h; BT, 1.21 ± 0.75 h; DHT, 2.83 ± 0.97 h; and E₂, 3.53 ± 1.93 h. The influence of application site was then evaluated by applying two TTD systems for 24 h to the abdomen, back, chest, shin, thigh, or upper arm, according to a sequential cross-over design. Hormone profiles were qualitatively similar at each site, but C'(ss) values showed significant differences (by ANOVA, P < 0.0001). Based on the BT levels, the rank ordering of the sites were: back > thigh > upper arm> abdomen > chest > shin. DHT/T and E₂/T ratios showed negligible site to site variation and were comparable to the results from the initial study. Estimates of T input, based on hormone levels and analysis of the systems used, averaged 4-5 mg/day for the abdomen, back, thigh, and upper arm and were lower and more variable for the chest and shin. Individual C'(ss) values for T and BT increased linearly with the T input rates (derived from used system analysis) across all studies (n = 235; r = 0.564 for T and r = 0.754 for BT). From these data, T and BT clearance rates were estimated for each patient, averaging 1248 ± 518 and 2435 ± 778 L/day, respectively. T clearance rates were proportional to the BT/T ratio (nonsex hormone-binding globulin-bound fraction). On the basis of these studies, the optimal sites of TTD system application were identified as the back, thigh, upper arm, and abdomen.