Testosterone supplementation for hypogonadal men by the nasal route (2008)
Abstract
Although multiple forms of testosterone replacement therapy are available to treat hypogonadism, none is ideal.
This article reports on the pharmacokinetics of an innovative nasal formulation of testosterone in hypogonadal men. The first study was undertaken in eight men with a baseline total testosterone (TT) of 130.8 ± 87.4 ng/dL and examined the pharmacokinetics of nasal testosterone given in a single dose of 7.6 mg, 15.2 mg, or 22.8 mg, respectively. The second study examined the pharmacokinetics of nasal testosterone (7.6 mg) given either twice or three times a day in 21 severely hypogonadal men (baseline TT in 20 patients <50 ng/dL, in one patient 152 ng/dL) for 14 days. The steady-state concentration of testosterone was within the normal range in all treatment groups, but only in the 3-times-a-day group was the 95% confidence interval completely within the physiological range. The average DHT level did not exceed the upper range of normal. The clinical global visual analog scale improved in the whole group receiving testosterone (p < 0.001). All adverse events in both studies were of mild to moderate intensity and were evaluated as unlikely or not related to the administered study drug. No patients dropped out during treatment.
Comparison with the normal circadian rhythm by computer modeling suggests that nasal testosterone can be used to mimic the normal diurnal pattern in eugonadal men. Thus, nasal testosterone can be administered safely to humans in doses that approximate serum concentrations in the normal physiological range.
Methods
*The test product (MPP 10, M et P Pharma AG) is a semisolid formulation containing testosterone. One applicator, intended for administration to one nostril, delivers 120 mg of a gel comprising 3.8 mg of testosterone in a proprietary formulation, consisting of castor oil, a mixture of glycerides and polyethylene esters, and a gelling agent. The product contains no preservatives and is filled into white unit-dose applicators that are formed using blow-fill-seal technology. One dose is given as one applicator per each nostril (i.e. a total dose of 7.6 mg of testosterone).
Study A
The objective of the study was to determine the pharmacokinetics of testosterone and DHT after single-dose administration of three different doses of MPP 10 and to determine the dose level for further studies. Eight hypogonadal men between 22 and 62 years (39.3 + 14.8 years), BMI 26.8 +5.4 kg/m2, were included and had morning serum TT levels at screening of 130.8 +87.4 ng/dL. Seven cases were with secondary hypogonadism (three prolactinomas, two non-functioning pituitary adenomas, one Kallmann’s syndrome, one with idiopathic hypogonadotropic hypogonadism); one case was identified as Klinefelter syndrome.
Design. Open, sequential, single escalating dose study (three treatment days, 7 days between the treatment days as wash-out period).
Dosing. Treatment Day 1: 7.6 mg testosterone;
Treatment Day 2: 15.2 mg testosterone;
Treatment Day 3: 22.8 mg testosterone.
Blood sampling. 0, 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 16, 24 h post-dose.
Pharmacokinetic evaluation TT. Cmax ¼ maximum concentration, Tmax ¼ time of maximum concentration, AUC0–24 h ¼ area under the curve, estimated for 0–24 h using the trapezoidal rule, NAUC0–24 h ¼ Normalised AUC, i.e. AUC/dose. For statistical comparisons (dose-linearity), baseline correction was applied by subtracting the baseline from all measured TT values before calculating Cmax and AUC. The baseline was calculated as the mean of the pre-dose and the 24 h TT value unless these values differed for more than a factor 2. If the latter was the case, the lowest value of the pre-dose and the 24-h concentration was used as the baseline. Zero was substituted for those values that became negative after baseline subtraction.
Safety monitoring. DHT levels, ear-nose-throat (ENT) and prostate examination, adverse events, laboratory measurements, vital signs.
Study B
The objective of the study was to determine the optimum dose scheme for the treatment with MPP 10. Twenty-one hypogonadal men were included. The characteristics of the patients are given in Table I.
Design. Open, randomized, multiple-doses, three arms, parallel-group study.
Dosing. (14 days): Group B1 – 7.6 mg testosterone two times a day (08:00 h, 14:00 h),
Group B2 – 7.6 mg testosterone two times a day (08:00 h, 20:00 h),
Group B3 – 7.6 mg testosterone three times a day (08:00 h, 14:00 h, 20:00 h).
Blood sampling. Days 1–13: pre-dose sample collection (between 06:00 and 07:00 h).
Day 14: blood sampling at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 6.25, 6.5, 6.75, 7, 7.5, 8, 9, 10, 12, 14, 16, 18 and 22 h after the morning administration.
Pharmacokinetic evaluation TT. Cmin ¼ minimum concentration, Cmax, AUC0–24 h, NAUC0–24 h, Cav ¼ average concentration, calculated as AUC0–24 h/24, PTF ¼ peak-trough fluctuation, calculated as (Cmax7 Cmin)/Cav. For comparison with Study A and for between-group comparisons, AUC0–24h was calculated applying a baseline correction. As baseline values the individual pre-dose TT concentrations before first study administration were taken. This baseline was applied assuming that suppression in this study was minimal because baseline TT was virtually at castrating level for most men.
Safety monitoring. DHT levels, ENT and prostate examination, adverse events, laboratory measurements, vital signs.
Results
Study A
Serum T levels and pharmacokinetics. Mean concentration-time curves of testosterone after administration of the three different doses of MPP 10 are shown in Figure 1.
The results indicate that physiological testosterone levels can be reached with all doses applied and that a dose of 22.8 mg does not produce supraphysiological concentrations. It must be emphasized that this latter dose was mainly investigated for safety reasons, and it is important to note that even with this dose concentrations did not substantially exceed those obtained with the 15.2 mg dose of testosterone.
Figure 1. Pharmacokinetic profile of TT (solid squares) and DHT (open squares) after single-dose administration of different doses of MPP 10 in study A. 7.6 mg T (squares), 15.2 mg T (circles), 22.8 mg T (triangles). The dashed line denotes lower limits of the normal range of TT based on morning serum samples. Error bars denote mean+SD.
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The pharmacokinetic parameters are listed in Table II.
The AUC did not linearly depend on the dose. The (baseline corrected) AUC 0–24 almost doubles with a dose of 15.2 mg as compared with 7.6 mg but only increases marginally when the dose is further increased to 22.8 mg. Also, the increase for Cmax is bigger between the low and medium dose than between the medium and the high dose. The maximum serum concentration is reached between 1 and 2 h after administration indicating a rapid absorption from the intranasal cavity.
Table II. Pharmacokinetic parameters of TT in study A after single escalating doses of MPP 10 in 8 men.
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Serum DHT levels. The concentration of DHT is in the low physiological range for a short time, decreasing thereafter (Figure 1).
The risk of supraphysiological concentrations is negligible.
Adverse events. Two adverse events (fever, nausea) occurred in one patient before the first administration. This patient was excluded from the study. There were no further drop-outs.
Study B
Serum T levels and pharmacokinetics. In this study, patients with very severe hypogonadism, virtually having castrated TT levels, were included. The pharmacokinetic parameters of testosterone for the three treatment groups are compiled in Table III, the corresponding serum concentration-vs.-time curves are shown in Figure 2.
Table III. Study B.
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Group B1– 7.6 mg testosterone two times a day (08:00 h, 14:00 h)
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time after administration (1h)
Group B2– 7.6 mg testosterone two times a day (08:00 h, 20:00 h)
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time after administration (1h)
Group B3- 7.6 mg testosterone three times a day (08:00 h, 14:00 h, 20:00 h)
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time after administration (1h)
The normalized baseline-corrected AUC values show that the extent of absorption of testosterone is virtually the same in each group. Cmin is low in all groups, but the patients started with very low baseline TT concentrations.
The trough concentrations rise rapidly during the first two days from the initial low castrate TT levels to reach a new steady-state between *200 and 400 ng/dL.
The mean of average steady-state concentrations remains within the physiological range in all treatment groups, but only in group B3 (t.i.d. administration), the 95% confidence interval is also entirely within the physiological range. In all groups, Cmax values of individual patients sometimes slightly exceeded the upper limit of the physiological range. Excursions above the physiological range are short-lasting. Twelve of a total of 22 values higher than 1000 ng/dL were observed in a single patient, who started with a trough level of 900 ng/dL after 13 days of dosing with the three times daily dosing regimen.
Serum DHT levels. The pharmacokinetic parameters of DHT for the three treatment groups are shown in Table IV.
These show that the average steady-state concentration of DHT did not exceed the upper limit of the physiological range (85 ng/dL), indicating no particular safety risk due to DHT pharmacokinetics. The corresponding serum concentration-vs.-time curves are shown in Figure 2. The curves show that even in group B3 the risk of a DHT level above the upper limit of the physiological range for a longer time is low. The larger standard deviations in groups B2 and B3 are caused mainly by the high concentrations in one patient each.
Adverse events. A total of 36 adverse events were observed during study B. All adverse events were of mild or moderate intensity. No serious adverse events were observed. The following organ systems were affected: psychiatric disorders, nervous system disorders, respiratory, thoracic, and mediastinal disorders, gastrointestinal disorders, skin, and subcutaneous tissue disorders, musculoskeletal, connective tissue, and bone disorders, renal and urinary system disorders, general disorders, and administration site condition. None of these events were evaluated as at least possibly related to drug treatment. No adverse values (i.e. improvement of condition) on day 14 compared with day 1 were observed. An important experience was that the AMS questionnaire was not fully compatible with the situation of the particular patients.
Discussion
The results of study A indicate that testosterone is well absorbed after nasal administration of different doses of MPP 10. The maximum serum concentration of testosterone is reached between 1 and 2 h after administration.
The exposure to exogenous testosterone increases approximately linearly between 7.6 and 15.2 mg but levels off with the higher dose of 22.8 mg. At dose levels above 15 mg absorption may be limited due to the restricted volume for nasal application of 0.05–0.15 mL [27]; because of the low solubility of testosterone, the medium and the high dose had to be administered by increasing the application volume to 0.24 and 0.36 mL, respectively.
*Thus, the lack of a further linear increase of testosterone levels with higher doses may reflect a saturation phenomenon at the site of absorption.
