madman
Super Moderator
Objective: Pharmacokinetic and efficacy data from a Phase 3 Testosterone Nasal Gel (TNG) study were stratified based on testosterone deficient patients’ baseline endogenous testosterone. Total testosterone (TT), gonadal hormones (LH and FSH), erectile function, mood and lean body mass for each group were compared. Of particular interest was the subset of patients who presented with very low baseline endogenous testosterone (<100 ng/dL), to determine if TNG is a suitable treatment option for severely testosterone deficient patients.
Materials and Methods: The phase 3 study has previously been described. 1 Testosterone deficient patients (serum TT <300 ng/dL) were treated with TNG for 3 months, followed by safety extension periods of 90 and/or 180 days. Pharmacokinetic parameters were calculated from serum hormone levels measured by LC-MS/MS on Days 30 and 90 along with efficacy measurements such as lean body mass, erectile function as measured using the International Index of Erectile Function (IIEF) and mood as measured using Positive and Negative Affect Schedule (PANAS). Efficacy was analyzed by comparing against baseline values. Baseline and/or pre-dose TT values were used for patient stratification. Linear regression was used to test the relationship between two parameters for non-stratified data.
Results: Pre-study endogenous testosterone readily correlated to pre-dose concentrations. Interestingly, TT Cmax (maximal concentration) was nearly identical across all cohorts at both Day 30 and 90, while Cavg (average concentration over a 24-hour time period) showed a slight positive dependence relative to pre-dose levels. LH levels remained in the normal range, but showed a stronger decrease for subjects with higher starting baseline than those with lower baseline testosterone. These observations affirm that TNG works with an active hypothalamic– pituitary–gonadal axis (HPG) that responds to each dose of TNG throughout the treatment period. Interestingly, patients with the lowest endogenous testosterone receive maximum exposure impact from each dose TNG. These severely testosterone deficient patients show similar efficacy improvements when compared to the remainder of the study population.
Conclusions: All testosterone deficient cohorts, including those with severe testosterone deficiency, were successfully treated with TNG.
Introduction: Testosterone deficiency syndrome (TDS), also known as late-onset hypogonadism, is a clinical and
biochemical syndrome that can occur in men in association with advancing age. The condition is characterized by deficient testicular production of testosterone. It may affect multiple organ systems and can result in substantial health consequences.
The Clinical diagnosis of TDS is made on the basis of recognized symptoms and persistent morning total testosterone levels below 300 ng/dL (10.4 nmol/L). Symptoms of TDS include (but are not limited to) decreased energy, decreased libido, impaired erectile function, depressed mood, decreased muscle mass and increased body fat.
In North America, TDS can be treated with exogenous testosterone using one of a variety of therapeutic options, including topical transdermal gels, oral and buccal agents, intra-muscular injections, subcutaneous injections, subcutaneous pellets and nasal products. Patients and physicians weigh advantages and disadvantages of each option to select a treatment that best fits the therapeutic needs, preferences, safety/tolerances and lifestyle. Factors may include convenience, cost, potential adverse local (irritation) or systemic (cardiovascular, hematocrit) reactions, transference, smell/odor and physician recommendations.
TNG 4.5% testosterone nasal gel (Natesto® ) is a thixotropic gel that is applied into the nasal cavity. Testosterone levels or symptoms are used to guide titration decisions between either twice daily or three times a day doses used to restore testosterone levels to the normal range. Surprisingly, patients report higher convenience with TNG than once-daily topical gels. The pharmacokinetic (PK) profile of TNG of different concentrations has been studied in a series of single and multidose PK studies, including in women, healthy volunteers with allergic rhinitis and TDS men. The 24-hour pharmacokinetic profile of testosterone for patients on TNG treatment has two or three discrete peaks (“pulses”) of testosterone provoked by LH secretions that occur on average every 2 hours. A maximal peak of testosterone appears at about 1h (Tmax) followed by a return to endogenous, pre-dose levels, 4-6 hours later (t1/2 ~1h). The nadir (trough) between doses correlates well with pre-treatment endogenous levels at diagnosis.
The unique, pulsatile, pharmacokinetic profile is believed to have limited impact on the HPG axis with significant trough time preserving luteinizing hormone (LH), follicle stimulating hormone (FSH), endogenous testosterone production and sperm counts, while also limiting excess RBC production, estradiol, DHT and PSA in clinical trials. However, it was previously unclear whether TNG was sufficient to produce strong efficacy outcomes when baseline endogenous production was very low, thus the impetus to perform a post-hoc analysis of Phase 3 data with particular attention to pre-study baseline and its effects on pharmacokinetics and symptomatic efficacy. Of particular interest was the subset of patients who presented with very low baseline endogenous testosterone (<100 ng/dL (3.5 nmol/L)) to determine if TNG is a suitable treatment option for this population.
Conclusions
Testosterone nasal gel treatment restores TT levels while preserving significant aspects of HPG function, including continued release of gonadotropins and production of endogenous testosterone, which allows maintenance of baseline levels. Both modest TDS (TT 250-300 ng/dL; (8.7 – 10.4 nmol/L)) and more severe TDS patients (TT 0-100 ng/dL (0 – 3.5 nmol/L), when treated with TNG, achieve max TT levels around 800 ng/dL (27.7 nmol/L). Efficacy, as measured by erectile function and mood were significantly improved to similar levels in both groups. The unique, ultradian, pulsatile nature of TNG, which does not depress endogenous testosterone production means that a wide range of testosterone deficient patients can effectively be treated with it.
Materials and Methods: The phase 3 study has previously been described. 1 Testosterone deficient patients (serum TT <300 ng/dL) were treated with TNG for 3 months, followed by safety extension periods of 90 and/or 180 days. Pharmacokinetic parameters were calculated from serum hormone levels measured by LC-MS/MS on Days 30 and 90 along with efficacy measurements such as lean body mass, erectile function as measured using the International Index of Erectile Function (IIEF) and mood as measured using Positive and Negative Affect Schedule (PANAS). Efficacy was analyzed by comparing against baseline values. Baseline and/or pre-dose TT values were used for patient stratification. Linear regression was used to test the relationship between two parameters for non-stratified data.
Results: Pre-study endogenous testosterone readily correlated to pre-dose concentrations. Interestingly, TT Cmax (maximal concentration) was nearly identical across all cohorts at both Day 30 and 90, while Cavg (average concentration over a 24-hour time period) showed a slight positive dependence relative to pre-dose levels. LH levels remained in the normal range, but showed a stronger decrease for subjects with higher starting baseline than those with lower baseline testosterone. These observations affirm that TNG works with an active hypothalamic– pituitary–gonadal axis (HPG) that responds to each dose of TNG throughout the treatment period. Interestingly, patients with the lowest endogenous testosterone receive maximum exposure impact from each dose TNG. These severely testosterone deficient patients show similar efficacy improvements when compared to the remainder of the study population.
Conclusions: All testosterone deficient cohorts, including those with severe testosterone deficiency, were successfully treated with TNG.
Introduction: Testosterone deficiency syndrome (TDS), also known as late-onset hypogonadism, is a clinical and
biochemical syndrome that can occur in men in association with advancing age. The condition is characterized by deficient testicular production of testosterone. It may affect multiple organ systems and can result in substantial health consequences.
The Clinical diagnosis of TDS is made on the basis of recognized symptoms and persistent morning total testosterone levels below 300 ng/dL (10.4 nmol/L). Symptoms of TDS include (but are not limited to) decreased energy, decreased libido, impaired erectile function, depressed mood, decreased muscle mass and increased body fat.
In North America, TDS can be treated with exogenous testosterone using one of a variety of therapeutic options, including topical transdermal gels, oral and buccal agents, intra-muscular injections, subcutaneous injections, subcutaneous pellets and nasal products. Patients and physicians weigh advantages and disadvantages of each option to select a treatment that best fits the therapeutic needs, preferences, safety/tolerances and lifestyle. Factors may include convenience, cost, potential adverse local (irritation) or systemic (cardiovascular, hematocrit) reactions, transference, smell/odor and physician recommendations.
TNG 4.5% testosterone nasal gel (Natesto® ) is a thixotropic gel that is applied into the nasal cavity. Testosterone levels or symptoms are used to guide titration decisions between either twice daily or three times a day doses used to restore testosterone levels to the normal range. Surprisingly, patients report higher convenience with TNG than once-daily topical gels. The pharmacokinetic (PK) profile of TNG of different concentrations has been studied in a series of single and multidose PK studies, including in women, healthy volunteers with allergic rhinitis and TDS men. The 24-hour pharmacokinetic profile of testosterone for patients on TNG treatment has two or three discrete peaks (“pulses”) of testosterone provoked by LH secretions that occur on average every 2 hours. A maximal peak of testosterone appears at about 1h (Tmax) followed by a return to endogenous, pre-dose levels, 4-6 hours later (t1/2 ~1h). The nadir (trough) between doses correlates well with pre-treatment endogenous levels at diagnosis.
The unique, pulsatile, pharmacokinetic profile is believed to have limited impact on the HPG axis with significant trough time preserving luteinizing hormone (LH), follicle stimulating hormone (FSH), endogenous testosterone production and sperm counts, while also limiting excess RBC production, estradiol, DHT and PSA in clinical trials. However, it was previously unclear whether TNG was sufficient to produce strong efficacy outcomes when baseline endogenous production was very low, thus the impetus to perform a post-hoc analysis of Phase 3 data with particular attention to pre-study baseline and its effects on pharmacokinetics and symptomatic efficacy. Of particular interest was the subset of patients who presented with very low baseline endogenous testosterone (<100 ng/dL (3.5 nmol/L)) to determine if TNG is a suitable treatment option for this population.
Conclusions
Testosterone nasal gel treatment restores TT levels while preserving significant aspects of HPG function, including continued release of gonadotropins and production of endogenous testosterone, which allows maintenance of baseline levels. Both modest TDS (TT 250-300 ng/dL; (8.7 – 10.4 nmol/L)) and more severe TDS patients (TT 0-100 ng/dL (0 – 3.5 nmol/L), when treated with TNG, achieve max TT levels around 800 ng/dL (27.7 nmol/L). Efficacy, as measured by erectile function and mood were significantly improved to similar levels in both groups. The unique, ultradian, pulsatile nature of TNG, which does not depress endogenous testosterone production means that a wide range of testosterone deficient patients can effectively be treated with it.
