Long Acting Testosterone Undecanoate Therapy in Men With Hypogonadism: Results of a Pharmacokinetic Clinical Study

Article Outline

• Abstract
• Methods
  • Patients
  • Bioanalytical Methods
  • Statistical Methods
• Results
  • Disposition and Demographics
  • Pharmacokinetics
  • Safety Parameters
• Discussion
• Conclusions
• Acknowledgments
• Appendix. The M-PGA Sample
• References
• Copyright

Purpose

We determined the pharmacokinetics and safety of 750 mg long acting testosterone undecanoate given intramuscularly at 0, 4 and 14 weeks to men with hypogonadism.

Materials and Methods

A 24-week, single arm, open label, multicenter trial in 130 hypogonadal men 18 years or older who were screened for serum total testosterone less than 300 ng/dl was performed at 31 research sites in the United States between March and November 2007. Testosterone undecanoate (750 mg) was administered at baseline, and at weeks 4 and 14. Serum testosterone samples were collected on days 4, 7, 11, 14, 21, 28, 42, 56 and 70 following injection 3. Safety was assessed, eg biochemical markers and adverse events, secondary to testosterone undecanoate treatment.

Results

Of the 130 patients 116 with a mean ± SE age of 54.2 ± 0.90 years completed the 24-week trial. Following the week 14 injection mean ± SD average serum testosterone was 494.9 ± 141.46 ng/dl during the 70-day dosing interval and mean ± SD maximum serum testosterone was 890.6 ± 345.11 ng/dl with a mean concentration within the young healthy adult male range (300 to 1,000 ng/dl) in 94% of patients and a mean maximum concentration of below 1,500 ng/dl in 92%. Mean ± SE hematocrit and hemoglobin increased from baseline to week 24 (43.3% ± 0.32% to 45.7% ± 0.35% and 14.6 ± 0.11 to 15.5 ± 0.13 gm/dl, respectively). Mean ± SE prostate specific antigen increased from baseline to 24 weeks (1.0 ± 0.08 to 1.3 ± 0.10 ng/ml). No prostate cancer or gynecomastia was observed during this 24-week study.

Conclusions

This 24-week clinical study demonstrated that 750 mg testosterone undecanoate depot injection administered intramuscularly at 0, 4 and 14 weeks achieves serum testosterone levels in the normal range during a 10-week dosing interval.

Key Words: testis, hypogonadism, testosterone, pharmacokinetics, injections, intramuscular

Abbreviations and Acronyms: AE, adverse event, BMI, body mass index, Cavg, mean concentration, Cmax, maximum concentration, Cmin, minimum concentration, FDA, Food and Drug Administration, M-PGA, male patient global assessment, PSA, prostate specific antigen, Tmax, time to maximum concentration, TU, testosterone undecanoate

Hypogonadism in men is a common clinical condition characterized by a deficiency of endogenous testosterone production that affects 4 to 5 million men in the United States.¹, ², ³ The normal range of serum testosterone in healthy men is generally defined as 300 to 1,000 ng/dl, although the range used can vary among laboratories depending on the assay method used and population characteristics.²

Various delivery methods are available for testosterone therapy, including oral preparations, transdermal patches and gels, buccal formulations, subcutaneous implants and intramuscular injection.², ⁴, ⁵, ⁶ Men who receive testosterone therapy show improvement in the signs and symptoms of hypogonadism, such as increased sexual interest and function, as well as improvements in mood, energy, bone density, muscle mass and sex hormone levels.⁷ However, all testosterone therapies have characteristics that can limit their usefulness. For instance, patients may be averse to the daily application of transdermal gels or patches, or object to frequent injections of current intramuscular formulations.

The undecanoate ester formulation of natural testosterone is a long acting, intramuscular, injectable testosterone therapy option that extends the current maximum treatment dosing interval approximately 4-fold compared with that of other injectable products and eliminates the need for daily topical application compared with gels and patches. TU (1,000 mg) given at a variable dosing interval is available for treating men with hypogonadism in more than 80 countries. Studies in Europe have demonstrated that 1,000 mg TU administered as an intramuscular injection at 10 to 14-week intervals is adequate to sustain normal testosterone levels in men with hypogonadism.⁸ This long acting formulation has been shown to be safe and well tolerated.⁸, ⁹, ¹⁰

In this 24-week study we assessed the pharmacokinetics and safety of long acting 750 mg TU given intramuscularly at 0, 4 and 14 weeks in men with hypogonadism. We determined whether this dosing regimen would provide the rapid attainment of clinically therapeutic testosterone with an acceptable low percent of men exceeding supraphysiological testosterone levels (more than 1,000 ng/dl) during the dosing interval.

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Methods 

This was a multicenter, open label, United States based study of the efficacy and safety of treatment with 750 mg TU in 3 ml castor oil (250 mg/ml) with injections administered to the deep gluteus muscle at week 0 (baseline), week 4 and every 10 weeks thereafter. A total of 130 participants were enrolled to ensure that at least 100 completed the study. A washout period of 28 days for injectable preparations, and 7 days for gels and patches was required in patients who had previously received testosterone therapy. Blood samples to determine the testosterone concentration were obtained immediately before each injection, and at days 4, 7, 11, 14, 21, 28, 42, 56 and 70 after injection 3.

Blood samples were obtained at baseline and at on treatment time points for PSA, hematology (including hemoglobin and hematocrit) and serum chemistry. Safety outcomes, including vital signs, electrocardiograms and physical examinations, were assessed before treatment and at on treatment time points. AEs were documented and classified using the MedDRA^® coding dictionary, version 9.1.

Patient satisfaction with treatment was assessed using M-PGA, a 5-item self-reported questionnaire, which was collected before injection 3. Patient perception of change from pretreatment in hypogonadal symptoms was assessed, including confidence/self-esteem, sexual performance, moods/behavior, overall feeling of well-being and satisfaction with the study treatment. Responses included very much improved, much improved, minimally improved, no change, minimally worse, much worse and very much worse. M-PGA responses were collapsed into improved, no change or worsened categories and tabulated. Patient satisfaction with study treatment was measured and tabulated by the response to the question, “Please rate your satisfaction with the study treatment according to the following scale: (1 = very much satisfied to 7 = very much dissatisfied)” with outcomes collapsed into satisfied, no opinion or not satisfied categories (see Appendix).

Patients 

Eligible participants were males who were at least 18 years old and who had primary or secondary hypogonadism and a morning (7:00 to 10:00 am) screening testosterone concentration of less than 300 ng/dl. Patients were excluded from study if they had an American Urological Association Prostate Symptom score of 15 or greater or significant prostatic symptoms; a history of carcinoma, tumors or induration of the prostate or the male mammary gland, including suspicion thereof; screening serum PSA more than 4 ng/ml or prostatic hyperplasia, defined as size more than 75 ml measured by transrectal ultrasonography; serious psychiatric disease or uncontrolled medical illness, as suspected from the history or clinical examination; or had used any sex hormones or steroidal anabolic drug supplements within 28 days before screening testosterone collection for pharmacokinetic assessment or at any time throughout the study. More than 60% of enrolled participants were on testosterone therapy before study entry.

Bioanalytical Methods 

Serum testosterone measurements from the pharmacokinetic assessments were considered the primary study measurements. The primary bioanalytical assessment for testosterone was done elsewhere. Using the internal standard testosterone-d3, testosterone was extracted from serum by liquid-liquid extraction. After evaporation under nitrogen the residue was reconstituted and analyzed using liquid chromatography with tandem mass spectrometry. The standard curve range was 20 to 5,000 ng/dl for testosterone using a serum sample volume of 0.5 ml. The lower limit of quantification was 20.0 ng/dl. Concentrations for calibration standards were within the range of 85.0% to 115.0% of theoretical, that is 80.0% to 120.0% at the lower limit of quantification. Average accuracy across 155 runs was derived by 9 theoretical concentrations. Average accuracy was almost 100% for each theoretical concentration threshold. The calibration curve average correlation coefficient was 0.9988%. Serum samples were batched in groups of 50 to 100 per run.

Statistical Methods 

This study was designed to be the basis for a new drug application and the decision criteria for the 2 primary end points in this study were provided by the FDA. Each end point, which was collected during injection interval 3, needed to be met to declare the treatment successful. End point 1 was based on mean serum testosterone during the 10-week dosing interval. To be a success the 10-week Cavg in a patient had to be within the young healthy adult male reference range of 300 to 1,000 ng/dl with Cavg derived as the AUC of the 10-week dosing interval divided by the duration of the dosing interval using the formula, Cavg = (AUC 0 to 10 weeks/10 weeks).

The proportion of participants with Cavg within the normal range was then derived. For treatment to be deemed effective the lower bound of the 2-sided 95% CI about the proportion of participants with Cavg within the normal range had to be no lower than 65% of patients and the point estimate was to be at least 75%. Given the large sample size, the normal approximation to the binomial was assumed when deriving the CI. Study sample size was chosen to achieve a prespecified precision (margin of error) for this outcome. Specifically a sample size of 73 would provide a 2-sided 95% CI, using the large sample normal approximation to the binomial, that extends no more than 0.10 from the observed proportion if that proportion is at least 0.75. Thus, assuming a response rate of 75% or greater the lower bound of the 95% CI would decrease no lower than 65%. Assuming a 10% dropout rate in year 1, up to 130 participants were enrolled in this study to allow for more than 100 to complete the injection interval 3 pharmacokinetic assessments.

End point 2 was based on the thresholds of the proportion of participants with a serum testosterone Cmax exceeding prespecified limits (table 1). Attainment of steady state was assessed using Helmert contrasts, in which trough testosterone, as collected at each injection visit, was tested against the mean of subsequent troughs starting with the week 4 injection trough with p = 0.05 used to determine whether steady state pharmacokinetics had been attained. Factors that may have been predictive of attained serum testosterone levels, as measured by pharmacokinetic parameters Cmax and Cavg during injection interval 3, were investigated.

Table 1. Observed serum total testosterone C_max FDA thresholds

Observed Cmax Limit (ng/dl)	Success Criteria (% participants)
1,500orLess	85%orGreater
1,800–Lessthan2,500	5%orLess
2,500orGreater	None

Time point for assessing this secondary outcome was after injection period 3 (weeks 14 to 24).

Patients who had a minimum of 4 testosterone concentration values obtained during injection interval 3 (weeks 14 to 24) were included in the pharmacokinetic and safety analysis. Pharmacokinetic parameters for serum testosterone by patient, including Cmax, Cavg during the 10-week dosing interval, Tmax and AUC for the 10-week dosing interval, were determined using noncompartmental methods with nominal (protocol scheduled) time from dosing used to estimate these pharmacokinetic parameters. Changes in safety variables, eg biochemical markers, were tabulated. AE tabulations included the overall incidence, that is the number and percent of participants, by body system and by preferred term with each participant contributing once to the incidence count of each AE type. WinNonLin^® Professional, version 5 was used to derive pharmacokinetic parameters. SAS^®, version 9.1 was used to perform statistical analysis.

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Results 

Disposition and Demographics 

Between March 26 and November 8, 2007, 130 patients were enrolled from 31 investigational centers in the United States, including 117 (90%) who were included in the pharmacokinetic analysis and 116 (89%) who completed the 24-week study (fig. 1). Patients were predominantly white with a mean ± SE age of 54.2 ± 0.90 years and a mean BMI of 32.0 kg/m². Almost 60% of the patients had a BMI greater than 30 kg/m². Mean ± SD screening testosterone was 214.7 ± 6.01 ng/dl (table 2). Most participants were diagnosed with hypogonadism between ages 45 and 55 years, and within 5 years before enrolling in the study with approximately 70% and 30% diagnosed with primary and secondary hypogonadism, respectively. Of the patients 62% were on testosterone therapy at the time of screening.

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• Fig. 1. 

  Flow chart of study participants

Table 2. Demographic and baseline characteristics in patients who received 750 mg TU

No. pts	130
Age:
Mean ± SE	54.2 (0.90)
Median (range)	55.0 (75.0)
No. age (%):
Younger than 30	1 (0.8)
30–Younger than 40	10 (7.7)
40–Younger than 50	30 (23.1)
50–Younger than 60	50 (38.5)
60–Younger than 70	33 (25.4)
70–Younger than 80	6 (4.6)
No. race (%):
White	97 (74.6)
Black	16 (12.3)
Hispanic	14 (10.8)
Other	3 (2.3)
Mean ± SE ht (cm)	177.8 (0.65)
Mean ± SE wt (kg)	101.2 (1.58)
Mean ± SE BMI (kg/m2)⁎	32.0 (0.48)
No. prior testosterone therapy (%):
Naïve	49 (37.7)
Nonnaïve	81 (62.3)
Screening inclusion serum total testosterone (ng/dl):
Mean ± SE	214.7 (6.01)
Median (range)	236.1 (24.3–298.8)

No patients were 80 years or older, or Asian.

Pharmacokinetics 

Figure 2 shows the group mean concentration-time profile during the 10-week dosing interval. Table 3 lists the key pharmacokinetic parameters. Average 10-week Cavg, Cmax and Cmin were each within the normal range, while median Tmax was 7 days after injection (range 4 to 42). The administration of 750 mg TU at baseline and again at week 4 resulted in the rapid attainment of therapeutic testosterone concentrations. After injection 3 at week 14 mean serum testosterone increased rapidly but remained well within the normal range. Levels gradually decreased during the 10-week dosing interval but remained within the normal range throughout the entire dosing interval, demonstrating that Cavg remained within the normal range at each time point measured.

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• Fig. 2. 

  Mean serum total testosterone after injection 3 of 750 mg testosterone undecanoate at weeks 14 to 24

Table 3. Pharmacokinetic parameters of serum total testosterone at steady state after TU injection 3 in pharmacokinetic population

Pharmacokinetic Parameter	No. Participants (%)	Mean ± SD	Min	Median	Max	% CV	Geometric Mean
AUC 0–70 days (ng/dl)	117 (100)	34,645.6±9,902.5	13,755.1	33,342.2	70,016.9	28.6	33,263.6
Day 70 Cmin (ng/dl)	117 (100)	323.5±99.1	138.2	316.9	611.1	30.6	309.0
Cmax (ng/dl)	117 (100)	890.6±345.1	311.0	813.6	1,758.5	38.8	826.8
Dose normalized Cmax (ng/dl)	117 (100)	1.2±0.5	0.4	1.1	2.3	38.8	1.1
Tlast (days)	117 (100)	70.0±0	70.0	70.0	70.0	0	70.0
Tmax (days)	117 (100)	10.0±7.1	4.0	7.0	42.0	71.1	8.4
Cavg (ng/dl):	117 (100)	494.9±141.5	196.5	476.3	1,000.2	28.6	475.2
Less than 300	6 (5.1)
300–1,000	110 (94.0)
Greater than 1,000	1 (0.9)

Pharmacokinetic analysis demonstrated that 110 patients (94%) treated with 750 mg TU intramuscularly had a testosterone Cavg within the clinically therapeutic range of 300 to 1,000 ng/dl during the 10 weeks after injection 3. Furthermore, more than 92% of patients had a Cmax of below 1,500 ng/dl during the study. Thus, as defined by the FDA, the 2 threshold criteria for success were met.

Safety Parameters 

AEs tended to be mild in severity and not serious, and most events were considered unrelated to treatment by study investigators. Table 4 lists the incidence of treatment emergent AEs reported by at least 1% of patients. Acne, fatigue and injection site pain were the most common events, which were each reported by fewer than 5% of patients. Immediately after injection 3, 1 patient experienced a mild nonproductive cough, which resolved without intervention within 10 minutes. No further events of cough occurred with subsequent injections. Coughing has been observed with other oil based testosterone formulations, eg testosterone enanthate.¹¹ Five participants discontinued treatment because of an AE, of which 4 (increased estradiol, mood swings, acne and deep vein thrombosis, respectively) were judged by the investigators to be at least possibly related to the study medication. One participant experienced myocardial infarction, which was judged to be unrelated to the study medication. No prostate cancer or gynecomastia was diagnosed during the course of the 24-week study.

Table 4. At least possibly related treatment emergent AEs by MedDRA preferred term in at least 2 participants each

Preferred Term	No. Participants (%)
Overall	130
At least 1 possibly related treatment emergent AE	31 (23.8)
Acne	6 (4.6)
Fatigue	4 (3.1)
Injection site pain	4 (3.1)
Irritability	2 (1.5)
Hyperhidrosis	2 (1.5)
Increased hemoglobin	2 (1.5)
Increased estradiol	2 (1.5)
Insomnia	2 (1.5)
Mood swings	2 (1.5)
Aggression	2 (1.5)
Increased PSA greater than 4 ng/ml	2 (1.5)
Disturbed attention	2 (1.5)

An increase in hemoglobin was noted in 2 participants (1.5%) but this resulted in no change in treatment. Overall mean ± SE hematocrit increased from 43.3% ± 0.32% at baseline to 45.7% ± 0.35% at week 24 (p <0.0001), while mean hemoglobin increased from 14.6 ± 0.11 to 15.5 ± 0.13 gm/dl (p <0.0001).

Mean ± SE PSA increased from 1.0 ± 0.07 ng/ml at baseline to 1.3 ± 0.10 ng/ml at week 24 (p = 0.0003). Two patients (1.5%) had baseline PSA more than 4 ng/ml after being enrolled with screening PSA less than 4 ng/ml. Of these 2 patients 1 was excluded from study after receiving injection 1. The other patient continued in the study following prostate biopsy, which revealed high grade prostatic intraepithelial neoplasia but no malignancy. An additional 2 patients had increases in PSA to more than 4 ng/ml during the treatment period, of whom 1 had a PSA of less than 4 ng/ml on repeat evaluation and 1 underwent prostate biopsy, which revealed no cancer. These 2 participants completed the study.

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Discussion 

We evaluated a novel injectable testosterone formulation that provides an extended dosing regimen. The pharmacokinetic outcomes of this study demonstrated that treatment with 750 mg TU administered intramuscularly at 0, 4 and 14 weeks resulted in normal serum testosterone during dosing interval 3 (weeks 14 to 24) in 94% of participants, exceeding the FDA requirement of greater than 75% by almost 20%. In addition, the number of participants with Cmax within the supraphysiological range was well within the safety parameters set by the FDA.

In this clinical study we used a lower dose of TU than reported in previous studies (TU is provided as a 1,000 mg intramuscular dose administered at 10 to 14-week variable dosing intervals in Europe).⁸, ¹⁰ This study demonstrated outcomes similar to those in studies in Europe, that is TU administered intramuscularly is safe and well tolerated. Treatment results in few AEs and the AEs that were observed were consistent with those in men on other testosterone therapies. No cases of prostate cancer were reported in this 24-week study and the mean change in PSA was small (0.3 ng/ml) during the treatment period. There are no data to suggest that a longer acting testosterone formulation influences the risk of prostate cancer adversely. No clinically meaningful changes in vital signs, physical examinations or other safety outcomes were noted and the injections were well tolerated.

Testosterone therapy has been used to treat hypogonadism for more than 5 decades.⁸ The goal of testosterone therapy is the restoration of clinically therapeutic levels of testosterone and the resulting alleviation of symptoms associated with testosterone deficiency.² The primary treatment options used in the United States are injectable and topical (transdermal) preparations. Short acting intramuscular injections of testosterone esters, such as testosterone cypionate and testosterone enanthate, have a longer half-life than natural testosterone. While they have been established as effective and well tolerated, these therapies require intramuscular injections, usually every 2 to 3 weeks. Currently available short acting injectable formulations also demonstrate wide fluctuations between Cmax and Cmin, which are associated with a variable symptom response known as the rollercoaster effect.⁸ This new therapeutic option extends the injection dosing interval over that of current injectable therapies from every 2 to 3 weeks to every 10 weeks, resulting in the need for only 5 injections per year.

Transdermal testosterone patches require daily application. They have been associated with skin irritation and rash, causing a dermatological reaction in up to 12% of men who use them.¹²

The most commonly used testosterone therapy options in the United States are topical gel preparations. Gels may be inconvenient because they require daily application and there are restrictions on bathing/swimming within the first several hours after application. A key advantage of treatment with TU is that it requires only 5 injections per year, which may translate into improved patient adherence to therapy.

There were a number of important limitations in this study. We examined the pharmacokinetics of testosterone during injection interval 3 but one cannot assume that the same results would apply to injection 1. Furthermore, this study included a population of men characterized by relatively high weight with an average BMI of 32 kg/m² and by prior treatment with testosterone therapy since greater than 60% had been treated with testosterone therapy before enrollment. A larger study in which an adequate number of participants is enrolled to assess the impact of treatment on participant subgroups by BMI or prior testosterone therapy classifications would be of interest. Moreover, while this study was 24 weeks long and, therefore, similar in duration to clinical studies in which other testosterone therapies have been assessed for FDA approval, hypogonadism is a chronic condition requiring prolonged treatment. We agree with the recommendations of the Institute of Medicine that longer term studies would provide valuable information.¹³ An extension of this study is ongoing out through an additional year of therapy to assess the long-term effects of 750 mg TU on safety and outcome parameters.

This study did not include a comparator arm and, thus, no direct comparison with other testosterone therapy preparations or other regimens of TU could be made. Cross-study comparison of outcomes revealed that the safety and pharmacokinetic profile resulting from treatment with TU is generally similar to those of available transdermal options with the obvious difference that TU pharmacokinetic parameters are based on 70-day dosing intervals compared with only 1 day for transdermal preparations.

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Conclusions 

TU (750 mg) intramuscular injection achieves sustained, consistent serum testosterone in the normal range during a 10-week dosing interval. This long acting testosterone therapy option extends the maximum treatment dosing interval beyond that of available injectable testosterone therapies and provides a potentially appealing alternative to the daily application of transdermal gels or patches. TU (750 mg) appears to be a safe, well tolerated and convenient treatment option in men with hypogonadism.

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Acknowledgments 

The primary testosterone bioanalytical assessment was done at Covance Bioanalytical Services, Indianapolis, Indiana.

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Appendix. The M-PGA Sample 

Please rate any changes in your symptoms of hypogonadism in the following questions. When answering these questions, please think about how your symptoms have changed compared with the time before you started the study drug treatment injections.

1. When thinking about your level of confidence or self-esteem, how much has this symptom changed in comparison to before you started the study drug treatment?

Very much improved

Much improved

Minimally improved

No change

Minimally worse

Much worse

Very much worse

2. When thinking about your satisfaction with sexual performance, how much has this symptom changed in comparison to before you started the study drug treatment?

Very much improved

Much improved

Minimally improved

No change

Minimally worse

Much worse

Very much worse

3. When thinking about your general moods and behavior, how much has this symptom changed in comparison to before you started the study drug treatment?

Very much improved

Much improved

Minimally improved

No change

Minimally worse

Much worse

Very much worse

4. When thinking about your overall feeling of well-being, how much has it changed in comparison to before you started the study drug treatment?

Very much improved

Much improved

Minimally improved

No change

Minimally worse

Much worse

Very much worse

5. Please rate your satisfaction with the study treatment according to the following scale:

Very much satisfied

Much satisfied

Minimally satisfied

Neither satisfied nor dissatisfied

Minimally dissatisfied

Much dissatisfied

Very much dissatisfied

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References 

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