Pharmacokinetics of a Transdermal Testosterone System in Men ...

Pharmacokinetics of a Transdermal Testosterone System in Men with End Stage Renal Disease Receiving Maintenance Hemodialysis and Healthy Hypogonadal Men

Atam B. Singh, Keith Norris, Nishit Modi, Indrani Sinha-Hikim, Ruoquing Shen, Tina Davidson and Shalender Bhasin

Divisions of Endocrinology, Metabolism, and Molecular Medicine (A.B.S., I.S.-H., R.S., T.D., S.B.) and Nephrology and Hypertension (K.N.), Charles R. Drew University of Medicine and Science, Los Angeles, California 90059; and Alza Corporation (N.M.), Mountain View, California 94043

Address correspondence and requests for reprints to: Shalender Bhasin, M.D., Professor of Medicine, UCLA School of Medicine, Chief, Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059.

Abstract

Androgen deficiency is common in men with end stage renal disease (ESRD) on maintenance hemodialysis. Pharmacokinetics of transdermal testosterone in men receiving maintenance hemodialysis have not been studied.

Our objective was to compare the pharmacokinetics of a transdermal testosterone system in healthy hypogonadal men and in men with ESRD on maintenance hemodialysis.

We recruited 10 healthy hypogonadal men and 8 medically stable men on maintenance hemodialysis, 18&endash;70 yr old, who had serum testosterone less than 300 ng/dL. After baseline sampling during a 24-h control period, two testosterone patches were applied daily for 28 days, to achieve a nominal delivery of 10-mg testosterone daily. In addition to single, pooled samples on days 7, 14, and 21, blood was drawn at 0, 2, 4, 6, 8, and 24 h on day 28 in healthy hypogonadal men and on an interdialytic day (day 21 or 28) as well as a dialysis day (day 21 or 28) in men on hemodialysis. On the dialysis day (day 21 or 28), serum free and total testosterone levels were measured hourly for 4 h before hemodialysis and for 4 h during hemodialysis. The dialysate was sampled for testosterone measurement.

Baseline mean SD total (92 ± 82 vs. 222 ± 50 ng/dL) and free (11 ± 9 vs. 27 ± 6 pg/mL) testosterone concentrations were lower in healthy hypogonadal men than in men with ESRD. After application of two testosterone patches, serum total and free testosterone concentrations rose into the midnormal range in both groups of men. Time-average, steady state (total testosterone, 506 ± 88 vs. 516 ± 86 ng/dL; free testosterone, 55 ± 9 vs. 67 ± 11 pg/mL), minimum, and maximum total and free testosterone concentrations were not significantly different between the two groups of men during treatment. Increments in total and free testosterone concentrations above baseline, baseline-subtracted areas under the total and free testosterone curves, and half-life of testosterone elimination (t1/2, 2.1 ± 0.1 vs. 2.1 ± 0.2 h, P = not significant) were not significantly different between the two groups. In men receiving hemodialysis, time-average, steady state, and maximal total and free testosterone concentrations and baseline-subtracted areas under the total and free testosterone curves were higher on dialysis day than on an interdialytic day. On the day of hemodialysis, time-average total and free testosterone concentrations were not significantly different during the 4 h before or during hemodialysis. The amount of testosterone removed in the dialysate (8.4 ± 1.6 µg during 4 h of hemodialysis) was small compared with the daily testosterone production rates in healthy young men. Serum dihydrotestosterone and estradiol concentrations increased into the normal male range and were not significantly different between the two groups. Percent suppression of LH was greater in men with ESRD than in healthy hypogonadal men.

A regimen of two Testoderm TTS testosterone patches (Alza Corp., Mountain View, CA) daily can maintain serum concentrations of total and free testosterone and its metabolites dihydrotestosterone and estradiol in the midnormal range in healthy hypogonadal men and men on hemodialysis. The amount of testosterone cleared by hemodialysis is small, and hemodialysis does not significantly affect serum total and free testosterone concentrations in men treated with the testosterone patch.