madman
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The Evolving Role of Novel Oral Agents for Testosterone Replacement Therapy; A Historical Perspective (2022)
Pratik Kanabur, Robert Brunner, Dalia Khera, Hunter A. Flores, and Mohit Khera*
Abstract
There have been multiple attempts at an oral testosterone option for men with testosterone deficiency (TD), however many have been unsuccessful due to severe adverse reactions and lack of efficacy compared with other options. Due to a recent development in the pharmacology of delivery of oral testosterone through a self-emulsifying drug delivery system, there has been the advent of new oral options for men suffering from TD. This review covers the history and challenges of oral testosterone, the development of a novel drug delivery system to allow men to absorb oral testosterone safely, and the efficacy of three oral testosterone options.— Jatenzo, Tlando and Kyzatrex. Clinicaltrials.gov identifier: NCT04467697.
Introduction
Testosterone (T), a steroid hormone, is the primary androgen in males and is necessary for a variety of physiologic processes, including sexual and reproductive function, cognition, metabolism, and body composition.1–3 Testosterone deficiency (TD), synonymous with male hypogonadism, is defined by two-morning serum total testosterone levels <300 ng/dL and having one or more symptoms attributable to low circulating levels of testosterone.4,5 Symptoms of TD include decreased energy, decreased libido, erectile dysfunction, decrease in muscle mass and strength, decrease in bone mass, increase in central body fat, anemia, and impaired memory, mood, concentration, and sleep.6,7
Testosterone decreases with age with a *1% annual decrease in free testosterone levels after the age of 30 or about a decrease of 100 ng/dL every 10 years.6,7 Approximately 20% of men over the age of 45 and 40% of men over the age of 80 are hypogonadal. Aging males are more likely to have an acquired cause or idiopathic etiology of hypogonadism. The decline in testosterone levels can be due to several factors, including the decline of Leydig cell function, the decline in pituitary-hypothalamic axis function with loss of circadian variation, an increase in the levels of sex hormone binding globulin, changes in testosterone receptor sensitivity, and the effects of altered inflammatory and metabolic states.
Moreover, a reason for the prevalence of hypogonadism can be ascribed to the acquisition of co-morbid conditions, such as obesity, diabetes, and metabolic syndrome, as men age.7–10 Previous studies have shown that hypogonadism is associated with abdominal adiposity, insulin resistance, and metabolic syndrome. A few studies have shown that treatment of diabetes and improvement in obesity lead to a modest increase in testosterone, without the restoration of testosterone concentrations to normal.11,12 Studies have even shown that over 50% of renal transplant patients had TD, and these patients were found to have lower levels of hemoglobin (Hb), glomerular filtration rate, and serum albumin.13
The high prevalence among the general population, burdensome symptoms, and the utilization in the improvement of comorbidities render TD a commonly encountered problem for physicians. There has been a significant rise in the number of prescriptions of testosterone in the United States over the past few years, which has accelerated the need to develop a superior tolerated formulation that is easier to use.14 The treatment options to increase testosterone levels and ameliorate TD symptoms include intramuscular injections, transdermal gels, implanted pellets, nasal sprays, and buccal tablets (Table 1).
Each of these formulations has certain drawbacks that most healthcare providers and patients are aware of, such as pain with injection, dermal irritation, testosterone transference, and others.15 The difficulties with the formulations can often lead to difficulty with adherence to daily treatments. What has been missing from the health care provider's armamentarium of testosterone therapy (TTh) is an oral testosterone formulation that can both comply with federal regulation stipulations for safety and meet the need for standards of efficacy.
Early oral testosterone was associated with serious hepatotoxicity and the later version of oral testosterone undecanoate (TU) was highly influenced in terms of absorption and clinical bioavailability from fat content in the patient’s diet, which led to intrapatient variability and questionable utility. A recent oral TU formulated in a distinctive self-emulsifying drug delivery system (SEDDS), Jatenzo, was recently developed to treat male hypogonadism. Another oral testosterone formulation, Tlando, was released in 2022 and a third formulation, Kyzatrex, was Food and Drug Administration (FDA) approved in 2022 The purpose of this review is to address the safety, efficacy, and durability of oral testosterone.
*History of Oral Testosterone
Pharmacologic Mechanism of Oral Testosterone
TU is a testosterone prodrug formulation that is lipophilic due to the long carbon sidechain and favors absorption via the lymphatic system, which is the opposite of other testosterone esters, which are more likely to be taken up by the portal system. TU has been integrated into a new proprietary SEDDS formulation. SEDDS stimulates a level of saponification of the lipophilic T esters, which leads to more preferential absorption by the intestinal lymphatic system. This leads to a decrease in first-pass hepatic metabolism.23 SEDDS formulations syndicate lipophilic and hydrophilic components, which promote the solubilization of molecules such as TU, which are normally lipophilic. Thus, they can be absorbed in the intestines without the necessity of maintaining a diet high in fat content.324
SEDDS is defined as a uniform amalgam of lipophilic oils (synthetic or natural) plus solid or liquid surfactants or hydrophilic solvents. On activation followed by a reduction in aqueous solution, which is what happens in the human gastrointestinal tract, these systems produce a fine oil in water emulsion, which is physically stable (unlikely to be degraded or absorbed through the portal system) and readily absorbed by the intestines to the bloodstream.25
The SEDDS-specific mechanism in the bloodstream has been well-studied in the literature. In the bloodstream and fatty tissue, TU undergoes a swift enzymatic de-esterification, which results in a release of testosterone. The free undecanoic acid component is metabolized via beta-oxidation to produce multiple acetyl-coenzyme-A compounds and a singular propionyl-coenzyme-A molecule, which assists with absorption. Next, the gut produces dihydrotestosterone (DHT) undecanoate and DHT through enzymatic activation with 5-alpha reductase.23
A phase II pharmacokinetics study23 showed that hypogonadal men who took TU with a SEDDS formulation had a dose-proportional response that was well tolerated. The specific formulation that was assessed comprised TU dissolved in lipid formulations with other compounds such as borage seed oil (a rich source of C-20 fatty acids) and peppermint oil along with a hydrophilic surfactant [hydrogenated castor oil (Cremophor RH 40)] to promote solubilization. These were encapsulated in soft gelatin capsules of various strengths, which would enable highly lipophilic molecules such as TU to be dissolved, and thus can be absorbed after a normal meal (without requiring a fat high content)
When experimental oral testosterone, which included 200 mg of TU in the proprietary prodrug SEDDS formulation, was administered twice a day, average serum T levels were able to attain a eugonadal testosterone level in more than 75% of patients. Within a month, 87% of men had mean blood T levels within the adult male range, and none of the patients were found to exhibit a hypergonadatropic response and have an average serum T level greater than 1500 ng/dL. Patients did have a better response with the intake of a meal compared with fasting, as patients given 200 mg of oral TU twice daily incorporated in a SEDDS formulation had over a twofold higher average T concentration with food intake.23
Further studies incorporating various levels of fat content in the diet are necessary to better elucidate the effect of food on TU with SEDDS formulation absorption. After these data are obtained, specific recommendations for dietary intake and the necessity of food intake with medication can be developed.
One consideration is the 5-alpha reductase enzymatic transition of T to DHT and the effect on various aspects such as lipid levels, muscle mass, sexual function, prostate size, hematocrit levels, etc. The most common mechanism that has been proposed is that the conversion of testosterone to DHT is not the sole pathway, but it does emphasize the level of testosterone in tissues with high 5a-reductase activity, including skin and prostate, compared with tissues with low 5a-reductase activity including bone and muscle.
One clinical trial showed that the increase in body mass composition (while decrease in fat) with graded testosterone levels did not change in men who took dutasteride (suppressing DHT) from those treated with a placebo. This showed that the DHT from the conversion of testosterone is not necessary to mediate the anabolic building of skeletal muscle.26
*Safety Profile of Oral Testosterone
*Pharmacokinetics and Dose Response of Oral Testosterone
*Primary and Secondary Efficacy of Oral Testosterone
Summary and Conclusions
Although the efficacy and demand of TTh through intramuscular injections, transdermal gels, and other formulations have been positive, the development of oral testosterone to add to the urologist’s armamentarium has been a focus of much pharmacologic research over the past 20 years. As previous oral testosterone treatments, such as methyltestosterone, have been associated with significant hepatotoxicity and cardiac risk, the focus has shifted to the utilization of TU as a potential oral regimen despite its previously documented issue with dietary influence.
Two new drugs, Jatenzo and Tlando, have been used in advanced drug delivery, such as SEDDS, to deliver a more stable and predictable dose-response curve regardless of diet. Although these drugs still exhibit adverse effects of polycythemia, changes in lipid composition and mild increases in SBP, their magnitudes are comparable to the effects seen in approved topical TTh. Importantly, they also do not appear to pose any clinically significant increase in PSA, IPSS, or AUASS as compared with topical testosterone.
These new oral testosterone treatments appear able to deliver a sustainable increase in serum testosterone to the eugonadal range with a low risk for hypergonadal levels. Specifically, Jatenzo has shown that 87.3% of patients reach eugonadal testosterone ranges at 120 days, and 85% of Tlando patients reach a safe eugonadal range below 1500 ng/dL as well. They also exhibit promising improvements in psychosexual outcomes, with both demonstrating improvements in PDQ scores. In addition, Jatenzo appears to improve bone density and lean body mass as well.
However, oral T was associated with a small but statistically significant increase in SBP versus the topical T. This observation indicates the need for regular monitoring of BP in men receiving testosterone replacement therapy, particularly in those with existing HTN. Another limitation is these drugs are the first in their class and still need adequate insurance coverage in order for uptake to be enthusiastic for patients and providers.
In addition, given their relative novelty, no established recommendations exist for follow-up intervals and dosing adjustments for patients who do experience an alteration in their BP or cholesterol. According to both Jatenzo trials, 74% of patients required some dosing adjustment over the study period, but only with regard to their serum testosterone level. More study is necessary to determine a safety follow-up regimen and dose adjustment protocol for patients exhibiting unsafe rises in BP or total cholesterol levels.
Finally, although an oral agent is likely a welcome alternative option to other formulations for many patients, medication adherence to a twice-daily dosing regimen (BID) may, nonetheless, present problems. Medication adherence in other chronic diseases has been studied frequently and has shown an inverse relationship between medication adherence and dosing frequency. In a meta-analysis on cardiovascular oral medications, Weeda et al demonstrated only a 50.4% adherence rate for BID regimens versus 74.2% for once-daily regimens.37
Another meta-analysis on oral anti-retroviral therapy for HIV showed similar findings, with patients being approximately three times more likely to be adherent to once-daily regimens than more frequent regimens (3.07, 95% CI 1.80–5.23; p < 0.001).38 Existing medication adherence rates for topical TTh have also been demonstrated to be as low as 15.4% at 1 year, however39 In short, oral formulations may increase compliance, whereas twice-daily dosing requirements may somewhat limit this advantage.
In conclusion, through many advances in pharmacologic delivery systems and testosterone formulation, oral testosterone has become a promising new avenue for TTH. Oral T administration is convenient, and twice-daily dosing with food (i.e., with breakfast and dinner and without the need for a high-fat content) is a simple regimen that should promote better patient adherence over transdermal and injectable T products that dominate use among hypogonadal men.
Both Jatenzo and Tlando provide a unique combination of convenience and ease of use with stable efficacious testosterone levels without the previous adverse effects of hepatotoxicity and increased cardiac risks. These drugs now represent an FDA-approved safe and effective oral testosterone agent for use in the United States.
Pratik Kanabur, Robert Brunner, Dalia Khera, Hunter A. Flores, and Mohit Khera*
Abstract
There have been multiple attempts at an oral testosterone option for men with testosterone deficiency (TD), however many have been unsuccessful due to severe adverse reactions and lack of efficacy compared with other options. Due to a recent development in the pharmacology of delivery of oral testosterone through a self-emulsifying drug delivery system, there has been the advent of new oral options for men suffering from TD. This review covers the history and challenges of oral testosterone, the development of a novel drug delivery system to allow men to absorb oral testosterone safely, and the efficacy of three oral testosterone options.— Jatenzo, Tlando and Kyzatrex. Clinicaltrials.gov identifier: NCT04467697.
Introduction
Testosterone (T), a steroid hormone, is the primary androgen in males and is necessary for a variety of physiologic processes, including sexual and reproductive function, cognition, metabolism, and body composition.1–3 Testosterone deficiency (TD), synonymous with male hypogonadism, is defined by two-morning serum total testosterone levels <300 ng/dL and having one or more symptoms attributable to low circulating levels of testosterone.4,5 Symptoms of TD include decreased energy, decreased libido, erectile dysfunction, decrease in muscle mass and strength, decrease in bone mass, increase in central body fat, anemia, and impaired memory, mood, concentration, and sleep.6,7
Testosterone decreases with age with a *1% annual decrease in free testosterone levels after the age of 30 or about a decrease of 100 ng/dL every 10 years.6,7 Approximately 20% of men over the age of 45 and 40% of men over the age of 80 are hypogonadal. Aging males are more likely to have an acquired cause or idiopathic etiology of hypogonadism. The decline in testosterone levels can be due to several factors, including the decline of Leydig cell function, the decline in pituitary-hypothalamic axis function with loss of circadian variation, an increase in the levels of sex hormone binding globulin, changes in testosterone receptor sensitivity, and the effects of altered inflammatory and metabolic states.
Moreover, a reason for the prevalence of hypogonadism can be ascribed to the acquisition of co-morbid conditions, such as obesity, diabetes, and metabolic syndrome, as men age.7–10 Previous studies have shown that hypogonadism is associated with abdominal adiposity, insulin resistance, and metabolic syndrome. A few studies have shown that treatment of diabetes and improvement in obesity lead to a modest increase in testosterone, without the restoration of testosterone concentrations to normal.11,12 Studies have even shown that over 50% of renal transplant patients had TD, and these patients were found to have lower levels of hemoglobin (Hb), glomerular filtration rate, and serum albumin.13
The high prevalence among the general population, burdensome symptoms, and the utilization in the improvement of comorbidities render TD a commonly encountered problem for physicians. There has been a significant rise in the number of prescriptions of testosterone in the United States over the past few years, which has accelerated the need to develop a superior tolerated formulation that is easier to use.14 The treatment options to increase testosterone levels and ameliorate TD symptoms include intramuscular injections, transdermal gels, implanted pellets, nasal sprays, and buccal tablets (Table 1).
Each of these formulations has certain drawbacks that most healthcare providers and patients are aware of, such as pain with injection, dermal irritation, testosterone transference, and others.15 The difficulties with the formulations can often lead to difficulty with adherence to daily treatments. What has been missing from the health care provider's armamentarium of testosterone therapy (TTh) is an oral testosterone formulation that can both comply with federal regulation stipulations for safety and meet the need for standards of efficacy.
Early oral testosterone was associated with serious hepatotoxicity and the later version of oral testosterone undecanoate (TU) was highly influenced in terms of absorption and clinical bioavailability from fat content in the patient’s diet, which led to intrapatient variability and questionable utility. A recent oral TU formulated in a distinctive self-emulsifying drug delivery system (SEDDS), Jatenzo, was recently developed to treat male hypogonadism. Another oral testosterone formulation, Tlando, was released in 2022 and a third formulation, Kyzatrex, was Food and Drug Administration (FDA) approved in 2022 The purpose of this review is to address the safety, efficacy, and durability of oral testosterone.
*History of Oral Testosterone
Pharmacologic Mechanism of Oral Testosterone
TU is a testosterone prodrug formulation that is lipophilic due to the long carbon sidechain and favors absorption via the lymphatic system, which is the opposite of other testosterone esters, which are more likely to be taken up by the portal system. TU has been integrated into a new proprietary SEDDS formulation. SEDDS stimulates a level of saponification of the lipophilic T esters, which leads to more preferential absorption by the intestinal lymphatic system. This leads to a decrease in first-pass hepatic metabolism.23 SEDDS formulations syndicate lipophilic and hydrophilic components, which promote the solubilization of molecules such as TU, which are normally lipophilic. Thus, they can be absorbed in the intestines without the necessity of maintaining a diet high in fat content.324
SEDDS is defined as a uniform amalgam of lipophilic oils (synthetic or natural) plus solid or liquid surfactants or hydrophilic solvents. On activation followed by a reduction in aqueous solution, which is what happens in the human gastrointestinal tract, these systems produce a fine oil in water emulsion, which is physically stable (unlikely to be degraded or absorbed through the portal system) and readily absorbed by the intestines to the bloodstream.25
The SEDDS-specific mechanism in the bloodstream has been well-studied in the literature. In the bloodstream and fatty tissue, TU undergoes a swift enzymatic de-esterification, which results in a release of testosterone. The free undecanoic acid component is metabolized via beta-oxidation to produce multiple acetyl-coenzyme-A compounds and a singular propionyl-coenzyme-A molecule, which assists with absorption. Next, the gut produces dihydrotestosterone (DHT) undecanoate and DHT through enzymatic activation with 5-alpha reductase.23
A phase II pharmacokinetics study23 showed that hypogonadal men who took TU with a SEDDS formulation had a dose-proportional response that was well tolerated. The specific formulation that was assessed comprised TU dissolved in lipid formulations with other compounds such as borage seed oil (a rich source of C-20 fatty acids) and peppermint oil along with a hydrophilic surfactant [hydrogenated castor oil (Cremophor RH 40)] to promote solubilization. These were encapsulated in soft gelatin capsules of various strengths, which would enable highly lipophilic molecules such as TU to be dissolved, and thus can be absorbed after a normal meal (without requiring a fat high content)
When experimental oral testosterone, which included 200 mg of TU in the proprietary prodrug SEDDS formulation, was administered twice a day, average serum T levels were able to attain a eugonadal testosterone level in more than 75% of patients. Within a month, 87% of men had mean blood T levels within the adult male range, and none of the patients were found to exhibit a hypergonadatropic response and have an average serum T level greater than 1500 ng/dL. Patients did have a better response with the intake of a meal compared with fasting, as patients given 200 mg of oral TU twice daily incorporated in a SEDDS formulation had over a twofold higher average T concentration with food intake.23
Further studies incorporating various levels of fat content in the diet are necessary to better elucidate the effect of food on TU with SEDDS formulation absorption. After these data are obtained, specific recommendations for dietary intake and the necessity of food intake with medication can be developed.
One consideration is the 5-alpha reductase enzymatic transition of T to DHT and the effect on various aspects such as lipid levels, muscle mass, sexual function, prostate size, hematocrit levels, etc. The most common mechanism that has been proposed is that the conversion of testosterone to DHT is not the sole pathway, but it does emphasize the level of testosterone in tissues with high 5a-reductase activity, including skin and prostate, compared with tissues with low 5a-reductase activity including bone and muscle.
One clinical trial showed that the increase in body mass composition (while decrease in fat) with graded testosterone levels did not change in men who took dutasteride (suppressing DHT) from those treated with a placebo. This showed that the DHT from the conversion of testosterone is not necessary to mediate the anabolic building of skeletal muscle.26
*Safety Profile of Oral Testosterone
*Pharmacokinetics and Dose Response of Oral Testosterone
*Primary and Secondary Efficacy of Oral Testosterone
Summary and Conclusions
Although the efficacy and demand of TTh through intramuscular injections, transdermal gels, and other formulations have been positive, the development of oral testosterone to add to the urologist’s armamentarium has been a focus of much pharmacologic research over the past 20 years. As previous oral testosterone treatments, such as methyltestosterone, have been associated with significant hepatotoxicity and cardiac risk, the focus has shifted to the utilization of TU as a potential oral regimen despite its previously documented issue with dietary influence.
Two new drugs, Jatenzo and Tlando, have been used in advanced drug delivery, such as SEDDS, to deliver a more stable and predictable dose-response curve regardless of diet. Although these drugs still exhibit adverse effects of polycythemia, changes in lipid composition and mild increases in SBP, their magnitudes are comparable to the effects seen in approved topical TTh. Importantly, they also do not appear to pose any clinically significant increase in PSA, IPSS, or AUASS as compared with topical testosterone.
These new oral testosterone treatments appear able to deliver a sustainable increase in serum testosterone to the eugonadal range with a low risk for hypergonadal levels. Specifically, Jatenzo has shown that 87.3% of patients reach eugonadal testosterone ranges at 120 days, and 85% of Tlando patients reach a safe eugonadal range below 1500 ng/dL as well. They also exhibit promising improvements in psychosexual outcomes, with both demonstrating improvements in PDQ scores. In addition, Jatenzo appears to improve bone density and lean body mass as well.
However, oral T was associated with a small but statistically significant increase in SBP versus the topical T. This observation indicates the need for regular monitoring of BP in men receiving testosterone replacement therapy, particularly in those with existing HTN. Another limitation is these drugs are the first in their class and still need adequate insurance coverage in order for uptake to be enthusiastic for patients and providers.
In addition, given their relative novelty, no established recommendations exist for follow-up intervals and dosing adjustments for patients who do experience an alteration in their BP or cholesterol. According to both Jatenzo trials, 74% of patients required some dosing adjustment over the study period, but only with regard to their serum testosterone level. More study is necessary to determine a safety follow-up regimen and dose adjustment protocol for patients exhibiting unsafe rises in BP or total cholesterol levels.
Finally, although an oral agent is likely a welcome alternative option to other formulations for many patients, medication adherence to a twice-daily dosing regimen (BID) may, nonetheless, present problems. Medication adherence in other chronic diseases has been studied frequently and has shown an inverse relationship between medication adherence and dosing frequency. In a meta-analysis on cardiovascular oral medications, Weeda et al demonstrated only a 50.4% adherence rate for BID regimens versus 74.2% for once-daily regimens.37
Another meta-analysis on oral anti-retroviral therapy for HIV showed similar findings, with patients being approximately three times more likely to be adherent to once-daily regimens than more frequent regimens (3.07, 95% CI 1.80–5.23; p < 0.001).38 Existing medication adherence rates for topical TTh have also been demonstrated to be as low as 15.4% at 1 year, however39 In short, oral formulations may increase compliance, whereas twice-daily dosing requirements may somewhat limit this advantage.
In conclusion, through many advances in pharmacologic delivery systems and testosterone formulation, oral testosterone has become a promising new avenue for TTH. Oral T administration is convenient, and twice-daily dosing with food (i.e., with breakfast and dinner and without the need for a high-fat content) is a simple regimen that should promote better patient adherence over transdermal and injectable T products that dominate use among hypogonadal men.
Both Jatenzo and Tlando provide a unique combination of convenience and ease of use with stable efficacious testosterone levels without the previous adverse effects of hepatotoxicity and increased cardiac risks. These drugs now represent an FDA-approved safe and effective oral testosterone agent for use in the United States.
