Pharmacokinetics and Relative Bioavailability of Absorbed Testosterone After Administration of a 1.62% Testosterone Gel to Different Application Sites in Men With Hypogonadism

Jodi Miller, PharmD, MS; Margaret Britto, PhD; Sherahe Fitzpatrick, MD; Cecilia McWhirter, MS; Samuel A. Testino Jr, PhD; John J. Brennan, PhD; Troy L. ZumBrunnen, PharmD

Disclosures

Endocr Pract. 2011;17(4):574-583. 

In This Article

Results

Patient Disposition and Demographics

A total of 36 men with hypogonadism were enrolled in this study and received at least one dose administration of study medication; 32 study subjects were included in the pharmacokinetic analyses, and 36 were included in the safety analyses. Four patients did not complete the study as planned. Of these 4 patients, 1 was withdrawn from the study because of an AE of dermatitis on the lower leg area, 2 were withdrawn because of predose testosterone levels >900 ng/dL (in accordance with protocol stipulations), and 1 chose to withdraw consent.

Of the 36 male subjects, 32 (89%) were classified as white and 4 (11%) were classified as black; 18 subjects (50%) were Hispanic or Latino. Overall, subjects enrolled in the study had a mean (± standard deviation) age of 51.7 (± 10.7) years (range, 29 to 73), mean height of 1.760 (± 0.072) m (range, 1.62 to 1.90), mean weight of 95.84 (± 11.65) kg (range, 73.4 to 113.9), and mean BMI of 30.89 (± 3.35) kg/m2 (range, 21.7 to 37.0). The age distribution was as follows: 3 subjects were 29 to 35 years old, 6 were 36 to 45 years old, 13 were 46 to 55 years old, 10 were 56 to 65 years old, and 4 were 66 to 73 years old.

Serum Hormone Levels

Before study entry, all study subjects were to have a single documented serum testosterone concentration <300 ng/dL at screening, based on chemiluminescent assay performed by the local site laboratory. All further testosterone concentrations obtained to support the primary end point were analyzed by LC-MS/MS. From the pharmacokinetic sampling assessments measured by the bioanalytical laboratory (LC-MS/MS method), mean baseline (day −1) concentrations of measured testosterone ranged from 65 to 847 ng/dL, with 18 subjects having at least 1 concentration >300 ng/dL at baseline.

After treatment with 1.62% testosterone gel, mean serum testosterone concentrations were within the eugonadal range (300 to 1,000 ng/dL) within 2 hours after a single drug administration on treatment day 1 and for the entire 24-hour dosing interval on treatment day 7 for all treatments.

On both treatment days 1 and 7, mean serum testosterone concentrations were higher for treatment B (application to the upper arms/shoulders) in comparison with treatment A (abdominal application). Treatment C yielded similar mean testosterone concentrations to treatment A on treatment day 1 (both treatments being abdominal applications on that day) and similar to treatment B on treatment day 7, when both of these applications were to the upper arms/shoulders. Mean DHT and E2 concentration-time profiles after treatment with testosterone gel followed the same general pattern as the testosterone data (Fig. 1).

Figure 1.

Mean serum testosterone (A and B), dihydrotestosterone (C and D), and estradiol (E and F) concentrations versus time profiles at baseline (day −1) and on treatment day 1 (single dose) and treatment day 7 (multiple doses). Light gray horizontal line (in A and B) = testosterone eugonadal range. Treatment A = once-daily application of 5.0 g of 1.62% testosterone gel to the abdomen for 7 days; treatment B = once-daily application of 5.0 g of 1.62% testosterone gel to the upper arms/shoulders for 7 days; and treatment C = once-daily application of 5.0 g of 1.62% testosterone gel to the abdomen for 3 days, followed by application to the upper arms/shoulders for 4 days.

Pharmacokinetic Results

Pharmacokinetic variables for testosterone on treatment days 1 and 7 of each treatment are summarized in Table 1. Mean observed Cav values were within the eugonadal range for all 3 treatments for both treatment days. Median tmax values (16 hours) were similar on treatment day 1 for all 3 treatments. Median tmax occurred at 4 to 8 hours on treatment day 7. Accumulation from treatment day 1 to treatment day 7, as measured by the accumulation ratios for AUC0–24 and Cmax, was greater for treatment A (1.35 and 1.50) than for treatment B (1.30 and 1.43, respectively). Treatment C showed the highest accumulation, 1.84 and 2.11, for treatment days 1 to 7. This reflected the change in application site from the abdomen on treatment day 1 to the upper arms/shoulders on treatment day 7.

Results of the statistical comparison of AUC0–24 and Cmax variables for testosterone for treatments A, B, and C on treatment days 1 and 7 are shown in Table 2. On treatment day 1, bioavailability was significantly (P<.0001) lower after treatment A (abdominal application) in comparison with treatment B (application to the upper arms/shoulders), with 33% and 38% decreases in mean AUC0–24 and Cmax values, respectively. Likewise, on treatment day 7, bioavailability was found to be significantly (P<.0001) lower for treatment A, with approximately 34% and 39% lower AUC0–24 values and Cmax values, respectively, in comparison with treatment B.

For treatment C (alternating application site schedule), AUC0–24 and Cmax values were 28% and 34% lower (P<.0001), respectively, than for treatment B (application to the upper arms/shoulders) on treatment day 1, whereas on treatment day 7 they were similar to those for treatment B. In comparison with treatment A (abdominal application), treatment C AUC0–24 and Cmax values were similar on treatment day 1 and 47% and 54% higher (P<.0001), respectively, on treatment day 7. The change in the application site in treatment C from treatment day 1 to day 7 complicates the interpretation of the relative bioavailability measurements for this treatment.

Steady-state testosterone concentrations were achieved by at least treatment day 2 for both treatments A (abdominal application) and B (upper arms/shoulders application) (Fig. 2). For treatment C (alternating application site schedule), steady-state conditions appeared to have been initially achieved by treatment day 2 during the abdominal application phase; however, conditions changed after treatment day 4, a reflection of the change in application site from the abdomen to the upper arms/shoulders after collection of the predose sample on treatment day 4. For treatments A (abdominal application) and B (upper arms/shoulders application), no statistically significant differences were observed in predose serum concentrations for any of the treatment days evaluated (days 2 to 7; earlier treatment days in comparison with later days; P>.1), indicating that steady state was achieved by day 2. For treatment C (alternating application site schedule), statistically significant differences (P<.1) were observed when days 2, 3, and 4 were compared with later days. These findings were a consequence of the change in application site that occurred on day 4.

Figure 2.

Mean predose trough serum testosterone concentration versus time profiles on treatment days 1, 2, 3, 4, 5, 6, and 7. See Figure 1 legend for details about treatment groups.

After the last application of testosterone gel on treatment day 7, mean testosterone concentrations returned approximately to baseline (day -1) levels after 48 hours for treatment A and after 72 hours for treatments B and C (Fig. 3).

Figure 3.

Mean serum testosterone concentration versus time profile after day 7 application of 1.62% testosterone gel across all treatments. See Figure 1 legend for details about treatment groups.

Safety

A total of 31 subjects (86%) exposed to study medication reported at least one treatment-emergent AE during the course of this study (Table 3). Application site treatment-emergent AEs were among the most frequent nonserious treatment-emergent AEs (reported in ≥10% of study subjects) and included 7 subjects (19%) with application site excoriations, 5 (14%) with application site papules, and 4 (11%) with application site dermatitis. Other nonserious treatment-emergent AEs were dry skin, arthropod bite, pruritus, and headache reported by 22%, 14%, 11%, and 11% of subjects, respectively. There was no placebo or other active treatment group to provide a comparison for AEs. One subject was withdrawn from the study because of an unrelated serious AE of dermatitis on the lower leg.

The frequency of nonserious treatment-emergent AEs was greatest in the treatment B group (application to the upper arms/shoulders—20 of 34 or 59%), in comparison with 19 of 34 (56%) in treatment A (abdominal application) and 16 of 34 (47%) in treatment C (alternating application site schedule). Most nonserious treatment-emergent AEs reported were mild in severity. Six subjects (17%) experienced events of moderate severity, including pain, pruritus, dermatitis, arthralgia, diarrhea, gastroesophageal reflux disease, headache, and folliculitis, each reported in 1 of 36 subjects (3%). No study subjects experienced treatment-emergent AEs of severe intensity.

Mean hematocrit decreased by −0.37% (range, −5.2% to 8.0%), and mean hemoglobin decreased by −1.6 g/dL (range, −16.0 to 29.0). Mean triglycerides, high-density lipoprotein, low-density lipoprotein, and very-low-density lipoprotein cholesterol levels decreased by −1.03 mmol/L (−17.16 to 0.46); −0.12 mmol/L (−0.40 to 0.12); −0.43 mmol/L (−1.27 to 1.47); and −0.47 mmol/L (−7.70 to 0.21), respectively. There were no overall trends in hematology or lipids that were judged to be clinically important. Similarly, no trends or clinically significant changes were noted in the clinical laboratory data, vital signs data, application site assessments, or ECG. Moreover, no significant findings on DRE or changes in PSA or IPSS were noted. No deaths occurred during the course of this study.

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