Allometric Scaling of Testosterone Enanthate Pharmacokinetics to Adolescent Hypogonadal Males (IM and SC Administration).

Context: Intramuscular (IM) testosterone enanthate (TE) and testosterone pellets were US Food and Drug Administration approved before 1962 for pediatric use but not studied in controlled trials in adolescents. Objective: An analysis using nonlinear mixed effect (NLME) modeling was designed to evaluate the adult pharmacokinetics (PK) of subcutaneous (SC) and IM TE. This model was used to simulate SC and IM TE administration in adolescents of different weight groups. Methods: Data from adult male patients in a phase 2 trial were used to characterize the PK of TE using population PK modeling for SC and IM administration: Allometry was used to scale PK parameters from the adult model to simulate adolescent (aged 12 to < 18 years) serum testosterone levels at body weights of 30, 40, 50, and 60 kg after weekly, every-other-week (EOW), and monthly SC and IM administration of 12.5, 25, 50, 75, and 100 mg TE regimens. Results: The final data set included 714 samples from 15 patients receiving 100 mg SC TE and 123 samples from 10 patients receiving 200 mg IM TE. In simulated populations, average serum concentration SC:IM ratios were 0.783, 0.776, and 0.757 at steady state for weekly, EOW, and monthly dosing groups, respectively. Simulated regimens of 12.5 mg SC TE monthly produced serum testosterone levels representative of early puberty and simulated pubertal stage progression following multiple subsequent testosterone dose increases. Conclusion: SC TE administration achieved a testosterone exposure-response relationship similar to IM TE in simulated adolescent hypogonadal males, which may reduce size of fluctuations in serum T and related symptoms.

Pharmacokinetics of testosterone therapies in relation to diurnal variation of serum testosterone levels as men age.

BACKGROUND: To improve symptoms associated with testosterone deficiency, many testosterone therapies are available that aim to restore serum testosterone (T) levels to the normal physiologic range. The magnitude, frequency, and duration between peak and trough T concentrations vary with route of administration, and none reflect normal endogenous daily diurnal T variations. OBJECTIVE: To compare pharmacokinetic profiles of serum T from approved T formulations with endogenous diurnal T variations in young and older men, and to consider whether there may be value in mimicking the diurnal T rhythmicity with exogenous testosterone therapies as men age. MATERIALS AND METHODS: A literature search of studies examining the diurnal variation of endogenous T in healthy men and men with testosterone deficiency was performed using PubMed in January 2020. Additional searches for serum T pharmacokinetic profiles of various testosterone therapy formulations were also conducted. Prescribing information for various T formulations was also reviewed. DISCUSSION AND CONCLUSION: Endogenous diurnal T variation is well described and appears to be blunted naturally as men age. Men with testosterone deficiency lack diurnal T variation and exhibit a flatter T profile compared with eugonadal men. Some T replacement options provide intraday T level variations similar to normal circadian secretion, and others provide a flatter exposure profile reflective of depot release. Others provide profiles that exceed the frequency and physiologic range of the natural diurnal variation of T. All exogenous T replacement dosing targets an increase in average T levels to within the normal physiologic range and improves symptoms associated with low T, but no single testosterone therapy can exactly mimic the normal diurnal T patterns seen in younger men and the blunted circadian T secretion of older men.

Testosterone Use in Adolescent Males: Current Practice and Unmet Needs.

Testosterone replacement therapy (TRT) is routinely prescribed in adolescent males with constitutional delay of growth and puberty (CDGP) or hypogonadism. With many new testosterone (T) formulations entering the market targeted for adults, we review current evidence and TRT options for adolescents and identify areas of unmet needs. We searched PubMed for articles (in English) on testosterone therapy, androgens, adolescence, and puberty in humans. The results indicate that short-term use of  T enanthate (TE) or oral  T undecanoate is safe and effective in inducing puberty and increasing growth in males with CDGP. Reassuring evidence is emerging on the use of transdermal  T to induce and maintain puberty. The long-term safety and efficacy of TRT for puberty completion and maintenance have not been established. Current  TRT regimens are based on consensus and expert opinion, but evidence-based guidelines are lacking. Limited guidance exists on when and how  T should be administered and optimal strategies for monitoring therapy once it is initiated. Only  TE and  T pellets are US Food and Drug Administration approved for use in adolescent males in the United States. Despite the introduction of a wide variety of new  T formulations, they are designed for adults, and their metered doses are difficult to titrate in adolescents. In conclusion, TRT in adolescent males is hindered by lack of long-term safety and efficacy data and limited options approved for use in this population. Additional research is needed to identify the route, dose, duration, and optimal timing for TRT in adolescents requiring androgen therapy.

Safety of a New Subcutaneous Testosterone Enanthate Auto-Injector: Results of a 26-Week Study.

INTRODUCTION: Patients with testosterone deficiency (TD) can be treated with exogenous testosterone (T) to achieve and maintain physiologic T levels and prevent negative clinical symptoms; with many testosterone replacement therapies currently available, this registration safety study was conducted to further characterize the clinical profile of chronically administered, concentration-guided subcutaneous testosterone enanthate (TE) dosing. AIM: The purpose of this study was to confirm the safety and characterize the pharmacokinetic (PK) profile of the subcutaneous TE auto-injector (SCTE-AI) in adult men with TD. METHODS: In this phase III, 26-week study, 133 men 18-75 years of age with symptomatic TD self-administered SCTE-AI 75 mg once weekly for 6 weeks from July 2015 to June 2016. Dosing was adjusted when indicated to 50 mg or 100 mg to maintain T trough levels between 350 and 650 ng/dL (12.1-22.5 nmol/L). PK data were collected from a subgroup of patients receiving 75 mg SCTE-AI through week 12. Safety, including ambulatory blood pressure monitoring (ABPM), lipid levels, and adverse drug reactions, and PK were assessed. MAIN OUTCOME MEASURES: The main outcomes were the documentation of the reproducibility of trough concentration-guided exposure to SCTE, 6-month safety profile, and PK data for the 75 mg dose SCTE. RESULTS: In total, 34 patients (25.6%) experienced adverse drug reactions; the most frequently reported were increased hematocrit (≥52%) in 10 patients (7.5%), injection-site hemorrhage in 6 patients (4.5%), injection-site bruising in 4 patients (3.0%), and increased prostate-specific antigen in 4 patients (3.0%). By week 26, mean systolic and diastolic blood pressure (BP) measured in the clinic increased by 3.4 mmHg (125.6-129.0 mmHg) and 1.8 mmHg (78.2-80.0 mmHg), respectively, from baseline. At week 12, ABPM showed 24-hour mean systolic and diastolic BP increases of 3.7 mmHg and 1.3 mmHg, respectively. All measured lipid fractions were below baseline levels at week 26. T, TE, dihydrotestosterone, and estradiol increased from weeks 1-12. T trough levels ranged from 300-650 ng/dL (10.4-22.5 nmol/L) in 82.4% and 83.2% of patients at weeks 12 and 26, respectively. Of the 965 assessed injections, mild pain was reported by 1 patient. CLINICAL IMPLICATIONS: Dosing with SCTE is well-tolerated overall, yet associated with a numerically small mean systolic BP increase. STRENGTHS & IMPLICATIONS: This study used a standardized ABPM protocol, confirming a numerically small systolic BP increase may be associated with reintroducing therapeutic T exposure in hypogonadal men. It is unknown at this time whether this applies with all routes of T supplementation. CONCLUSION: SCTE-AI has a favorable safety profile and is well-tolerated, with a stable PK profile. Gittelman M, Jaffe JS, Kaminetsky JC. Safety of a New Subcutaneous Testosterone Enanthate Auto-Injector: Results of a 26-Week Study. J Sex Med 2019;16:1741-1748. Clinicaltrials.gov Identifier: NCT02504541.

A 52-Week Study of Dose Adjusted Subcutaneous Testosterone Enanthate in Oil Self-Administered via Disposable Auto-Injector.

PURPOSE: In this open label, single arm, dose blinded, 52-week registration phase study we evaluated the efficacy and safety of a subcutaneous testosterone enanthate auto-injector administered weekly to men with hypogonadism. MATERIALS AND METHODS: A total of 150 patients were initiated on a 75 mg subcutaneous testosterone enanthate auto-injector self-administered weekly. Dose adjustments were made at week 7 to 50, 75 or 100 mg testosterone enanthate based on the week 6 total testosterone trough concentration. If required, dose adjustments continued through the extended treatment phase. Pharmacokinetic and clinical laboratory parameters, treatment emergent adverse events and injection site reactions were captured. RESULTS: The primary end point was met since 92.7% of patients achieved an average total testosterone concentration of 300 to 1,100 ng/dl (mean ± SD 553.3 ± 127.29) at week 12. A maximum concentration of less than 1,500 ng/dl was achieved by 91.3% of patients and no patient had a level greater than 1,800 ng/dl at week 12. The mean total testosterone trough concentration was 487.2 ± 153.33 ng/dl at week 52. Of the patients more than 95% reported no injection related pain. The most frequently reported treatment emergent adverse events were increased hematocrit, hypertension and increased prostate specific antigen, which led to discontinuation in 30 men. There were no study drug related serious adverse events. CONCLUSIONS: The dose adjusted subcutaneous testosterone enanthate auto-injector demonstrated a steady serum total testosterone pharmacokinetic profile with small peak and trough fluctuations. The device was safe, well tolerated and virtually painless, indicating that this subcutaneous testosterone enanthate auto-injector offers a testosterone delivery system that is a convenient weekly option to treat testosterone deficiency.

Summative Usability Evaluation of the SCTE-AI Device: A Novel Prefilled Autoinjector for Subcutaneous Testosterone Administration.

BACKGROUND: The subcutaneous testosterone enanthate (TE) autoinjector (SCTE-AI) is a single-use, pre-filled, disposable autoinjector intended for testosterone (T) self-administration in adult males with T deficiency. AIM: To evaluate the usability of the market configuration of the SCTE-AI, including packaging and instructions for use (IFU), in order to identify and mitigate any preventable patterns of use errors that could result in harm. METHODS: 4 groups of participants (injection-naïve or injection-experienced patients or caregivers) were randomized to 1 of 3 doses (50, 75, and 100 mg) of TE and either trained (ie, reviewed the IFU and shown how to properly inject) or not trained (only given the IFU). After simulated at-home use, participants were asked questions regarding the comprehensibility of the IFU and the intuitiveness/usability of the device. All tasks were measured as success, use error, or close call (participant initiated an error but recovered in time). MAIN OUTCOME MEASURE: Usability (success rates, errors, and close calls) of the drug/device combination by adult males with T deficiency or their caregivers. RESULTS: 65 patients received 1 dose of TE, and 59 patients received 2 doses. Overall, 99 of 123 (80.5%) attempted injections resulted in administration of 1 full dose. Injection success rates were high and comparable among the various user groups. The most common use error (21 of 24) was due to not holding the autoinjector on the abdomen long enough (at least 8 seconds). Few critical drug delivery and safety errors or close calls were observed. No unmitigated use errors by patients or caregivers were apparent that could result in harm or have a negative impact on treatment. SCTE-AI was well tolerated. CLINICAL IMPLICATIONS: The SCTE-AI development process resulted in a subcutaneous, TE autoinjection device that is intuitive to use, with clear labeling and packaging and an easy-to-understand IFU, providing an option for T-deficient adult males to self-inject subcutaneously at home. STRENGTH & LIMITATIONS: The strengths of the study include use of a patient-ready drug/device combination for self-administration and inclusion of both injection-naïve and injection-experienced patients and caregivers. The main limitation of the study is the presence of observers/cameras that may have distracted or created performance anxiety, potentially contributing to errors. CONCLUSION: Results of this usability validation study indicate that the SCTE-AI device is safe and intuitive to use, with a low potential for harm and is associated with a high rate of injection success, regardless of prior training or experience. Arora S, Moclair B, Murphy K, et al. Summative Usability Evaluation of the SCTE-AI Device: A Novel Prefilled Autoinjector for Subcutaneous Testosterone Administration. J Sex Med 2018;15:1707-1715.

Pharmacokinetic Profile of Subcutaneous Testosterone Enanthate Delivered via a Novel, Prefilled Single-Use Autoinjector: A Phase II Study.

INTRODUCTION: Hypogonadism is one of the most common male endocrine problems. Although many treatments are currently available, unmet need exists for new testosterone (T) replacement therapies that are simple to administer and use, are safe, and mimic physiologic T levels. AIM: The study aim was to determine the pharmacokinetics (PK), safety, and tolerability of T enanthate (TE) administered via a novel single-use autoinjector system, which was designed to eject high-viscosity solutions from a prefilled syringe fitted with a five-eighths-inch 27-gauge needle. METHODS: Thirty-nine men with hypogonadism entered this dose-finding, open-label, parallel-group study. Patients were washed out of their topical T regimens and randomized to receive 50 or 100 mg of subcutaneous (SC) TE weekly. The reference group were patients with hypogonadism who were maintained on standard 200-mg intramuscular (IM) TE. MAIN OUTCOME MEASURE: The primary outcome measure was the PK profile of SC TE, analyzed in reference to T levels used by the Food and Drug Administration to approve T products. Secondary outcome measures were safety and tolerability assessments. RESULTS: Both doses of SC TE achieved normal average concentrations of serum T within a 168-h dosing interval after injection. Concentration ranges were similar at all time points following 50-mg SC TE injections and following the third injection in the 100-mg arm. Mean steady-state T concentration at week 6 was 422.4 and 895.5 ng/dL for the 50- and 100-mg SC TE arms, respectively. SC TE demonstrated PK dose proportionality. SC TE restored normal serum T with low variation relative to 200-mg IM without clinically significant adverse events. CONCLUSIONS: Administration of TE via this novel injection system restored T levels to normal range in men with hypogonadism. SC TE dosed weekly demonstrated steady, dose-proportional measures of exposure and was well-tolerated. Kaminetsky J, Jaffe JS, Swerdloff RS. Pharmacokinetic profile of subcutaneous testosterone enanthate delivered via a novel, prefilled single-use autoinjector: A phase II study. Sex Med 2015;3:263-273.

Nearly pain-free self-administration of subcutaneous methotrexate with an autoinjector: results of a phase 2 clinical trial in patients with rheumatoid arthritis who have functional limitations.

BACKGROUND: A methotrexate autoinjector (MTXAI) was developed for self-administration of subcutaneous (SC) methotrexate by patients with rheumatoid arthritis (RA). The MTXAI circumvents the need for vials, needles, and syringes and may therefore improve dosing accuracy, handling risks, and patient adherence. OBJECTIVES: The objective of this study was to evaluate actual human use of the MTXAI in patients with RA and determine its reliability, robustness, safety, local tolerance, and ease of use. METHODS: In this phase 2, multicenter, open-label, single-dose, single-arm, in-clinic US study, adults (N = 101) treated with methotrexate for 3 months or longer were trained to use the MTXAI and assigned to 10, 15, 20, or 25 mg methotrexate based on previous treatment and disease status. Patients completed training confirmation and ease-of-use questionnaires. Pain was evaluated immediately after self-administration and at follow-up with a 100-mm visual analog scale (0 = no pain, 100 = worst possible pain). RESULTS: At screening, 90.1% of patients had moderate to severe functional limitations (class II-IV). All patients successfully completed the study. All devices functioned correctly and as intended. The device was rated easy to use by 98%, and instructions clear and easy to follow by 100% of patients. On the visual analog scale, mean and median pain scores were 3.6/100 and 1.0/100 mm, respectively, immediately after self-administration, and were lower at follow-up. Most patients (92.3%) had no administration-site erythema; 7.7% had minimal erythema. CONCLUSIONS: The SC MTXAI was well tolerated and considered easy to use by patients with RA. Improving SC methotrexate delivery may increase patient tolerance of self-administration, possibly improving adherence.

Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses ≥15†mg may be overcome with subcutaneous administration.

OBJECTIVE: To compare the relative bioavailability, safety and tolerability of oral methotrexate (MTX) and subcutaneous (SC) MTX administered via an auto-injector (MTXAI) in patients with rheumatoid arthritis (RA). METHODS: In this randomised, multicenter, open-label, three-way crossover study, patients ≥18 years with adult RA undergoing treatment with MTX for ≥3 months were assigned to receive MTX 10, 15, 20 and 25 mg weekly in a random sequence of three treatments: oral, SC into the abdomen and SC into the thigh. For 24 h after administration of each treatment, blood samples were collected for pharmacokinetic analysis and injection sites were assessed. RESULTS: Forty-seven patients completed the study. Systemic exposure of oral MTX plateaued at doses ≥15 mg/week. In contrast, SC MTX demonstrated a linear increase in systemic exposure that was greater than oral MTX at each dose. No unexpected AEs were noted for either formulation. CONCLUSIONS: Unlike oral MTX, the systemic exposure of SC MTX did not plateau over the doses studied, particularly at doses ≥15 mg/week. In this study, higher systemic MTX exposure was not associated with increases in AEs. Patients with an inadequate clinical response to oral MTX may benefit from higher drug exposure by switching to SC MTX. TRIAL REGISTRATION NUMBER: NCT01618968.