madman
Super Moderator
Abstract
Introduction
Testosterone deficiency is a clinical disorder due to either failure of the testes to produce testosterone or failure of the hypothalamus or pituitary to produce sufficient gonadotropins. Previous formulations of oral testosterone therapy, particularly methyltestosterone,have been associated with adverse liver effects. Many different routes of testosterone delivery have been developed, each with their own administrative benefits and challenges. Newer formulations of oral testosterone undecanoate (TU) provide a convenient administration option, although their use has been limited by hepatotoxicity concerns based on older methyltestosterone data, and prescribing physicians may still be concerned about adverse liver effects.
Objectives
In this review, we discuss the history of oral testosterone development, clarify the mechanism of action of oral TU, and describe the relevant liver safety findings.
Methods
Relevant literature was allocated to present a review on the history of oral TU development and the mechanism of action of oral TU. We pooled data from individual studies of oral TU products to present a safety summary.
Results
Overall, safety results from studies of the newer formulations of oral TU showed that increased liver function test values are not generally associated with oral TU formulations and that no clinically significant liver toxicities were noted in clinical trials of oral TU.
Conclusion
Continued research into the safety of oral TU will contribute to a better understanding of the potential risks in patients receiving this therapy, an outcome that highlights the importance of providing patient education and reassurance regarding oral TU safety.
Introduction
Male testosterone deficiency is a clinical syndrome characterized by low testosterone due to malfunction of the testes or failure of the hypothalamus/pituitary to produce stimulatory hormones.1,2 Patients with testosterone deficiency often experience symptoms such as fatigue, depressed mood, loss of lean muscle mass, and reduced sexual desire.2,3 Testosterone therapy is used to achieve therapeutic testosterone levels and symptom improvement.4,5 The guidelines of the American Urological Association recommend initiation of testosterone at minimal doses to achieve a normal physiologic testosterone range of 450-600 ng/dL and that signs and symptoms of testosterone deficiency be re-evaluated within 3 months to determine if dosing adjustments are necessary.4 The guidelines also recommend that patients with testosterone deficiency who are receiving testosterone therapy undergo adjunctive testing, including measurement of serum luteinizing and follicle-stimulating hormones, prolactin, estradiol,hemoglobin, and hematocrit. At the time of this report,however, no recommendations had been reported regarding monitoring with liver function tests (LFTs).4
Testosterone undecanoate (TU) package inserts bear a label with a warning stating that oral methyltestosterone has been associated with serious hepatic adverse events, and long term therapy with intramuscular testosterone enanthate has produced hepatic adenomas. While no specific recommendations for LFT monitoring are provided, prescribers are still advised to report any signs or symptoms of hepatic dysfunction (ie, jaundice), which may indicate drug-induced liver injury (DILI).6-8
Hepatic dysfunction due to DILI may indicate a severe liver injury or irreversible liver failure that is fatal or requires liver transplantation.9 Because most drugs that cause DILI do so infrequently,9 evaluation for DILI is important and includes severity categories that may be described according to liver injury descriptions in the drug label: level 1, steatosis; level 2, cholestasis and steatohepatitis; level 3, liver aminotransferases increase; level 4, hyperbilirubinemia; level 5, jaundice; level 6, liver necrosis; level 7, acute liver failure; and level 8, hepatotoxicity.10 On the basis of these DILI severity classes, liver injury from DILI associated with methyltestosterone was categorized up to level 5 (jaundice).10,11 In a study of the US Food and Drug Administration (FDA) Adverse Event Reporting System, examinations of the frequency of DILI associated with testosterone treatment resulted in a reported odds ratio <1, suggesting that there is no major concern for possible development of DILI in patients undergoing treatment with testosterone.12
Hy’s Law is a principle used to identify patients at high risk of severe liver damage from a medication and is based on observations by Hy Zimmerman, a leading researcher in DILI. Hy’s Law focuses on hepatocellular injury, highlights that jaundice is a warning sign of injury, and provides threshold values for elevated liver enzymes and bilirubin that indicate a patient is at high risk for DILI. While it is a helpful tool to raise suspicion, Hy’s Law is not a definitive test, and when it is used to assess a patient, further investigation by a doctor is warranted.9,13,14 A combination of diagnostic laboratory blood tests that are used to identify a potential DILI case include the following: increased aminotransferase (AT) >3× upper limit of normal (ULN) compared to control; increased AT >5×,10×, or 20× ULN in modest numbers of test group patients and not seen in the control group; or 1 or more cases of newly increased total serum bilirubin >2× ULN in a setting of pure hepatocellular injury, with no other explanation, accompanied by an overall increased incidence of AT >3× ULN in a test group patients compared to the control group. According to Hy’s Law, a finding of 2 of the abovementioned diagnostic indicators (and probably even 1) is considered highly predictive that the drug has the potential to cause severe DILI.9
Multiple routes of testosterone delivery have been approved for use, including oral, buccal, intranasal, transdermal, subcutaneous, and intramuscular (Table 1).15 The routes of administration and FDA-licensed doses of the testosterone agents presented here have not been known to cause hepatic adverse effects, although the use of androgenic anabolic steroids has been associated with hepatotoxicity.16-22 Oral administration of testosterone offers convenient dosing without injections, skin and nasal irritation, risk of transference, or risk of pellet extrusion, and recent trends in other disease states have shown patient preference for oral therapies over other regimens.5,15,23 Despite these benefits, prescription rates of oral testosterone have steadily declined.5 Possible explanations for current hesitation regarding the use of oral TU include concerns for hepatotoxicity demonstrated in earlier methylated testosterone formulations and unfavorable pharmacokinetics and multiple dosing requirements of the early TU product Andriol® (Merck Canada Inc, Kirkland, QC,Canada).5,23 Additional hesitancies among clinicians with regard to prescribing oral TU may be due to a lack of insurance coverage and/or high cost, a known issue in the United States.24
Oral TU development
TU was first introduced in Europe in the 1970s as Andriol, an esterified form of testosterone that bypassed first-pass metabolism in the liver and, when coupled with an oleic acid vehicle, increased lymphatic absorption in the gut.25,27 Andriol was approved in many countries but never in the United States due in part to high dependence of concentration on dietary fat intake.28–31 The oleic acid vehicle used to increase absorption required Andriol to be refrigerated to maintain stability.25 The Andriol formulation was updated to a castor oil and propylene glycol vehicle in a new formulation (Andriol Testocaps), which increased the shelf life of the medication, improved the consistency in drug concentration,and reduced the effect of dietary fat.23,25,32 This necessitated multiple capsules throughout the day to maintain adequate drug levels.23
Advancements to the self-emulsifying drug delivery system (SEDDS) allowed for the development of novel oral TU formulations (JATENZO®, Clarus Therapeutics, Northbrook, IL, United States; TLANDO®, Antares Pharma, Inc.,San Diego, CA, United States) that produced physiologic concentrations of testosterone without concern for meal fat content.33–36 Another oral formulation of TU uses a phytosterol carrier vehicle (KYZATREX™,Marius Pharmaceuticals, Raleigh, NC, United States).7,25
Oral TU mechanism of action
After oral administration, the TU molecule is primarily absorbed into the intestinal lymphatic system by chylomicrons, improving solubility in fat.36,37 It is released into systemic circulation by the thoracic duct and converted to testosterone, predominantly avoiding absorption into the portal vein and circumventing first-pass metabolism in the liver (Fig. 2). This mechanism is supported by evidence describing TU lymphatic absorption rates of 93.0% to 99.8%in a thoracic lymph duct–cannulated dog model.38 Further research has demonstrated that lymphatic drug transport in humans is similar to transport in species with higher body mass, such as dogs, suggesting that lymph flow and lipid transport in humans may be predicted from animal models via allometric scaling.39
Chylomicrons are lipid spheroids formed in enterocytes that facilitate the transport of lipids, especially entities of high lipophilicity.36 Chylomicrons are necessary for the absorption of oral TU and are released in response to lipid ingestion and digestion, and thus, the administration of oral TU with a meal is required.36 Historically, evidence has suggested unreliable oral bioavailability, fluctuating serum levels, and short half life when oral TU was not taken with food. However, current evidence suggests that meal fat content does not influence the bioavailability of novel formulations of oral TU.15,25,36 Therefore, oral TU requires administration with food, but there is no evidence to support improved absorption with increased meal fat.33,34
In a phase 3, open-label study of hypogonadal men undergoing testosterone replacement therapy (NCT02722278), patients receiving JATENZO demonstrated a trend toward higher free testosterone levels and a greater decrease in sex hormone–binding globulin (SHBG) compared to patients receiving Axiron.40 Higher free testosterone and decreased SHBG in patients receiving oral testosterone have been further corroborated by the results of a phase 3, randomized, active controlled study of patients with testosterone deficiency (SOAR, ClinicalTrials.gov: NCT02081300), in which patients receiving TLANDO demonstrated a noticeable decrease in SHBG and increased free testosterone compared to those receiving topical AndroGel 1.62%.41 Patients treated with oral TU or with topical or injectable testosterone may experience some small but noticeable first-pass metabolism that may reduce the concentration of the active drug, as evidenced by a decrease in SHBG and high-density lipoprotein and increase in free testosterone.33,42,43 Understanding more about the safety aspect of oral TU liver metabolism will help determine real-world implications for this effect.
TU safety
Oral formulations of TU bear a warning citing possible hepatic adverse effects following prolonged use of 17-alpha alkyl androgens (methyltestosterone).6-8 Although oral TU therapies have demonstrated a lack of hepatic AEs in clinical studies and evidence supports the lymphatic absorption of oral TU, these therapies are still regarded with trepidation concerning the potential for hepatic adverse events.33,34,39 In the following section, we discuss safety findings pertaining to the liver from studies of currently available oral TU products(Table 2).
Testosterone undecanoate
Studies have shown that the first form of oral TU, Andriol ,was rarely associated with decreased liver function.
JATENZO
Studies have shown that treatment with JATENZO has not led to increased LFTs or clinically significant liver toxicities.
TLANDO
Studies with TLANDO have shown that oral TU is not associated with increased LFTs and may demonstrate a positive liver effect.
KYZATREX
KYZATREX (NCT03198728), 314 patients were randomized to receive KYZATREX 400 mg in the morning and 200 mg in the evening titrated based on plasma testosterone or AndroGel 1.65%.52 Patients were assessed for change from baseline to end of treatment (time of early withdrawal or at day 365) LFTs (ALT, AST, total bilirubin, and ALP).52 Results showed greater change from baseline in LFTs for KYZATREX compared to AndroGel for ALP, ALT, and bilirubin, and no improvement in AST: mean (SD) change from baseline: ALP,−4 (11.31) vs −1.5 (10.37) U/L; ALT, −0.4 (19.84) vs 0.9(14.64) U/L; bilirubin, −0.032 (0.2157) vs 0.026 (0.2117) mg/dL; and AST 2.4 (27.18) vs 1.0 (9.69) U/L. No liver-related AEs were identified.52 Further research into the effect that KYZATREX has on liver safety is needed to assess whether there is concern for Hy’s law and DILI.
Overall, oral TU studies have shown that contrary to concerns about the previous formulations of oral TU therapy,which contained methylated testosterone, the newer formulations of oral TU are safer in relation to liver assessments.
Summary of clinical findings for oral TU
Taken together, these results suggest that increased LFTs are not generally associated with oral testosterone formulations, and no clinically significant liver toxicities were noted in clinical trials of oral TU. These medications are in the early stages of development, making it crucial to monitor liver events in larger populations of clinical practice. If signs o rsymptoms of liver dysfunction do arise, such as increased LFTs, it is imperative that clinicians report these signs or symptoms of hepatic dysfunction. To prevent the development of DILI and a cumulative effect on the liver, clinicians should advise caution in the use of oral TU combined with drugs known to cause hepatotoxicity, including isoniazid, labetalol, and the anti-convulsant felbamate, and use in patients with pre-existing liver disease.9
Safety results for oral TU products do not indicate a concern for DILI, and continued efforts to evaluate the safety of oral TU will be beneficial in determining the risk of DILI in patients receiving this therapy. Clinical trials have shownt hat oral TU may be used safely in men without an observed increase in LFTs, and results from a single-arm study using MRI studies, suggest a possible beneficial effect of oral TU on liver fat improvement. However, further research is necessary to fully understand these findings in patients with testosterone deficiency and NAFLD/nonalcoholic steatohepatitis, and real world evidence demonstrating the liver effect of oral TU is needed. The data outlined in this review could be reassuring for clinicians and patients who are thinking about using oral TU.
Introduction
Testosterone deficiency is a clinical disorder due to either failure of the testes to produce testosterone or failure of the hypothalamus or pituitary to produce sufficient gonadotropins. Previous formulations of oral testosterone therapy, particularly methyltestosterone,have been associated with adverse liver effects. Many different routes of testosterone delivery have been developed, each with their own administrative benefits and challenges. Newer formulations of oral testosterone undecanoate (TU) provide a convenient administration option, although their use has been limited by hepatotoxicity concerns based on older methyltestosterone data, and prescribing physicians may still be concerned about adverse liver effects.
Objectives
In this review, we discuss the history of oral testosterone development, clarify the mechanism of action of oral TU, and describe the relevant liver safety findings.
Methods
Relevant literature was allocated to present a review on the history of oral TU development and the mechanism of action of oral TU. We pooled data from individual studies of oral TU products to present a safety summary.
Results
Overall, safety results from studies of the newer formulations of oral TU showed that increased liver function test values are not generally associated with oral TU formulations and that no clinically significant liver toxicities were noted in clinical trials of oral TU.
Conclusion
Continued research into the safety of oral TU will contribute to a better understanding of the potential risks in patients receiving this therapy, an outcome that highlights the importance of providing patient education and reassurance regarding oral TU safety.
Introduction
Male testosterone deficiency is a clinical syndrome characterized by low testosterone due to malfunction of the testes or failure of the hypothalamus/pituitary to produce stimulatory hormones.1,2 Patients with testosterone deficiency often experience symptoms such as fatigue, depressed mood, loss of lean muscle mass, and reduced sexual desire.2,3 Testosterone therapy is used to achieve therapeutic testosterone levels and symptom improvement.4,5 The guidelines of the American Urological Association recommend initiation of testosterone at minimal doses to achieve a normal physiologic testosterone range of 450-600 ng/dL and that signs and symptoms of testosterone deficiency be re-evaluated within 3 months to determine if dosing adjustments are necessary.4 The guidelines also recommend that patients with testosterone deficiency who are receiving testosterone therapy undergo adjunctive testing, including measurement of serum luteinizing and follicle-stimulating hormones, prolactin, estradiol,hemoglobin, and hematocrit. At the time of this report,however, no recommendations had been reported regarding monitoring with liver function tests (LFTs).4
Testosterone undecanoate (TU) package inserts bear a label with a warning stating that oral methyltestosterone has been associated with serious hepatic adverse events, and long term therapy with intramuscular testosterone enanthate has produced hepatic adenomas. While no specific recommendations for LFT monitoring are provided, prescribers are still advised to report any signs or symptoms of hepatic dysfunction (ie, jaundice), which may indicate drug-induced liver injury (DILI).6-8
Hepatic dysfunction due to DILI may indicate a severe liver injury or irreversible liver failure that is fatal or requires liver transplantation.9 Because most drugs that cause DILI do so infrequently,9 evaluation for DILI is important and includes severity categories that may be described according to liver injury descriptions in the drug label: level 1, steatosis; level 2, cholestasis and steatohepatitis; level 3, liver aminotransferases increase; level 4, hyperbilirubinemia; level 5, jaundice; level 6, liver necrosis; level 7, acute liver failure; and level 8, hepatotoxicity.10 On the basis of these DILI severity classes, liver injury from DILI associated with methyltestosterone was categorized up to level 5 (jaundice).10,11 In a study of the US Food and Drug Administration (FDA) Adverse Event Reporting System, examinations of the frequency of DILI associated with testosterone treatment resulted in a reported odds ratio <1, suggesting that there is no major concern for possible development of DILI in patients undergoing treatment with testosterone.12
Hy’s Law is a principle used to identify patients at high risk of severe liver damage from a medication and is based on observations by Hy Zimmerman, a leading researcher in DILI. Hy’s Law focuses on hepatocellular injury, highlights that jaundice is a warning sign of injury, and provides threshold values for elevated liver enzymes and bilirubin that indicate a patient is at high risk for DILI. While it is a helpful tool to raise suspicion, Hy’s Law is not a definitive test, and when it is used to assess a patient, further investigation by a doctor is warranted.9,13,14 A combination of diagnostic laboratory blood tests that are used to identify a potential DILI case include the following: increased aminotransferase (AT) >3× upper limit of normal (ULN) compared to control; increased AT >5×,10×, or 20× ULN in modest numbers of test group patients and not seen in the control group; or 1 or more cases of newly increased total serum bilirubin >2× ULN in a setting of pure hepatocellular injury, with no other explanation, accompanied by an overall increased incidence of AT >3× ULN in a test group patients compared to the control group. According to Hy’s Law, a finding of 2 of the abovementioned diagnostic indicators (and probably even 1) is considered highly predictive that the drug has the potential to cause severe DILI.9
Multiple routes of testosterone delivery have been approved for use, including oral, buccal, intranasal, transdermal, subcutaneous, and intramuscular (Table 1).15 The routes of administration and FDA-licensed doses of the testosterone agents presented here have not been known to cause hepatic adverse effects, although the use of androgenic anabolic steroids has been associated with hepatotoxicity.16-22 Oral administration of testosterone offers convenient dosing without injections, skin and nasal irritation, risk of transference, or risk of pellet extrusion, and recent trends in other disease states have shown patient preference for oral therapies over other regimens.5,15,23 Despite these benefits, prescription rates of oral testosterone have steadily declined.5 Possible explanations for current hesitation regarding the use of oral TU include concerns for hepatotoxicity demonstrated in earlier methylated testosterone formulations and unfavorable pharmacokinetics and multiple dosing requirements of the early TU product Andriol® (Merck Canada Inc, Kirkland, QC,Canada).5,23 Additional hesitancies among clinicians with regard to prescribing oral TU may be due to a lack of insurance coverage and/or high cost, a known issue in the United States.24
Oral TU development
TU was first introduced in Europe in the 1970s as Andriol, an esterified form of testosterone that bypassed first-pass metabolism in the liver and, when coupled with an oleic acid vehicle, increased lymphatic absorption in the gut.25,27 Andriol was approved in many countries but never in the United States due in part to high dependence of concentration on dietary fat intake.28–31 The oleic acid vehicle used to increase absorption required Andriol to be refrigerated to maintain stability.25 The Andriol formulation was updated to a castor oil and propylene glycol vehicle in a new formulation (Andriol Testocaps), which increased the shelf life of the medication, improved the consistency in drug concentration,and reduced the effect of dietary fat.23,25,32 This necessitated multiple capsules throughout the day to maintain adequate drug levels.23
Advancements to the self-emulsifying drug delivery system (SEDDS) allowed for the development of novel oral TU formulations (JATENZO®, Clarus Therapeutics, Northbrook, IL, United States; TLANDO®, Antares Pharma, Inc.,San Diego, CA, United States) that produced physiologic concentrations of testosterone without concern for meal fat content.33–36 Another oral formulation of TU uses a phytosterol carrier vehicle (KYZATREX™,Marius Pharmaceuticals, Raleigh, NC, United States).7,25
Oral TU mechanism of action
After oral administration, the TU molecule is primarily absorbed into the intestinal lymphatic system by chylomicrons, improving solubility in fat.36,37 It is released into systemic circulation by the thoracic duct and converted to testosterone, predominantly avoiding absorption into the portal vein and circumventing first-pass metabolism in the liver (Fig. 2). This mechanism is supported by evidence describing TU lymphatic absorption rates of 93.0% to 99.8%in a thoracic lymph duct–cannulated dog model.38 Further research has demonstrated that lymphatic drug transport in humans is similar to transport in species with higher body mass, such as dogs, suggesting that lymph flow and lipid transport in humans may be predicted from animal models via allometric scaling.39
Chylomicrons are lipid spheroids formed in enterocytes that facilitate the transport of lipids, especially entities of high lipophilicity.36 Chylomicrons are necessary for the absorption of oral TU and are released in response to lipid ingestion and digestion, and thus, the administration of oral TU with a meal is required.36 Historically, evidence has suggested unreliable oral bioavailability, fluctuating serum levels, and short half life when oral TU was not taken with food. However, current evidence suggests that meal fat content does not influence the bioavailability of novel formulations of oral TU.15,25,36 Therefore, oral TU requires administration with food, but there is no evidence to support improved absorption with increased meal fat.33,34
In a phase 3, open-label study of hypogonadal men undergoing testosterone replacement therapy (NCT02722278), patients receiving JATENZO demonstrated a trend toward higher free testosterone levels and a greater decrease in sex hormone–binding globulin (SHBG) compared to patients receiving Axiron.40 Higher free testosterone and decreased SHBG in patients receiving oral testosterone have been further corroborated by the results of a phase 3, randomized, active controlled study of patients with testosterone deficiency (SOAR, ClinicalTrials.gov: NCT02081300), in which patients receiving TLANDO demonstrated a noticeable decrease in SHBG and increased free testosterone compared to those receiving topical AndroGel 1.62%.41 Patients treated with oral TU or with topical or injectable testosterone may experience some small but noticeable first-pass metabolism that may reduce the concentration of the active drug, as evidenced by a decrease in SHBG and high-density lipoprotein and increase in free testosterone.33,42,43 Understanding more about the safety aspect of oral TU liver metabolism will help determine real-world implications for this effect.
TU safety
Oral formulations of TU bear a warning citing possible hepatic adverse effects following prolonged use of 17-alpha alkyl androgens (methyltestosterone).6-8 Although oral TU therapies have demonstrated a lack of hepatic AEs in clinical studies and evidence supports the lymphatic absorption of oral TU, these therapies are still regarded with trepidation concerning the potential for hepatic adverse events.33,34,39 In the following section, we discuss safety findings pertaining to the liver from studies of currently available oral TU products(Table 2).
Testosterone undecanoate
Studies have shown that the first form of oral TU, Andriol ,was rarely associated with decreased liver function.
JATENZO
Studies have shown that treatment with JATENZO has not led to increased LFTs or clinically significant liver toxicities.
TLANDO
Studies with TLANDO have shown that oral TU is not associated with increased LFTs and may demonstrate a positive liver effect.
KYZATREX
KYZATREX (NCT03198728), 314 patients were randomized to receive KYZATREX 400 mg in the morning and 200 mg in the evening titrated based on plasma testosterone or AndroGel 1.65%.52 Patients were assessed for change from baseline to end of treatment (time of early withdrawal or at day 365) LFTs (ALT, AST, total bilirubin, and ALP).52 Results showed greater change from baseline in LFTs for KYZATREX compared to AndroGel for ALP, ALT, and bilirubin, and no improvement in AST: mean (SD) change from baseline: ALP,−4 (11.31) vs −1.5 (10.37) U/L; ALT, −0.4 (19.84) vs 0.9(14.64) U/L; bilirubin, −0.032 (0.2157) vs 0.026 (0.2117) mg/dL; and AST 2.4 (27.18) vs 1.0 (9.69) U/L. No liver-related AEs were identified.52 Further research into the effect that KYZATREX has on liver safety is needed to assess whether there is concern for Hy’s law and DILI.
Overall, oral TU studies have shown that contrary to concerns about the previous formulations of oral TU therapy,which contained methylated testosterone, the newer formulations of oral TU are safer in relation to liver assessments.
Summary of clinical findings for oral TU
Taken together, these results suggest that increased LFTs are not generally associated with oral testosterone formulations, and no clinically significant liver toxicities were noted in clinical trials of oral TU. These medications are in the early stages of development, making it crucial to monitor liver events in larger populations of clinical practice. If signs o rsymptoms of liver dysfunction do arise, such as increased LFTs, it is imperative that clinicians report these signs or symptoms of hepatic dysfunction. To prevent the development of DILI and a cumulative effect on the liver, clinicians should advise caution in the use of oral TU combined with drugs known to cause hepatotoxicity, including isoniazid, labetalol, and the anti-convulsant felbamate, and use in patients with pre-existing liver disease.9
Safety results for oral TU products do not indicate a concern for DILI, and continued efforts to evaluate the safety of oral TU will be beneficial in determining the risk of DILI in patients receiving this therapy. Clinical trials have shownt hat oral TU may be used safely in men without an observed increase in LFTs, and results from a single-arm study using MRI studies, suggest a possible beneficial effect of oral TU on liver fat improvement. However, further research is necessary to fully understand these findings in patients with testosterone deficiency and NAFLD/nonalcoholic steatohepatitis, and real world evidence demonstrating the liver effect of oral TU is needed. The data outlined in this review could be reassuring for clinicians and patients who are thinking about using oral TU.
