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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 12 4500-4510
Copyright © 2000 by The Endocrine Society

From the Clinical Research Centers

Long-Term Pharmacokinetics of Transdermal Testosterone Gel in Hypogonadal Men1

Ronald S. Swerdloff, Christina Wang, Glenn Cunningham, Adrian Dobs, Ali Iranmanesh, Alvin M. Matsumoto, Peter J. Snyder, Thomas Weber, James Longstreth, Nancy Berman and the Testosterone Gel Study Group2

Divisions of Endocrinology, Departments of Medicine/Pediatrics, Harbor-University of California-Los Angeles Medical Center and Research and Education Institute (R.S.S., C.W., N.B.), Torrance, California 90509; Veterans Affairs Medical Center, Baylor College of Medicine (G.C.), Houston, Texas 77030; The Johns Hopkins University (A.D.), Baltimore, Maryland 21287; Veterans Affairs Medical Center (A.I.), Salem, Virginia 24153; Veterans Affairs Puget Sound Health Care System, University of Washington (A.M.M.), Seattle, Washington 98108; University of Pennsylvania Medical Center (P.J.S.), Philadelphia, Pennsylvania 19104; Duke University Medical Center (T.W.), Durham, North Carolina 27705; Unimed Pharmaceuticals, Inc. (J.L.), Deerfield, Illinois 60015

Address all correspondence and requests for reprints to: Christina Wang, M.D., General Clinical Research Center, Harbor-University of California-Los Angeles Medical Center, 1000 West Carson Street, Torrance, California 90509-2910. E-mail: wang{at}gcrc.humc.edu

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 9–14% 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 48–72 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.




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