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Department of Endocrinology (M.K., A.B.G.), St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom; University of Freiburg (M.S., M.R.), Freiburg 79110, Germany; Royal Hallamshire Hospital (D.C., R.J.R.), Sheffield, United Kingdom; Department of Endocrinology (G.S., H.S.), Max-Planck Institute of Psychiatry, Munich 80804, Germany; and Royal Free Hospital (P.M.B.), London NW3 2QG, United Kingdom
Address all correspondence and requests for reprints to: Prof. Ashley B. Grossman, Department of Endocrinology, St. Bartholomew’s Hospital, London, EC1A 7BE, United Kingdom. E-mail: a.b.grossman{at}qmul.ac.uk
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Abstract |
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Sixty-six patients were randomized into two groups; one applied the buccal system twice daily, whereas the other applied the transdermal patch daily, in each case for 7 d. Serum total testosterone and dihydrotestosterone concentrations were measured at d 1, 3 or 4, and 6, and serially over the last 24 h of the study. Pharmacokinetic parameters for each formulation were calculated, and the two groups were compared. The tolerability of both formulations was also evaluated.
Thirty-three patients were treated with the buccal preparation, and 34 were treated with the transdermal patch. The average serum testosterone concentration over 24 h showed a mean of 18.74 nmol/liter (SD =; 5.90) in the buccal system group and 12.15 nmol/liter (SD =; 5.55) in the transdermal patch group (P < 0.01). Of the patients treated with the buccal system, 97% had average steady-state testosterone concentrations within the physiological range (10.41–36.44 nmol/liter), whereas only 56% of the transdermal patch patients achieved physiological total testosterone concentrations (P < 0.001 between groups). Testosterone concentrations were within the physiological range in the buccal system group for a significantly greater portion of the 24-h treatment period than in the transdermal patch group (mean, 84.9% vs. 54.9%; P < 0.001). Testosterone/dihydrotestosterone ratios were physiological and similar in both groups. Few patients experienced major adverse effects from either treatment. No significant local tolerability problems were noted with the buccal system, other than a single patient withdrawal. We conclude that this buccal system is superior to the transdermal patch in achieving testosterone concentrations within the normal range. It may, therefore, be a valuable addition to the range of choices for testosterone replacement therapy.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Striant is a controlled- and sustained-release buccal mucoadhesive system containing 30 mg of testosterone and bioadhesive excipients. It was approved by the U.S. Food and Drug Administration June 19, 2003, as "Striant (testosterone buccal system) mucoadhesive." In the current study, we compared the effect and the safety profile of this buccal system (administered twice daily) to a registered testosterone transdermal patch (5 mg, once a day) for the treatment of testosterone deficiency in men for 7 d in a randomized, open-label, multicenter, parallel arm study.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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We enrolled 67 patients at five sites in the United Kingdom and
Germany. All sites were tertiary regional referral centers for
endocrine disorders. Patient characteristics are shown in Table 1
. Testosterone-deficient men with a
morning (0900 h) serum testosterone less than 6.94 nmol/liter, normal
age-related prostate-specific antigen levels, and hematocrit less than
50 were included in the study. Patients with an American
Urological Association System Index for Prostatism score greater than 7
were excluded. After an appropriate washout period of their previous
testosterone replacement (>6 months for implants, >4 wk for
injections, and >1 wk for skin patches), patients had a baseline
series of blood investigations performed (including alanine
aminotransferase, 
-glutamyl transpeptidase, sodium, potassium,
creatinine, total cholesterol, high-density lipoprotein, triglycerides,
and glucose), a 12-lead electrocardiogram, blood count
(including hemoglobin, hematocrit, white blood cell and differential
count, and red blood cell count) and physical examination. If eligible
for the study, they formally consented and then received either the
buccal system (30 mg twice daily at 0800 and 2000 h) or the
transdermal patch (5 mg once a day at 2200 h) in a randomized
manner. Twice-daily blood samples were taken on d 3, 4, and 6, and
multiple 24-h blood samples were taken on d 7 and 8. A follow-up visit
with blood sampling occurred at 2–14 d after treatment was
discontinued.
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Serum was assayed for total testosterone [IMMULITE, Diagnostic Products Corp., Los Angeles, CA (11); normal range, 10.41–36.44 nmol/liter], dihydrotestosterone (DHT) (RIA with extraction, Esoterix, San Diego, CA; normal range, 1.03–2.92 nmol/liter), estradiol [IMMULITE, Diagnostic Products Corp.; normal range (male) <0.21 nmol/liter], FSH, LH, SHBG, full blood count, and liver function tests (Nova-Medical, Medi-Lab, Copenhagen, Denmark).
In each center, the appropriate ethical committee approval was sought and obtained before any patient was initiated into the trial, and all patients provided written informed consent.
Formulations
Andropatch (SmithKline Beecham Pharmaceuticals, Uxbridge, UK) or Androderm (Astra/Promed, Lutan, UK) 5 mg was supplied as single patches and used according to the manufacturers’ instructions. In brief, a patch was applied once each day to a clean, dry, hairless area, and the site of application rotated over the course of 7 d. The buccal system (Striant) was supplied as a mucoadhesive system containing 30 mg of testosterone dispersed in a matrix containing the bioadhesive polymer, polycarbophil, along with other inert ingredients including hydro-xypropylcellulose, monohydrated lactose, and cornstarch. The testosterone is slowly released from the matrix after buccal application. At application, each system was held in position on the gum above the right or left canine for a period of 30 sec. They were then left in situ for 12 h, after which the system was slid gently downward and replaced by another system for the next dosing interval.
Statistical analysis
Sample size estimation was performed on the basis of the
following assumptions on the mean testosterone levels in steady state:
average control mean total testosterone level was assumed to be 17.35
nmol/liter (SD = 34%) and of the buccal system 19.09
nmol/liter (SD =12%). Because mean serum concentrations
less than 10.41 nmol/liter define testosterone deficiency, the effect
size (d) of the control treatment vs. no treatment
was estimated to be 6.94 nmol/liter. The noninferiority margin 
< d was set to 2/3(d) = 4.65 nmol/liter. According to appropriate
guidelines on statistics in clinical trails, the 
-level for this
one-sided comparison was set to 0.025. The power of the test (1 –
ß) was required to be 80%. Then sample size N per group was
estimated using the following formula:
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and
z1–ß, denote the 100 x (1 – )
% and the 100 x (1 – 0.8) % points of the standard normal
distribution, respectively. Because the SD of
difference is not known a priori, calculations were
made for different values of SD varying from 0.69
to 5.90 nmol/liter. As a conservative assumption, it is assumed that
SD will not exceed 5.90 nmol/liter; therefore, a
sample size of 26 patients per group would be required. The
noninferiority lower limit has been set to be above 80% for the ratio
of least-squares geometric means, rather than above 4.65 nmol/liter for
the difference between means. Ninety percent confidence intervals (CIs)
for the originally planned difference between nontransformed means and
the protocol-specified 95% CIs were also calculated. The primary analysis, noninferiority, and the secondary analysis, superiority of the buccal system vs. the transdermal patch was calculated on the same endpoint by ANOVA using 95% CIs. Fisher’s exact test, mean and SD, or median and minima and maxima were used as appropriate.
Pharmacokinetic analysis
Concentration vs. time data were summarized by noncompartmental estimation methods using the PK software program WinNonlin Professional (versions 3.1 and 3.2) (Pharsight, Mountain View, CA). The following pharmacokinetic parameters were analyzed:
An analysis was performed to assess the homogeneity of the treatment effects across centers by the inclusion of a treatment by center interaction term in the ANOVA model for the primary analysis. This term was not statistically significant and was therefore not included in the model. Hence, conclusions can be made consistently across all centers. The statistical package SAS (version 8.2; SAS Institute, Cary, NC) was used. Significance was taken at P < 0.05.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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). Mean testosterone levels on d 7 and 8
are shown in Fig. 2. In the buccal system
group, the mean concentrations at all time points were within the
physiological range. By contrast, in the transdermal patch group, mean
concentrations at five timepoints were outside of the physiological
range. For both mean (0–24 h) and minimum testosterone levels, the
proportion of patients with values outside the physiological range was
lower in the buccal system group than in the transdermal patch group,
the differences being statistically significant (P <
0.001 for both). For peak testosterone levels, the proportion of
patients with values outside the physiological range was higher in the
buccal system group, although this was not statistically significant.
The serum testosterone concentrations over the 24-h period were higher
for patients receiving the buccal system than for patients in the
transdermal patch group (mean AUC ± SD,
451.31 ± 140.71 h*nmol/liter vs. 304.63 ± 134.46
h*nmol/liter; 95% CI 1.25, 1.91; P < 0.00001). For
the buccal system group, the mean maximum 24-h testosterone (31.58
nmol/liter) and the mean minimum 24-h testosterone (11.10 nmol/liter)
values were within the physiological range. For the transdermal patch
group, the mean maximum 24-h testosterone levels (20.68 nmol/liter)
were within the physiological range, but the mean minimum 24-h
testosterone levels (5.76 nmol/liter) were below the physiological
range. The proportion of subjects within the physiological range over
24 h was 84.8% for the buccal system and 55.1% for the patch
group. The proportion of patients above 10.41 nmol/liter over 24 h
was 88.4% for the buccal system group and 55.1% for the patch group.
For the buccal system group, 27.7% had a peak level above 36.44
nmol/liter, whereas none were above this level in the patch group.
Testosterone concentrations were within the physiological range in the
buccal system group for a significantly greater portion of the 24-h
treatment period than in the transdermal patch group (mean, 84.9%
vs. 54.9%; P < 0.001). Overall, these
results indicate that patients receiving the buccal system were more
likely to have testosterone concentrations within the physiological
range than patients receiving a transdermal patch.
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The median estradiol concentrations increased from baseline to d 7, and returned to baseline values at the follow-up visit. The median increase from baseline to d 7 was significantly greater in the buccal system group (55.07 pmol/liter) than in the transdermal patch group (34.87 pmol/liter; P < 0.001). After discontinuation of treatment, the levels rapidly returned to baseline values.
The percentage of patients reporting adverse events (AEs) in all body systems were similar between the two groups, with 17 patients (51.5%) in the buccal system group reporting a total of 28 AEs, and 16 patients (47.1%) in the transdermal patch group reporting a total of 37 AEs. A single patient was discontinued from the buccal system group due to tenderness and blistering of the gum. The most common AEs reported for both treatment groups were application-site disorders [reported by six patients (18.2%) in the buccal system group and six patients (17.6%) in the transdermal patch group]. Patients in both groups experienced application-site erythema [reported by two patients (6.1%) in the buccal system group and five patients (14.7%) in the transdermal patch group] and application-site irritation [two patients (6.1%) in the buccal system group and one patient (2.9%) in the transdermal patch group].
There were no clinically significant changes in mean or median hematology or clinical chemistry parameters from baseline to follow-up in either treatment group.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Current forms of injectable testosterone include the long-established depot injections and implants. The depot injections currently consist of a mix of one or more oily esters, and are extremely cheap, but need to be repeated every 1–4 wk. They can also be painful by im injection. However, the most unacceptable aspect of these formulations is the grossly nonphysiological pharmacokinetic profiles of testosterone that they produce (6, 14). This can be improved by giving smaller doses more frequently, e.g. 100 mg weekly, but clearly at the expense of comfort and convenience (14). The recently introduced longer-acting injectable testosterone undecanoate needs injections every 10–12 wk, and wider experience will establish its place in testosterone replacement therapy (10). Implants are generally more acceptable to patients, but the actual implantation requires a surgical procedure, albeit a small one, and unless they are being performed in a center with considerable experience in their use, there can be unacceptably high extrusion rates. Oral testosterone undecanoate rarely produces physiological levels of testosterone and must be administered several times a day (15).
The newer testosterone patches were thought originally to offer a superior form of replacement therapy, but due to the requirement for a high dose of testosterone to be delivered transdermally, the current patches are relatively large and can be cosmetically unsightly. The high rate of dermatological AEs experienced with some of these formulations has also limited their use (16). The scrotal patch, although providing physiological levels of testosterone, results in supraphysiological levels of DHT as a consequence of the high rate of testosterone metabolism in scrotal skin compared with that at other dermal application sites (17). There are increasing amounts of available data on the dermal gel formulation, suggesting it to be effective and without any application-site side effects and negligible interpersonal testosterone transfer (7, 8, 9, 11, 12, 18, 19, 20). A preliminary study of the use of a different, noncontrolled/sustained release buccal testosterone preparation has been reported earlier, where six subjects were taking one or two 10-mg buccal systems applied to the lower gum (21). Testosterone levels rose to within the normal range and improved scores in sexual function were achieved, although the duration of the increased testosterone level after the application of the system was rather short (2–4 h) (21). A sublingual preparation, cyclodextrin testosterone, has also been tested in the past, but limited experience is available with this preparation (22). More recently, three doses of a buccal preparation were tested on healthy volunteers pretreated with gonadotropin agonist, and favorable hormone profiles were achieved (23).
Our results show that this testosterone buccal system mucoadhesive produces physiological testosterone levels in hypogonadal men, and is superior to the transdermal patch in achieving testosterone concentrations within the normal range. It represents a promising new agent that requires further longer-term study.
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Acknowledgments |
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Footnotes |
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Abbreviations: AE, Adverse event; AUC, area under the curve; CI, confidence interval; DHT, dihydrotestosterone.
Received February 24, 2003.
Accepted October 15, 2003.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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-androstan-17 ß-ol-3-one (dihydrotestosterone)
by skin slices of man. J Clin Invest 48:371–379
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