Pharmacokinetics and metabolism of a permeation-enhanced testosterone transdermal system in hypogonadal men

Influence of application site - A clinical research center study

A. Wayne Meikle, Stefan Arver, Adrian S Dobs, Steven W. Sanders, Lakshminaryan Rajaram, Norman A. Mazer

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1832-1840
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume81
Issue number5
DOIs
StatePublished - 1996

Fingerprint

Pharmacokinetics
Metabolism
Permeation
Testosterone
Dihydrotestosterone
Research
Thigh
Abdomen
Arm
Hormones
Thorax
Systems Analysis
Globulins
Analysis of variance (ANOVA)
Cross-Over Studies
Androgens
Multicenter Studies
Estradiol
Analysis of Variance
Reference Values

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Pharmacokinetics and metabolism of a permeation-enhanced testosterone transdermal system in hypogonadal men : Influence of application site - A clinical research center study. / Meikle, A. Wayne; Arver, Stefan; Dobs, Adrian S; Sanders, Steven W.; Rajaram, Lakshminaryan; Mazer, Norman A.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 81, No. 5, 1996, p. 1832-1840.

Research output: Contribution to journalArticle

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abstract = "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.",
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