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From The Clinical Research Centers |
Division of Endocrinology, Departments of Medicine (C.W., B.C., L.H., B.S., R.S.S.) and Pediatrics (N.B.), Harbor–UCLA Medical Center and Research and Education Institute, Torrance, California 90509; and Unimed Pharmaceuticals, Inc. (J.A.L., S.F., R.E.D.), Buffalo Grove, Illinois 60089
Address correspondence and requests for reprints to: Christina Wang, Clinical Study Center Box 16, Harbor–UCLA Medical Center, 1000 West Carson Street, Torrance, California 90509. E-mail: wang{at}gcrc.humc.edu
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Abstract |
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dihydrotestosterone (DHT), and estradiol before, during (days 1,
2, 3, 5, and 7), and after (days 8, 9, 11, 13, and 15) application of T
gel. Multiple blood samples were drawn on the 1st and 7th day after gel
application; single samples were obtained just before the next T gel
application on other days (24 h after the previous gel application).
The T gel dried in less than 5 min, left no residue, and produced no
skin irritation in any of the subjects. Mean serum T levels,
irrespective of application at one site or four sites followed the same
pattern: rising to 2- to 3- and 4- to 5-fold above baseline at 0.5 and
24 h after first application, respectively. Thereafter, serum T
levels reached steady state and remained at 4- to 5-fold above baseline
(at the upper limit of the normal adult range) for the duration of gel
application and returned to baseline within 4 days after stopping
application. The application of T gel at four sites (application skin
area approximately four times that of one site) resulted in a mean area
under the curve (AUC0–24h) for serum T levels on the 7th
day (868 ± 72 nmol*h/L, mean ± SEM), which was
23% higher but not significantly different (P = 0.06)
than repeated application at one site (706 ± 59 nmol*h/L). This
could be due to the limited number of subjects studied (n = 9).
Mean serum DHT levels followed the same pattern as serum T, achieving
steady-state levels by 2 days. The mean concentration of serum DHT on
the 7th day was significantly higher after application at four sites
(9.15 ± 1.26 nmol/L, P < 0.05) than at one site
(6.9 ± 0.77 nmol/L). These serum DHT levels were at or above the
normal adult male range. Serum DHT:T ratio was not significantly
altered by T gel application. Serum estradiol levels followed the same
pattern as serum T and showed no significant difference between the
one- or four-site application. We conclude that transdermal daily
application of 100 mg T gel resulted in similar steady levels of serum
T. The surface area of the skin to which the gel was applied had only a
modest impact on serum T and DHT levels. Mean serum levels of T and DHT
was higher by 23% and 33%, respectively, despite application of the
gel to four times the skin area in the four sites compared with the one
site group. Because of the greater dosage flexibility provided,
hydroalcoholic T gel application over multiple sites seems to be an
effective and nonskin-irritating method of transdermal T delivery for
hypogonadal men. Dose-ranging studies are required to determine dosage
regimens for T gel application as a replacement therapy in hypogonadal
men. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Each of the patches also has the disadvantages of having fixed dose
increments (patches delivering 5–6 mg per day) and is clearly visible.
Although the present transdermal delivery system of T has problems, the
skin remains an attractive route for delivery of steroids. When an open
system of hydroalcoholic gel of a steroid is applied to the skin, the
steroid is rapidly absorbed into the stratum comeum, which forms a
reservoir and acts as a rate-controlling membrane. The steroid is then
gradually diffused from this skin reservoir over several hours,
reaching steady-state levels in the serum (14). We report the
pharmacokinetics of a nonpatch T hydroalcoholic gel applied to the skin
in hypogonadal men. In this initial study, we compared serum T,
5-dihydrotestosterone (DHT), and estradiol (E2) levels
after application of the same dose of T gel for 7 days either to one
area or to four different areas of the body to examine the effect of
area of skin surface of application on serum T pharmacokinetics.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Ten hypogonadal men between 26 and 59 yr, (mean, 43.2 yr) were recruited at the Harbor–UCLA Medical Center. Six men were white, two black, one non-white Hispanic, and one Asian. Four of the subjects had Klinefelter’s syndrome, two had Kallman’s syndrome, two had pituitary tumors (treated), one had primary testicular failure, and one with unknown cause. Their screening serum T levels were below 8.7 nmol/L (250 ng/dL). All had received prior T replacement, nine subjects were receiving injections, and one applying patches. The subjects were screened for the study at least 6 weeks after their last T injection and 2 weeks after the last application of the T patch. Aside from hypogonadism, the subjects did not have significant medical history or drug or alcohol abuse. Their baseline blood counts, chemistry, and serum prostate-specific antigen levels were all within normal limits. The study was approved by the Human Subjects Committee of the Harbor–UCLA Medical Center. All subjects signed a written consent form after discussion and explanation of the study.
T gel
T gel formulated as a 1.0% hydroalcoholic gel (AndroGel) was manufactured by Besins Iscovesco (Paris, France) and supplied by Unimed Pharmaceuticals, Inc. (Buffalo Grove, IL). Approximately 250 mL T gel was provided in a glass bottle fitted with a metered-dose pump. Each actuation of the pump will deliver 2.25 g T gel (22.5 mg T). All patients received the same lot number of T gel. After application of the T gel to the skin, the gel dried immediately within 5 min with no apparent residue on the skin surface.
Study design
The subjects were randomly assigned to apply 10 g gel (100
mg T) at a single site (left arm/shoulders) or at the four different
separate sites (left and right arms/shoulders and left and right
abdomen) with each application separated by 2–3 min and whole
application process application completed within 6–8 min once daily
for 7 days (days 1–7). After a 7-day wash out period (days 8–14),
each subject was then crossed over to receive the alternate regimen for
another 7 days of T gel application (days 15–21), followed by another
7 days of wash out (Fig. 1
). Subjects
were admitted to the General Clinical Research Center (GCRC) at
Harbor–UCLA Medical Center for 24 h on days 1, 7, 15, and 21 when
blood samples for serum T assays were drawn at 30, 15, and 0 min before
and 0.5, 1, 2, 4, 6, 8, 12, 18, and 24 h after T gel application.
Serum DHT levels were measured on samples drawn on days 7 and 21 (after
seven daily T gel applications). The gel was applied at about 0800
h each morning, usually after a shower. The application took 3–5 min.
In addition, the subjects returned to the study center on days 3, 5, 9,
11, 13, 17, 19, 23, 27, and 29 for blood sampling for serum T, DHT, and
E2 before gel application and for examination of the sites
of application for skin irritation. Blood samples were drawn on day 29
for complete blood counts and clinical chemistry. Sera obtained were
kept frozen at -20 C until assays were performed. All samples from a
subject for each hormone were measured in the same assay.
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Serum T levels were measured after extraction with ethylacetate and hexane by a specific RIA using reagents from ICN (Costa Mesa, CA). The cross-reactivities of the antiserum used in the T RIA were 3.4% for DHT, 2.2% for 3ß androstanediol, 2.0% for 11 oxotestosterone, and less than 1% for all other steroids tested. The lower limit of quantitation of serum T measured by this assay was 0.87 nmol/L (25 ng/dL). All results below this value were reported as 0.87 nmol/L. The mean accuracy (recovery) of the T assay, determined by spiking steroid free serum with varying amounts of T (0.9–52 nmol/L), was 104% (range, 92–117%). The intra-assay and interassay coefficients of the T assay was 7.3 and 11.1% at the normal adult male range, which in our laboratory was 10.33–36.17 nmol/L (298–1043 ng/dL).
Serum DHT was measured by RIA after potassium permanganate treatment of
the sample, followed by extraction. The methods and reagents of the DHT
assay were provided by DSL (Webster, TX). The cross-reactivities of the
antiserum used in the RIA for DHT were 1.9% for androstenedone, 1.4%
for E2, 0.02% for T (after potassium permanganate
treatment and extraction), 0.25% for androstanediol, 0.19% for 3
androstanediol-glucuronide, and not detectable for other steroids
tested. This low cross-reactivity against T was further confirmed by
spiking steroid free serum with 35 nmol/L (1000 pg/dL) of T and taking
the samples through the DHT assay. The results even on spiking with
over 35 nmol/L of T was measured as less than 0.1 nmol/L of DHT. The
lower limit of quantitation of serum DHT in this assay was 0.43 nmol/L.
All values below this value were reported as less than 0.43 nmol/L. The
mean accuracy (recovery) of the DHT assay determined by spiking steroid
free serum with varying amounts of DHT from 0.43–9 nmol/L was 101%
(range, 83–114%). The intra-assay and interassay coefficients of
variation for the DHT assay were 7.8 and 16.6%, respectively, for the
adult male range, which in our laboratory was 1.06–6.66 nmol/L.
Serum E2 levels were measured by a direct assay without extraction with reagents from ICN. The intra-assay and interassay coefficients of variation of E2 were 6.5 and 7.1%, respectively, for normal adult male range (E2, 63–169 pmol/L). The lower limit of quantitation of the E2 was 18 pmol/L. All values below this value were reported as 18 pmol/L. The cross-reactivities of the E2 antibody were 6.9% for estrone, 0.4% for equilenin, and less than 0.01% for all other steroids tested. The accuracy of the E2 assay was assessed by spiking steroid free serum with increasing amount of E2 (18–275 pmol/L). The mean recovery of E2 compared with the amount added was 99.1% (range, 95–101%).
Statistical analyses
Descriptive statistics for each of the hormone levels were calculated. Before analysis, each variable was examined for its distributional characteristics and, if necessary, transformed to meet the requirements of a normal distribution. The pharmacokinetics of T gel was assessed using area under the curve from 0–24 h (AUC0–24) generated by the 24 h of multiple blood sampling for T on days 1, 7, 15, and 21. The AUC was computed using the linear trapezoid method. The mean T concentrations over the 24 h after gel application (Cmean) was calculated as the AUC0–24 divided by 24 h.
Comparisons within subjects between one-site and four-site applications on a single value, either a specific day or difference between 2 days, used paired t tests or, if more than 2 days were involved, repeated measured ANOVA was used. To test for an application order effect, t tests for independent groups were used to compare subjects applying T gel to one site first to subjects applying T gel to four sites first (order) on all the variables. Because there were no effects of order of the T gel application regimen (one site first or four sites first), this variable was not included in the subsequent analyses. The data in the tables and graphs is for all subjects applying T gel to one or four sites and not separated by order of application (days 1–7 or days 15–21).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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One subject assigned to the T gel application to four sites group did not return for study visit after day 13 due to personal reasons. The data from this subject were not included for analyses. None of the patients had any evidence of skin irritation. There was no adverse event that was ascribed to the T gel application, except for the report of increased libido in one subject. Other complaints that may possibly relate included mild asthenia, hyperkinesis, and depression. Mean hemoglobin (screening, 15.0 ± 5.6; day 29, 13.7 ± 4.4 g/dL, mean ± SEM), hematocrit (screening, 44 ± 2%; day 29, 40 ± 1%), and red blood cell counts (screening, 4.8 ± 0.2; day 29, 4.3 ± 0.1 1012/L) were significantly decreased on day 29 (P < 0.05) after multiple blood sampling for the pharmacokinetics studies. There were no other significant changes in blood cell counts or serum chemistries at screening and at the end of the study (day 29). Compliance of T gel application was estimated by change in the T gel bottle weights and was determined to be 96.1% (range, 60.7–108.9%).
Serum T levels and pharmacokinetics
The serum T concentrations and pharmacokinetics after T gel
application to one site or four sites are shown in Table 1. The baseline serum T concentrations
(Cbaseline) of the subjects before T gel application were
similar and below the normal adult range of our laboratory (10.3
nmol/L). After first application of T gel to one site, serum T levels
rose rapidly to 2.4 times the baseline concentration and into the
normal range within 30 min. The levels continued to slowly rise
throughout the day to 4.2-fold of Cbaseline at 24 h
(Fig. 2). Application of T gel to four
sites produced the same serum T profile. Serum T levels rose rapidly to
within the normal range by 30 min, and to 4.5-fold of
Cbaseline at 24 h (Fig. 2). The mean serum T
concentration (Cmean) over 24 h, serum T concentration
at 24 h (C24), and the area under the serum T levels
from 0–24 h (AUC0–24) after T gel application were not
significantly different for the application at one vs. four
sites (Table 1).
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).
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. The serum
T levels before T gel application was 4- to 5-fold higher than baseline
(one site, 25.87 ± 5.19 nmol/L; four sites, 27.57 ± 4.10
nmol/L vs. Cbaseline). Serum T levels at 24
h (C24) on the 7th day were not statistically different
from the serum T levels at 24 h (C24) after the first
T gel application both in the one site and four sites group. On the 7th
day after application, the maximum serum T concentrations attained
after one site and four sites were 46.32 ± 5.64 and 53.92 ±
3.87 nmol/L (P = 0.10, one vs. four sites),
which were above the upper limit of the normal adult male range. The
maximum levels were attained between 4 and 8 h after application.
The levels then gradually declined but remained at the upper limit of
the normal range. The serum T levels were maintained within a
relatively narrow range throughout the 24 h, with the peak
concentration not more than three times the trough concentration. The
mean serum T levels over 24 h (Cmean), as well as the
AUC0–24 on the 7th day, were 23% higher after the four
sites vs. the one site applications (Table 1
), which did not
reach statistical significance (P = 0.06). The
AUC0–24 increased between the 1st and 7th day (dose) of T
gel for both application regimens. This increase was significant only
for the one-site application (P < 0.01).
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). After 2 additional days (day 11), the serum T
levels fell to below the normal range and were not statistically
different from Cbaseline. In our laboratory, the range of AUC0–24 for eugonadal men was 197–848 nmol1h/L. After T gel application daily for 7 days, the AUC0–24 in the hypogonadal men were at or above the normal range. Most of the hypogonadal men in this study achieved peak serum T levels about twice that of the midpoint of the normal range. The normal daily production rate of T was reported to be about 6–7 mg/day (15). Based on estimation from the pharmacokinetic data, approximately 9–14 mg T was delivered to the patient’s circulation in this study from the T gel, assuming all endogenous T was suppressed and there was no change in clearance rate. Therefore, the estimated bioavailability of T gel was 9–14%.
Serum DHT levels
The serum DHT levels before and 7 days after daily application of
T gel are shown in Table 2 and Figs. 3 and 4. The Cbaseline for serum DHT was similar in the
subjects before DHT application, and the serum DHT to serum T ratio
(DHT:T ratio) was within the normal range (0.05–0.33). Serum DHT
levels increased and DHT:T ratio remained slightly but not
significantly higher during the daily T gel applications (Fig. 3).
After the seventh daily dose of T gel, the mean serum DHT levels at
0 h were significantly increased to the upper limit of normal
range after one-site application and above the normal range after
application at four sites. Serum DHT:T ratio was also significantly
higher in the four sites compared with the one-site group (Table 2).
The mean DHT levels achieved throughout this 7th day were above the
normal range for both regimens. Application of T gel at four sites led
to serum DHT levels significantly (P < 0.05, 33%)
above those after application at a single site (Fig. 4). After
withdrawal of T gel, the serum DHT levels fell to baseline levels on
day 11 and followed the same pattern as serum T.
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The mean baseline E2 concentrations of the hypogonadal
men were between 62 and 57 pmol/L for the one site and four site
groups, respectively, which were at the lower limit of the normal range
for eugonadal men (62.7–169.3 pmol/L). During T gel application, the
mean serum E2 levels rose 30–50% to reach 73–88 pmol/L
(Fig. 5). After the discontinuation of
the T gel, the mean serum E2 concentration fell to reach
baseline levels by day 11. There was no significant difference in the
levels of E2 attained after gel application to one or four
sites. The ratio of serum E2 to serum T did not change
significantly during T gel application (data not shown).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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After the first application of T gel to hypogonadal men, serum T levels rose to the normal range within 30 min, then the levels gradually rose throughout the following 24 h. By the end of the 1st day, the levels attained were comparable with the subsequent steady-state predose levels on the 3rd, 5th, and 7th days of application. The serum T levels were 4- to 5-fold above the baseline at the upper limit of the normal range. These serum patterns were similar, irrespective of the number of sites of application. Comparing the AUC0–24 after one site to four sites of application showed that applying the gel over a larger surface area might have produced slightly higher concentrations. The single-site application approximated 300–500 cm2 of skin surface area compared with the four-site application area of 1200–2000 cm2. Despite the 4-fold differences in surface area, the differences in AUC0–24 after steady-state achievement on the 7th day between the four-site and one-site application was about only 23% (statistically not significant). The failure to reach statistical significance may be related to the small number of subjects studied. This suggested that the surface area over which the gel was applied had only a modest impact on the pharmacokinetic parameters of serum T. This may imply that the amount of T absorbed and released into circulation was more dependent on the amount of steroid applied and not to the area over which it was applied. Dose-related pharmacokinetics studies (currently in progress) would answer this question.
Examination of the serum T levels showed that steady state was achieved at the end of the 1st day. Thereafter, the T gel application resulted in maintenance of this steady-state level. This would be anticipated because T absorbed through the skin is stored in the skin as a reservoir. The T is then slowly transported from the reservoir to the circulation, providing a natural mechanism mimicking a sustained release delivery system. After withdrawal of gel application, the levels of serum T decreased to about 40–50% by 48 h and to baseline hypogonadal levels by 96 h. Once steady state is achieved, serum T levels showed very small peak to trough executions. The peak T levels were not more than the three times the trough within 24 h. It should be noted that the mean serum T concentration attained at steady state was 5- to 6-fold above baseline on the 7th day and this level was in the upper quartile of the normal range. Three and four patients from the one-site and four-site groups, respectively, had serum T levels above the normal range. This suggests that a lower daily dose of 25, 50, or 75 mg T gel may be a more appropriate androgen replacement dose for many subjects. Based on the mean serum T concentration achieved after 100 mg daily gel application and assuming that all endogenous T production was suppressed and clearance was unchanged, approximately 9–14% of the applied T was bioavailable. The bioavailability of T gel is similar to the bioavailability after application of a hydroalcoholic DHT gel to the skin (16).
Serum DHT levels followed the same pattern as T. Steady-state levels of
serum DHT was achieved by the 2nd day after gel application. On the 7th
day, serum DHT levels were at or above the normal range. On withdrawal
of T gel, serum DHT levels fell to reach baseline by day 11. Because
5 reductase enzymes (type 1 and 2) are present in the skin, it is
anticipated that more DHT might be converted from the T gel applied
over a larger surface area. A small, but significantly higher, mean
serum DHT level was achieved when the gel was applied to four sites
vs. one site. However, the increase in serum levels was only
33% compared to the 4-fold increase in the surface area of
application, again implying that surface area to which the gel was
applied had only a modest impact on serum DHT levels. More importantly,
serum DHT:T ratio, although slightly increased with T gel treatment,
did not reach statistical significance and remained within the normal
adult male range. The results are comparable to those reported after
application of the nonscrotal skin patches (Androderm, Testostoderm
TTS) (9, 12). Similar to serum DHT, serum E2 followed the
same pattern. After T gel application, serum E2 levels
reached the normal range within 24 h and remained at this level
during continued gel application. Serum E2 to T ratio
showed no significant change throughout the application.
We conclude from this preliminary study of this open system of transdermal application of a hydroalcoholic T gel that this formulation provided an effective once-daily delivery of an adequate dose of T for androgen replacement therapy of hypogonadal men. Continued application led to steady-state levels of T with small peak to trough fluctuations. The transdermal delivery of T resulted in appropriate and parallel increases in DHT and E2. The T gel caused no apparent skin irritation or adverse effects. The efficacy of T gel at this and lower daily dosages should be explored for the long-term treatment of hypogonadal men.
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Acknowledgments |
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Footnotes |
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Received October 7, 1999.
Revised November 4, 1999.
Accepted November 12, 1999.
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