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From the Clinical Research Centers |
Department of Medicine, Johns Hopkins University School of Medicine (A.S.D., R.A.), and the Departments of Epidemiology (D.R.H.) and Biostatistics (M.-C.C.), Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205
Address all correspondence and requests for reprints to: Adrian Dobs, M.D., M.H.S., 600 North Wolfe Street, Blalock 906B, Johns Hopkins Hospital, Baltimore, Maryland 21287-4906. E-mail: adobs{at}welchlink.welch.jhu.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Among the newest preparations are T transdermal patches intended for either scrotal (4) or nonscrotal application (5). Both types of patch have been shown to effectively deliver therapeutic levels of T with daily application. However, the scrotal patch, while providing physiological levels of T, results in supraphysiological levels of dihydrotestosterone (DHT), apparently as a result of the high rate of T metabolism in scrotal skin compared with that at other dermal application sites (6). The nonscrotal patch, in contrast, produces physiological levels of T and its metabolites (DHT and estradiol). This preparation appears promising, but clinical experience is limited at this time (5, 7).
Other forms of administration of T, including sublingual T/cyclodextrin combinations, biodegradable T microspheres (8), sc T pellets (9), and T bucciclate (10), are either under clinical investigation or available only outside the United States. Disadvantages of these preparations include short half-life, bitter taste, discomfort associated with administration, extrusion from the implant site, and batch variation in bioavailability (1).
Buccal administration of T via the buccal mucosa (lining of the cheek), however, largely overcomes these disadvantages by delivering the drug directly into the systemic circulation. Absorption of drugs via the mucous membranes of the oral cavity was first noted for nitroglycerin in 1847 and recently reviewed by Harris and Robinson (11). This method of administration is distinct from sublingual delivery, in which the drug is placed on the ventral surface of the tongue and the floor of the month. Compared to sublingual administration, buccal transport is less permeable and potentially better suited for sustained delivery systems. In this study, we assessed the effectiveness and safety of a bucally administered T tablet intended for use under conditions associated with the absence or deficiency of endogenous T. In addition, we characterized the pharmacokinetic profiles of total and free T, DHT, and estradiol after administration of the buccal T tablet.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Fourteen hypogonadal men (documented serum total T, 
250
ng/dL), aged 22–72 yr, who had previously received im androgen
replacement therapy for at least 3 months before enrollment were
entered into the study. Patients with known or suspected carcinoma of
the prostate or breast were excluded from the study, as were patients
with a history of prostate disease or impotence from nonhormonal
conditions. Those with an American Urological Association System Index
for Prostatism score greater than 7 or a hematocrit greater than 53
were also excluded. All patients gave written informed consent to
participate, and the study protocol was approved by the institutional
review board of the participating center.
Study design
This was a double blind, randomized, placebo-controlled, parallel group study with two consecutive phases. Patient eligibility was determined within the 2-week period preceding admission to the study. During screening, the patients’ medical histories were obtained, and they underwent a physical examination, clinical laboratory tests, urinalysis, and an American Urological Association evaluation. Patients deemed eligible then entered the first phase (phase 1) of the study, which consisted of a single treatment day followed by 6-week washout period. On the treatment day, patients received an injection of their current im T therapy. The sexual function and general health of the patients as well as the efficacy of their current androgen replacement therapy were assessed during phase 1. The second phase (phase 2) lasted approximately 8 weeks and comprised two consecutive 4-week treatment periods (periods 1 and 2) during which the efficacy and safety of the buccal tablets were assessed. Pharmacokinetic profiles of T were obtained on day 1 (the first day of period 1) and at the end of period 2.
Buccal T treatment
Patients admitted to the study were randomly assigned to receive either buccal T tablets or buccal placebo tablets. Each buccal T tablet (Watson Corp., State College, PA) contained 10 mg of the hormone, and each placebo tablet contained 3 mg pseudoephedrine HCl (for taste matching). During period 1, patients took one tablet per day of their assigned medication. The tablets were administered through placement just off the midline of the buccal cavity along the lower gum surface below the teeth. The patients were instructed to avoid drinking, gargling, spitting, or brushing their teeth for 30 min after drug administration. An increase in the dosage to two tablets daily (one tablet every 12 h) was permitted after the follow-up visit at the end of period 1 if treatment with one tablet was judged inadequate by the physician and patient. Patients were asked to judge whether they felt adequately replaced. During period 2, patients took either one or two buccal tablets of hormone or placebo daily, as specified at the follow-up visit.
Serum hormone and pharmacokinetic evaluations
Blood samples for measurement of serum hormone levels [total T, free T, estradiol, DHT, LH, FSH, PRL, and sex hormone-binding globulin (SHBG)] were obtained during both phase 1 and phase 2. Phase 1 samples were collected before T injection, between days 5–7 after injection, and 6 weeks after injection. The hormone levels obtained at completion of the 6-week washout period served as the baseline. Phase 2 samples were collected during the first follow-up visit after initiation of buccal T therapy (between days 25–32 of period 1), 0.5 h before and after the daily dose. In addition, blood samples for determination of 24-h pharmacokinetic profiles of total T, free T, estradiol, and DHT were obtained on day 1 of period 1 and at the end of period 2. Collection times for these blood samples were 0.5 h before treatment, immediately before treatment (time 0), and 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 h after treatment.
Hormone assays
Serum was assayed for total T, bioavailable T, free T, FSH, LH, SHBG, and T3 uptake by SmithKline Beecham Clinical Laboratories using standard radiometric assays and RIAs. The bioavailable T test provides information on the T that is both free and loosely bound to albumin (12). In the range of the results reported here, the intra- and interassay coefficients of variation for the tests indicated above ranged from 3.0–4.5% and from 4.2–10.9%, respectively.
Sexual function evaluation
Objective and subjective measures of sexual function were assessed. As an objective measure, nocturnal penile tumescence (NPT) was monitored in a sleep laboratory 5–7 days after im T injection, at the end of the 6-week washout period, and at the end of 8 weeks of buccal T therapy. Patients were evaluated 1 week after im T for consistency purposes, although differences in serum T levels were expected. Each NPT study was conducted over a full night and involved sleep electroencephalograms, penile glans circumference measurements, axial rigidity measurements based on tonometry, and visual ratings by the patients and trained technicians for the percent maximum rigidity of the erections at the time of rigidity measurements. The NPT studies were performed during the night, after subjects had taken the buccal T or placebo the morning before. The primary measures used for analyses were maximum rigidity, maximum NPT increase, and total time of full erection.
Subjective measures included the Watts Sexual Function Questionnaire. The Watts questionnaire is a 17-item instrument that assesses several components of sexual function, including libido, arousal, orgasm, frequency of sexual activities, and satisfaction. Possible scores for each item range from 0–5, with higher scores indicating better sexual function. Evaluations were completed by the patients before administration of the last dose of im T, 5–7 days after the im injection, at the end of the 6-week washout period, on the day before the first buccal dose, and at the end of 4 and 8 weeks of buccal therapy.
Safety assessments
All adverse events occurring during the study were recorded. In addition, clinical laboratory parameters (serum chemistry, hematology, and liver function), lipid parameters, serum prostate-specific antigen levels, and bone parameters were monitored monthly during phases 1 and 2.
Statistical analyses
Data was entered into PARADOX and analyzed by SAS (Statistical Analysis Software version 6.03, SAS Institute, Durham, NC). Results are presented as the mean ± SD for the participants in the pharmacokinetic studies. P < 0.05 was considered statistically significant. Relationships between selected variables were analyzed by simple linear regression analysis. Changes in sexual function from NPT and questionnaires were evaluated using repeated measures ANOVA while patients were receiving injections, in the washed-out hypogonadal phase, and after 2 months of placebo or active therapy. Further analysis using paired t tests was performed, comparing changes in values at the three time points, and unpaired t test, comparing placebo vs. active buccal T. Areas under the curve were calculated using the trapezoidal method. Sexual function assessments had stable distributions, but hormone measurements were skewed. The logarithmic transformation removed these conditions and stabilized the distributions of laboratory variables; thus, it was used in statistical analyses.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Thirteen patients with a diagnosis of primary (6 patients) or
secondary (7 patients) hypogonadism were randomized to treatment (Table 1
). An additional patient was not
randomized because of scheduling problems. Twelve of the 13 patients
completed all scheduled evaluations, and 1 completed all but the
evaluation performed after 8 weeks of buccal T treatment. Of the 6
patients with primary hypogonadism, 5 had Klinefelter’s syndrome, and
1 had had trauma-related orchidectomy. The patients with secondary
hypogonadism included 3 with age-related changes, 2 with pituitary
tumors, 1 with Kallmann’s disease, and 1 with hypogonadism of unknown
etiology.
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Sex hormone levels
Serum T, DHT, and estradiol levels (mean ± SD)
measured at each evaluation interval during phase 1 (final im injection
and washout period) and phase 2 (buccal T or placebo treatment),
including the levels obtained 0.5 h after buccal administration of
T, are listed in Table 2. Table 1
lists
the free T levels.
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On day 1 of treatment period 1, the mean serum T level obtained 30 min after treatment was significantly elevated for patients receiving buccal T compared with that in patients receiving placebo (mean, 2790.0 vs. 136.0 ng/dL; P < 0.001). The basal T level after 8 weeks of treatment with buccal T (183.8 ng/dL) was similar to that observed at baseline, i.e. the end of the washout period (176.9 ng/dL), indicating that the serum half-life of T after administration in the buccal tablet formulation does not result in sustained accumulation at steady state. Free T levels paralleled those of total T.
Serum gonadotropins and SHBG
The mean serum FSH level in the men (n = 5) with primary
gonadal failure was 14.8 ± 12.8 during im therapy and increased
to 33.3 ± 9.9 mIU/mL after 6 weeks of wash-out (P
< 0.05). Similarly, the serum LH concentrations during im and
hypogonadal state were 8.1 ± 3.7 and 23.0 ± 10.4 mIU/mL,
respectively, (P < 0.05). There were no significant
changes in the SHBG concentrations (Table 3).
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Pharmacokinetics of buccal T
Twenty-four-hour profiles of total T, determined after the initial
single dose of one 10-mg buccal T tablet and again after 8 weeks of
daily administration of either one or two tablets per day, were similar
(Fig. 1, a and b). After the initial dose
of buccal T, the average serum T level increased to a peak within about
0.5 h after administration and returned to baseline values by 4–6
h after treatment (Fig. 1a). Compared with reference total T levels of
225–900 ng/dL, the levels obtained with buccal T were
supraphysiological for 1.5–4 h immediately after administration. A
similar profile was seen at the end of 8 weeks of buccal T
administration (Fig. 1b), demonstrating that accumulation did not
occur.
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Serum levels of DHT essentially paralleled those of T (Table 2). DHT
levels were elevated more than 2-fold 1 week after the im
administration of T enanthate compared with pretreatment values. As
shown in Fig. 1, c and d, posttreatment DHT levels after buccal T
administration remained elevated for only a short period and tended to
have elimination characteristics that paralleled those of serum T.
After the first dose, peak DHT levels occurred 0.5–1.5 h after tablet
ingestion and returned to baseline by 12 h. After 4 weeks of
buccal T treatment, the DHT level measured 0.5 h after ingestion
of one tablet was significantly increased relative to the baseline
value (109.8 vs. 16.0 ng/dL). Basal DHT levels measured
after both 4 and 8 weeks of buccal T therapy (21.3 and 26.6 ng/dL,
respectively) were similar to the baseline value, indicating the
absence of DHT accumulation. The T/DHT ratio remained relatively
constant (between 6.9–14.4), except 0.5 h after buccal T
administration at week 4, when the ratio increased to more than twice
that of the baseline value (25.4 vs. 11.1 ng/dL). After 8
weeks of treatment, the mean initial peak concentration of serum DHT
during the 24-h pharmacokinetic profile was comparable to that seen
with treatment on day 1 after the first buccal dose (184 vs.
118 ng/dL; P = 0.15), suggesting no accumulation of
DHT.
Serum estradiol levels (Table 2) were similar to those measured at
baseline, except on days 5–7 after im T treatment, when they were
approximately 3 times the baseline value (76.7 vs. 23.9
pg/mL), and 0.5 h after administration of buccal T, when they were
about twice the baseline value (44.0 pg/mL).
Twenty-four-hour hormone profiles (Fig. 1f) showed that after 8 weeks
of buccal T treatment, the serum concentration of estradiol just before
treatment was higher in the active than in the placebo group (39
vs. 22 pg/mL), indicating that administration of buccal T
resulted in elevation of serum estradiol levels. However, except for
peak levels during the first 2 h posttreatment, estradiol levels
were below the upper limit of 50 pg/mL during the sampling period. The
FSH, LH, and SHBG concentrations for the group as a whole remained
relatively unchanged at all sampling times compared with baseline
values.
Sexual function evaluation
NPT. NPT data obtained 5–7 days after im injection, at the
end of the 6-week withdrawal period, and after 8 weeks of treatment
with buccal T showed that the values for maximum penile rigidity,
maximum NPT circumference, and maximum duration of NPT were similar
during im and buccal T treatment (Fig. 2, a–c). Conversely, the values for these parameters after 8 weeks of
treatment with placebo were similar to those seen during androgen
withdrawal, i.e. during a hypogonadal state. The group
x treatment interaction was significant for greater maximum rigidity
(F = 4.78; df = 4,18; P = 0.008) and duration
of full NPT (F = 5.36; df = 4,19; P = 0.005)
after 8 weeks of T vs. placebo treatment.
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, a–c. With respect to the
frequency of sexual desire, there was a higher positive response in the
active treatment groups than in the placebo group after 5–7 days of im
T injection and after 8 weeks of buccal T therapy. Moreover, this
difference between active and placebo treatments was present at the end
of the washout period when the men were hypogonadal (Fig. 3a).
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Safety
Clinical chemistries and hematology. Total bilirubin, direct bilirubin, and indirect bilirubin values were all higher in patients receiving active treatment than in those receiving placebo at all evaluations, including those before and 5–7 days after im T injection. Therefore, the differences appear not to be related to treatment.
No clinically significant differences between the buccal T and placebo
treatment groups were observed for albumin, alkaline phosphatase,
-glutamyl transferase, alanine aminotransferase, aspartate
aminotransferase, total protein, A/G ratio, or globulin (data not
shown). Statistically significant changes were seen in some analytes;
however, these were sporadic, and values remained within the normal
range.
No clinically or statistically significant changes between the buccal T and placebo treatment groups were seen in hematology parameters, including hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and red blood cell, white blood cell, differential, and platelet counts (data not shown). Also, no changes were detected between the treatment groups with respect to PTH levels or osteocalcin levels. In those subjects eventually randomized to active transbuccal T vs. placebo, the prostate-specific antigen levels during im therapy were 0.817 ± 0.469 vs. 0.7 ± 0.469, respectively. Eight weeks after randomization, the levels were 0.94 ± 0.76 vs. 0.400 ± 0.234, respectively (P = NS).
Lipids. Lipid parameters, including total cholesterol, high density lipoprotein (HDL), and low density lipoprotein, were evaluated 5–7 days after im T injection, at the end of the 6-week washout period, and after 8 weeks of buccal T treatment. At 5–7 days after injection, patients in the active treatment and placebo groups combined had statistically significantly (P = 0.03) lower serum levels of HDL (40 ± 5 mg/dL) than the combined groups at the end of the washout period, when the patients were in a hypogonadal state (47 ± 7 mg/dL). Comparison of lipid levels 5–7 days after im injection and after 8 weeks of buccal T therapy showed significantly higher levels of total cholesterol (P = 0.045) and HDL (P = 0.016) in the group treated with buccal T. No differences in lipid parameters were found between patients during periods of buccal T therapy and androgen withdrawal.
Adverse events. All men receiving the active buccal therapy or the taste-matched placebo complained of a tolerable bitter taste.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Administration of the buccal dosage form of T significantly (P = <0.001) elevated levels of T compared with levels in patients given placebo (2790 vs. 136.0 ng/dL). The pattern of delivery was pulsatile, with peak levels occurring within 30 min of ingestion of the buccal tablets and levels returning to baseline within 4–6 h of administration. Importantly, T levels were supraphysiological for only 1.5–4 h immediately after buccal administration. This contrasts with the experience with im injected preparations, which often produce T levels above the upper limit of normal for several days after administration (3). We evaluated men of varying ages and did not observe any consistent differences between age and pharmacokinetics. However, our sample size was inadequate for a complete analysis.
Accumulation of T did not occur, even with daily treatment for 8 weeks. This finding was not unexpected, as the 30- to 100-min estimated half-life of T (5, 14, 15, 16) is considerably shorter than the 12- or 24-h treatment interval. Not surprisingly, in men with primary testicular failure, serum gonadotropin levels were lower in men treated with im T than levels during the hypogonadal state or after treatment with buccal T. The lack of effect of the buccal T preparation on gonadotropin suppression can be attributed to the lower total T exposure (area under the curve) compared to that with im treatment.
Of particular interest is the impact of the buccal formulation on
levels of T metabolites, especially DHT. The scrotal T delivery system
(Testoderm T transdermal system, Alza Pharmaceuticals, Palo Alto, CA)
mentioned above produces T concentrations within normal ranges.
However, with continued daily use, serum DHT levels are elevated 4- to
10-fold (2, 17, 18, 19, 20). In contrast, the buccal T formulation produced DHT
levels in the normal range for eugonadal men (25–95 ng/dL). The values
for the buccal tablet are based on a single dose of 10 mg T. The area
under the curve for DHT using 10 mg buccal T is only 31% of the 24-h
DHT concentration achieved with use of the scrotal patch. The 24-h T
load to the systemic circulation (7730 pg/h·mL) for a 10 mg/day dose
is roughly equivalent to the T level of 6960 pg/h·mL obtained with
the scrotal patch. Thus, the buccal T formulation, although producing
comparable T levels, considerably reduces the impact of DHT on the
system (Table 4).
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No apparent complications related to treatment were noted after 8 weeks of buccal T therapy. Elevations in hemoglobin with androgen treatment can be either beneficial or detrimental. This form of replacement therapy may be of advantage in men with elevated hemotocrits. HDL levels did not decrease, as has been observed with other T modalities (24, 25), suggesting that the lower total exposure to T may not cause the usual fall in HDL observed with other forms of T administration. Moreover, serum prostate-specific antigen levels remained in the normal range, and there were no signs of prostatism. This suggests a possible advantage of the buccal formulation, which has only a limited daily effect on T-sensitive tissues such as the prostate.
In conclusion, this buccal formulation of T significantly elevated levels of T in hypogonadal men and improved both objective and subjective measures of sexual function. Further, the buccal tablets were well tolerated and were not associated with clinically significant effects on prostate or lipid parameters. Thus, buccal T may prove an important alternative for T replacement in hypogonadal men and warrants further evaluation in long term studies.
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Footnotes |
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Received January 16, 1997.
Revised September 2, 1997.
Accepted September 27, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-androstane-17ß-ol-3-one (dihydrotestosterone) by
skin slices of man. J Clin Invest. 48:371–379.
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) or placebo
(
) buccal tablets. Subjects were studied at the time of initial
exposure and after 8 weeks of daily therapy.
