madman
Super Moderator
* Oral TRT, particularly testosterone undecanoate (TU), offers notable convenience. TU is absorbed via the lymphatic system, bypassing first-pass hepatic metabolism, making it a promising agent for TRT. Its absorption, however, is influenced by dietary factors, such as lipid intake, thus the high-fat consumption promoting lymphatic absorption. Pharmaceutical technology developed TU formulations incorporate special self-emulsifying systems that enhance lymphatic absorption regardless of food fat content. This lymphatic absorption allows for stable testosterone levels, positioning TU as a viable also for an oral treatment option.
* In the USA, there had been a broad search for novel oral drug delivery system that could offer required therapeutic concentrations independent of ingestion a rich-fat meal. Based on specific properties of the self-emulsifying drug delivery system (SEDDS) JATENZO and TLANDO utilizes for lymphatic uptake of TU with safe therapeutic effects without evidence of liver dysfunction. The SEDDS described herein integrates a high-HLB surfactant, a co-surfactant, and a TU-dissolving carrier oil. In brief within the GI tract, self-emulsification occurs, enlarging the interfacial area and the lipophobic environment promoting the enhanced absorption of TU 26
Abstract
Male hypogonadism, or Testosterone Deficiency (TD), involves decreased testicular function, leading to low androgen levels and impaired sperm production. This condition can negatively impact quality of life and increase cardiovascular risks. The adult hypogonadism frequently occurs over 40 in men, and it is characterized by persistent symptoms alongside low testosterone levels, typically below 300 ng/dL. Supplementation with testosterone as a replacement therapy (TRT) is hormonal enhancement found to be effective; however, the delivery methods vary, each with specific advantages and drawbacks. The TRT has potentially life-changing effects, patients feel improved quality of life in several aspects: more energy and muscular strength, increased libido, improved mood, etc. as the most frequent reported outcome.
Oral TRT, particularly testosterone undecanoate (TU), offers notable convenience. TU is absorbed via the lymphatic system, bypassing first-pass hepatic metabolism, making it a promising agent for TRT. Its absorption, however, is influenced by dietary factors, such as lipid intake, thus the high-fat consumption promoting lymphatic absorption. Pharmaceutical technology developed TU formulations incorporate special self-emulsifying systems that enhance lymphatic absorption regardless of food fat content. This lymphatic absorption allows for stable testosterone levels, positioning TU as a viable also for an oral treatment option.
2. Lymphatetic pathway for absorption
3. Testosterone undecanoate (TU)
4. Highlights of PK characteristics of a TU formulation
5. Weakness of the TRT by oral TU / The effect of food on bioavailability
6. Clinical observations
7. Regulatory and marketing status
TU which is lipophilic long-chain ester preserves the androgenic activity that has been attributed to formation of T via systemic hydrolysis of lymphatically transported TU.
The TU as a prodrug formulation, was selected for TRT because it is specific characteristics: highly lipophilic and is manly absorbed via intestinal lymphatics bypassing hepatic metabolism in contrast with other T formulations, such as esters, which are less lipophilic and mainly absorbed via the portal system. and these latter are ineffective in the treatment of male androgen deficiency syndromes due to extensive first-pass metabolism in liver, which otherwise also raises safety concerns. (TU), which is intended to enhance delivery bioavailability via intestinal lymphatics. Andriol® and Andriol Testocaps® were marketed in more than 80 countries.
Furthermore, it is unlikely that treatment of hypogonadal men with this TU formulation would yield average serum T levels in real life conditions in a majority of men to meet the current regulatory and clinical scrutiny.
Due to the low bioavailability and the uncertain absorption process, the oral formulation of Andriol® and Andriol Testocaps® did not meet the stated regulatory standards for safety and efficacy, (i.e. on avg. serum T concentrations for at least 75% of treated men and the Cmax peak T below 1500 ng/dL) the FDA (USA) refused granting the Marketing Authorization thus did not allow the distribution in the USA. In Europe, with strict endocrinological control the oral TU used for TRT. However, in the beginning of 2020 it was removed (e.g. in Hungary) from the therapeutic protocol.
In the USA, there had been a broad search for novel oral drug delivery system that could offer required therapeutic concentrations independent of ingestion a rich-fat meal. Based on specific properties of the self-emulsifying drug delivery system (SEDDS) JATENZO and TLANDO utilizes for lymphatic uptake of TU with safe therapeutic effects without evidence of liver dysfunction. The SEDDS described herein integrates a high-HLB surfactant, a co-surfactant, and a TU-dissolving carrier oil. In brief within the GI tract, self-emulsification occurs, enlarging the interfacial area and the lipophobic environment promoting the enhanced absorption of TU 26
Lately, the slightly modified oral TU formulations were developed as Jatenzo, Tlando, Kyzatrex and marketed globally (also in the USA). The injectable formulations of TU depot injection (Aveed and Nebido) remain the most cost-effective therapeutic option and these are appropriate for most patients as an initial therapy25. Transdermal administration includes gels, liquids and patches since the 80’s.
The latest TU SEDDS dosage form is predicated on the requirement for a high-fat meal to optimize absorption.
- JATENZO® (2019; Clarus Therapeutics Inc., USA) obtained FDA approval as the first oral TRT indicated for primary and central hypogonadism. Like other exogenous androgens, JATENZO was designed with a self-emulsifying drug delivery system that integrates hydrophilic and lipophilic components to promote intestinal lymphatic uptake. This formulation enables administration with a standard meal (15–45 g fat) rather than the previously necessary high-fat diet. Following ingestion, serum testosterone rises rapidly, reaching a peak at 2–4 hours and gradually diminishing toward sub-physiologic levels by about 9 hours, which underpins a twice-daily dosing strategy25
- TLANDO® (2022, Lipocine Inc., USA), another TU oral formulation utilizing SEDDS, has recently been authorized by the FDA for managing of male hypogonadism. This capsule contains 112.5 mg of TU in a unique triglyceride/lipid formulation (with an antioxidant: ascorbyl palmitate). Consistent with all other TU preparations, this lipid emulsification is intended to maximalize the absorption of TU through the intestinal lymphatic system. This formulation was postulated to avoid dose adjustment when employed twice daily for TRT. Since preparation does not require dose titration, regular blood testing simplifying both usage and dosage monitoring25
An open-label trial with TLANDO (225 mg twice daily) for 24 days in hypogonadal men demonstrated stable 24-hour average serum testosterone in 80% of participants without dose adjustment. In a smaller cohort, dietary fat content diets had no effect on bioavailability25,26
- KYZATREX® (2022, Marius Pharmaceuticals, USA) Unique to Kyzartrex is a TU softgel formulation that includes vitamin E and phytosterols to promote lymphatic absorption while aiming to minimize hepatic exposure. In a clinical trial 88% of male participants maintained mean serum testosterone within the eugonadal range (95% CI 82–93), supporting FDA authorization. The product provides 100 mg, 150 mg, and 200 mg capsules; the recommended starting dose is 200 mg orally twice daily with meals, with subsequent titration after seven days according to serum T levels25
In general, matching the right patient with the right TU formulation to ensure good compliance is essential for maintaining long-term satisfaction of TRT, therefore, individualizing therapy is important2
8. Conclusion
Treatment options for male hypogonadism, particularly in cases of LOH, as characterized by low serum T levels and associated symptoms and impaired QoL, include various delivery methods. The oral formulations of TU offering notable advantages in convenience and patient preference. However, the efficacy of oral T has traditionally been limited by first-pass hepatic metabolism. Advances in formulation, such as TU, have improved bioavailability through lymphatic absorption, especially when taken with lipid-rich meals. processes. Despite these improvements, variability in dietary habits and individual responses remains a challenge, affected serum T levels and treatment consistency. Newer formulations of TU with castor oil and propylene glycol laurate instead of oleic acid, has similar PK and provide improved storage conditions.
A thorough understanding of these factors is essential for optimizing therapy, ensuring safety, and achieving desired clinical outcomes. It can be concluded that orally administered TU is a valuable tool for TRT. Continued research aims to improve bioavailability in formulation innovations and personalized treatment strategies will further enhance management of hypogonadism to ensure the right plasma testosterone levels, by the availability of various formulations for TRT.
Over the past two decades, testosterone replacement therapy (TRT) prescription rates have risen worldwide, largely driven by claims that testosterone enhances energy and endurance. This increase, however, does not appear to reflect treatment of patients concordant with clinical guidelines. Although other TRT formulations are available, oral TU remains an important option for individual therapy, and the comparisons among different testosterone products underscoring the need for further research to optimize personalized treatment strategies.
* In the USA, there had been a broad search for novel oral drug delivery system that could offer required therapeutic concentrations independent of ingestion a rich-fat meal. Based on specific properties of the self-emulsifying drug delivery system (SEDDS) JATENZO and TLANDO utilizes for lymphatic uptake of TU with safe therapeutic effects without evidence of liver dysfunction. The SEDDS described herein integrates a high-HLB surfactant, a co-surfactant, and a TU-dissolving carrier oil. In brief within the GI tract, self-emulsification occurs, enlarging the interfacial area and the lipophobic environment promoting the enhanced absorption of TU 26
Abstract
Male hypogonadism, or Testosterone Deficiency (TD), involves decreased testicular function, leading to low androgen levels and impaired sperm production. This condition can negatively impact quality of life and increase cardiovascular risks. The adult hypogonadism frequently occurs over 40 in men, and it is characterized by persistent symptoms alongside low testosterone levels, typically below 300 ng/dL. Supplementation with testosterone as a replacement therapy (TRT) is hormonal enhancement found to be effective; however, the delivery methods vary, each with specific advantages and drawbacks. The TRT has potentially life-changing effects, patients feel improved quality of life in several aspects: more energy and muscular strength, increased libido, improved mood, etc. as the most frequent reported outcome.
Oral TRT, particularly testosterone undecanoate (TU), offers notable convenience. TU is absorbed via the lymphatic system, bypassing first-pass hepatic metabolism, making it a promising agent for TRT. Its absorption, however, is influenced by dietary factors, such as lipid intake, thus the high-fat consumption promoting lymphatic absorption. Pharmaceutical technology developed TU formulations incorporate special self-emulsifying systems that enhance lymphatic absorption regardless of food fat content. This lymphatic absorption allows for stable testosterone levels, positioning TU as a viable also for an oral treatment option.
2. Lymphatetic pathway for absorption
3. Testosterone undecanoate (TU)
4. Highlights of PK characteristics of a TU formulation
5. Weakness of the TRT by oral TU / The effect of food on bioavailability
6. Clinical observations
7. Regulatory and marketing status
TU which is lipophilic long-chain ester preserves the androgenic activity that has been attributed to formation of T via systemic hydrolysis of lymphatically transported TU.
The TU as a prodrug formulation, was selected for TRT because it is specific characteristics: highly lipophilic and is manly absorbed via intestinal lymphatics bypassing hepatic metabolism in contrast with other T formulations, such as esters, which are less lipophilic and mainly absorbed via the portal system. and these latter are ineffective in the treatment of male androgen deficiency syndromes due to extensive first-pass metabolism in liver, which otherwise also raises safety concerns. (TU), which is intended to enhance delivery bioavailability via intestinal lymphatics. Andriol® and Andriol Testocaps® were marketed in more than 80 countries.
Furthermore, it is unlikely that treatment of hypogonadal men with this TU formulation would yield average serum T levels in real life conditions in a majority of men to meet the current regulatory and clinical scrutiny.
Due to the low bioavailability and the uncertain absorption process, the oral formulation of Andriol® and Andriol Testocaps® did not meet the stated regulatory standards for safety and efficacy, (i.e. on avg. serum T concentrations for at least 75% of treated men and the Cmax peak T below 1500 ng/dL) the FDA (USA) refused granting the Marketing Authorization thus did not allow the distribution in the USA. In Europe, with strict endocrinological control the oral TU used for TRT. However, in the beginning of 2020 it was removed (e.g. in Hungary) from the therapeutic protocol.
In the USA, there had been a broad search for novel oral drug delivery system that could offer required therapeutic concentrations independent of ingestion a rich-fat meal. Based on specific properties of the self-emulsifying drug delivery system (SEDDS) JATENZO and TLANDO utilizes for lymphatic uptake of TU with safe therapeutic effects without evidence of liver dysfunction. The SEDDS described herein integrates a high-HLB surfactant, a co-surfactant, and a TU-dissolving carrier oil. In brief within the GI tract, self-emulsification occurs, enlarging the interfacial area and the lipophobic environment promoting the enhanced absorption of TU 26
Lately, the slightly modified oral TU formulations were developed as Jatenzo, Tlando, Kyzatrex and marketed globally (also in the USA). The injectable formulations of TU depot injection (Aveed and Nebido) remain the most cost-effective therapeutic option and these are appropriate for most patients as an initial therapy25. Transdermal administration includes gels, liquids and patches since the 80’s.
The latest TU SEDDS dosage form is predicated on the requirement for a high-fat meal to optimize absorption.
- JATENZO® (2019; Clarus Therapeutics Inc., USA) obtained FDA approval as the first oral TRT indicated for primary and central hypogonadism. Like other exogenous androgens, JATENZO was designed with a self-emulsifying drug delivery system that integrates hydrophilic and lipophilic components to promote intestinal lymphatic uptake. This formulation enables administration with a standard meal (15–45 g fat) rather than the previously necessary high-fat diet. Following ingestion, serum testosterone rises rapidly, reaching a peak at 2–4 hours and gradually diminishing toward sub-physiologic levels by about 9 hours, which underpins a twice-daily dosing strategy25
- TLANDO® (2022, Lipocine Inc., USA), another TU oral formulation utilizing SEDDS, has recently been authorized by the FDA for managing of male hypogonadism. This capsule contains 112.5 mg of TU in a unique triglyceride/lipid formulation (with an antioxidant: ascorbyl palmitate). Consistent with all other TU preparations, this lipid emulsification is intended to maximalize the absorption of TU through the intestinal lymphatic system. This formulation was postulated to avoid dose adjustment when employed twice daily for TRT. Since preparation does not require dose titration, regular blood testing simplifying both usage and dosage monitoring25
An open-label trial with TLANDO (225 mg twice daily) for 24 days in hypogonadal men demonstrated stable 24-hour average serum testosterone in 80% of participants without dose adjustment. In a smaller cohort, dietary fat content diets had no effect on bioavailability25,26
- KYZATREX® (2022, Marius Pharmaceuticals, USA) Unique to Kyzartrex is a TU softgel formulation that includes vitamin E and phytosterols to promote lymphatic absorption while aiming to minimize hepatic exposure. In a clinical trial 88% of male participants maintained mean serum testosterone within the eugonadal range (95% CI 82–93), supporting FDA authorization. The product provides 100 mg, 150 mg, and 200 mg capsules; the recommended starting dose is 200 mg orally twice daily with meals, with subsequent titration after seven days according to serum T levels25
In general, matching the right patient with the right TU formulation to ensure good compliance is essential for maintaining long-term satisfaction of TRT, therefore, individualizing therapy is important2
8. Conclusion
Treatment options for male hypogonadism, particularly in cases of LOH, as characterized by low serum T levels and associated symptoms and impaired QoL, include various delivery methods. The oral formulations of TU offering notable advantages in convenience and patient preference. However, the efficacy of oral T has traditionally been limited by first-pass hepatic metabolism. Advances in formulation, such as TU, have improved bioavailability through lymphatic absorption, especially when taken with lipid-rich meals. processes. Despite these improvements, variability in dietary habits and individual responses remains a challenge, affected serum T levels and treatment consistency. Newer formulations of TU with castor oil and propylene glycol laurate instead of oleic acid, has similar PK and provide improved storage conditions.
A thorough understanding of these factors is essential for optimizing therapy, ensuring safety, and achieving desired clinical outcomes. It can be concluded that orally administered TU is a valuable tool for TRT. Continued research aims to improve bioavailability in formulation innovations and personalized treatment strategies will further enhance management of hypogonadism to ensure the right plasma testosterone levels, by the availability of various formulations for TRT.
Over the past two decades, testosterone replacement therapy (TRT) prescription rates have risen worldwide, largely driven by claims that testosterone enhances energy and endurance. This increase, however, does not appear to reflect treatment of patients concordant with clinical guidelines. Although other TRT formulations are available, oral TU remains an important option for individual therapy, and the comparisons among different testosterone products underscoring the need for further research to optimize personalized treatment strategies.
