Testosterone Undecanoate Formulation Research Articles

A phase III, single-arm, 6-month trial of a wide-dose range oral testosterone undecanoate product.

Oral testosterone undecanoate (TU) formulations may provide effective, safe, and easily titratable testosterone replacement therapy. Demonstrate efficacy and safety of a novel oral TU formulation. An open-label, single-arm, multi-center trial treated 155 hypogonadal men for 180 days. Treatment began at 200 mg TU twice daily with meals; doses were titrated over two 28-day cycles to between 100 and 800 mg TU daily, measuring average testosterone (T Cavg) after 90 days. Ambulatory blood pressure monitoring (ABPM) occurred at baseline, 120, and 180 days. Titrations used a randomized blood sample taken 3-, 4-, or 5-h post-morning dose. Outcomes used sodium fluoride/ethylenediaminetetraacetate plasma testosterone (T) values; serum results were also reported. Blood pressure (ABPM and in-clinic) was evaluated for change from baseline. After titration, 87.8% of KYZATREX™ treated participants (worse-case scenario) and 96.1% of 90-day completers achieved eugonadal mean plasma T values. Serum T Cavg was 452 ng/dL and maximum T concentrations (T Cmax) met all FDA criteria. Participant eugonadal percentages were comparable across subgroups for age, weight, and body mass index. Diet had no effect on participant eugonadal percentages. KYZATREX was well tolerated, with no drug-related serious adverse events (SAE) and one adverse drug reaction (hypertension) observed in 2% or more of participants. Systolic ambulatory blood pressure increased 1.7 mmHg (95% confidence interval: 0.3-3.1). At baseline, 36% of 155 participants were receiving anti-hypertensive medication and 22% were diabetic. No dose increases occurred in existing anti-hypertensive medication; five participants (3.2%) started anti-hypertensive medication. KYZATREX provided safe and effective testosterone levels within the normal range in hypogonadal male study participants. URL: https://clinicaltrials.gov/ unique identifier NCT04467697, conducted under NCT03198728. Post-completion, clinicaltrials.gov requested creation of the separate NCT04467697 identifier. All subjects were recruited under NCT03198728.

FRI431 Erythrocytosis Associated With Oral Testosterone Replacement

Abstract Disclosure: A.A. Engel: None. J.L. Sarvaideo: None. Background: A growing prevalence in male hypogonadism has led to increased interest in the most common adverse event, erythrocytosis. Defined by hematocrit (HCT) > 49-51%, the incidence varies depending on the testosterone formulation.3 The formulations with the lowest risk of erythrocytosis are intranasal testosterone (0-2%) and oral testosterone (0.03%).3 A phase 3 clinical trial of testosterone undecanoate (Jatenzo) reported 4.8% patients experienced an increase in hematocrit, although not severe enough to warrant therapy discontinuation.2 We present a case of erythrocytosis with oral testosterone undecanoate that prompted a change in therapy. Clinical Case: Our patient is a 55-year-old male with secondary hypogonadism potentially related to obesity (BMI 37 kg/m²). AM total testosterone (TT) 151 (348-1197 ng/dL), free testosterone 4.6 pg/mL (6.8-21.5 pg/mL) and LH 3.8 mIU/mL. Labs confirmed. Secondary work-up negative. HCT 43.6% prior to any therapy. Patient treated with injectable testosterone. Despite decreasing to testosterone cypionate 80 mg weekly his HCT increased to 52.7% with a TT of 544 ng/dL. He was switched to oral testosterone undecanoate 237 mg twice daily given presumably lower risk of erythrocytosis. However, HCT increased to 55.1% and TT to 1542 ng/dL. Patient donated blood and oral testosterone dose decreased to 158 mg twice daily with starting HCT 48.9%, but this increased to 53.7%. TT 522 ng/dL. Therapy stopped with improvement of HCT to 45.8%-48.9%, TT 192 ng/dL, and SHBG 20 g/dL. Erythropoietin remained normal. Patient does not smoke cigarettes nor has OSA. Conclusion: We present a case of oral testosterone undecanoate complicated by persistent erythrocytosis despite dose reduction. Testing for contributing etiology was unrevealing. Oral testosterone replacement is considered the formulation least likely to cause erythrocytosis. Certain patient characteristics like OSA, advanced age, obesity, type II diabetes mellitus and an elevated HCT > 50% can predict the likelihood of erythrocytosis although its specific etiology is unclear.3 Proposed mechanisms include elevation in dihydrotestosterone, erythropoietin stimulation, suppression of hepcidin and relation to androgen receptor CAG repeat length.1 Providers should be aware of the possibility of erythrocytosis on oral testosterone. Further research is needed to determine predictive characteristics for erythrocytosis and etiology. Reference: 1. Aghazadeh, M, et al. Elevated dihydrotestosterone is associated with testosterone induced erythrocytosis. J Urol. 2015; 194(1): 160-165. 2. Swerdloff, S, et al. A new oral testosterone undecanoate formulation restores testosterone to normal concentrations in hypogonadal men. J Clin Endocrinol Metab. 2020; 105)8): 1-17. 3. White, J, et al. Testosterone therapy and secondary erythrocytosis. IJIR: Your Sexual Medicine Journal. 2022; 34: 693-697. Presentation: Friday, June 16, 2023

Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety

BackgroundLong-term data evaluating the efficacy and safety of oral testosterone undecanoate (oral TU; JATENZO) in adult hypogonadal men provides important information for healthcare professionals who prescribe testosterone replacement therapy (TRT). AimTo determine the efficacy and safety of long-term oral TU therapy, including its impact on total testosterone (T) levels and psychosexual functioning. MethodsHypogonadal men, between 18 and 75 years old, (mean age 56.2; 87.2% white) who completed a 12-month, open-label, multicenter, randomized, active-controlled trial were given the opportunity to enroll in a 12-month extension study. Among the 129 eligible TU-treated subjects, 86 chose this option, and 69 completed 24 months of uninterrupted oral TU therapy. OutcomesThe efficacy of oral TU was documented by measuring total serum T concentrations; sexual function was measured using the Psychosexual Daily Questionnaire (PDQ). For safety, liver function tests, cardiovascular endpoints, and prostate health were measured. ResultsOver 2 years, total serum T concentrations for patients treated with oral TU were in the eugonadal range (300–1,000 ng/dL [10–35 nmol/L]; mean ± SD: 617 ± 427 ng/dL [21 ± 15 nmol/L]) and increased significantly from baseline (P < .0001). For sexual function, mean score changes versus baseline for all PDQ domains at all time points were significantly improved (P < .0011 for all). For the sexual activity and sexual desire components, patient scores were consistently greater than validated thresholds for clinically meaningful change. Typical T-induced safety changes were observed, including a 3–6 mm Hg increase in systolic blood pressure (P < .05); a slight increase in hematocrit (P < .0001) that stayed <48% throughout the study; no clinically significant changes in prostate-specific antigen levels; and decreased high-density lipoprotein cholesterol (-9.8 ± 0.9 mg/dL from baseline; P < .0001). There were no clinically significant changes from baseline in liver function tests. Clinical ImplicationsOver 2 years of treatment, this novel oral TU formulation maintained total T concentrations in mideugonadal ranges, with improvements in sexual function and no clinically significant changes in liver function or other safety concerns previously associated with oral TRT. Strengths & LimitationsThese are the first long-term data to evaluate the efficacy and safety of a novel formulation of oral TU; the comparative long-term safety of oral TU would be strengthened by confirmatory studies versus other TRT formulations. ConclusionOral TU offers a safe and effective long-term treatment option for men with hypogonadism.Honig S, Gittelman M, Kaminetsky J, et al. Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety. J Sex Med 2022;19:1750–1758.

Two-year administration data of an oral testosterone undecanoate (TU) formulation in hypogonadal men

ABSTRACT Introduction An oral testosterone (T) replacement therapy (TRT) would be the preferred administration route for many hypogonadal men. Until recently, the only oral TRT approved in the US was methyl-T which has been associated with hepatotoxicity. The safety of a novel oral T undecanoate (TU) formulation was evaluated in hypogonadal men with two-year follow up. Methods Two open-label, multicenter, dose-titration trials were conducted in hypogonadal men (serum T ≤ 300 ng/dL) age 18-75 years. Trial I was a randomized, active-controlled, 2-arm, 12-month study. Trial 2 was a long-term extension of those who completed Trial 1. Statistical analyses were only conducted with the subjects who completed Trial 1 and continued treatment in Trial 2, thus providing up to 2 full years of data. Safety was assessed by physical exam, AE reporting, and routine clinical laboratory measurements. Results Overall, 86 subjects participated in both studies. T concentration increased from 193.75 ± 9.44 ng/dL (Mean ± SEM) at baseline (BL) to 475.5 ± 49.7 ng/dL after 24 Mo of therapy with oral TU, and 84% of men achieved T in eugonadal range (300-1000 ng/dL) after 90 days of therapy. Mean T concentrations remained in the eugonadal range throughout Trial 2. There were no clinically significant changes in liver function tests – ALP (64.05 ± 1.95 to 53.74 U/L ± 1.86 U/L), ALT (27.8 ± 1.40 to 26.7 ± 1.6 U/L), AST (21.6 ± 0.76 to 22.0 ± 1.0 U/L), and bilirubin (0.58 ± 0.03 to 0.52 ± 0.03 mg/dL) throughout the two studies. At d270, one subject had an ALT level of 227 U/L, which was &amp;gt; 4x the ULN (ULN for ALT = 45 U/L). Despite continued use of oral TU, ALT was measured again on d290, and the level dropped to 87 U/L, &amp;lt; 2x ULN. This was the only instance of an LFT elevation. There was a modest initial increase in prostate-related growth endpoints (i.e. PSA and prostate volume) that stabilized over time. Although there was a slight increase in prostate-growth related endpoints, there were no significant changes in IPSS total score (-0.06 ± 3.9 vs BL). There were significant, yet modest, increases in mean HCT (44.3 ± 0.3 to 46.6 ± 0.5%, p &amp;lt; 0.001) and cuff systolic BP (127.1 ± 1.2 to 131.8 ± 1.67 mmHg vs BL, p = 0.006). The change in CV endpoints, including HDL-C, hematocrit, and BP, changed initially and stabilized throughout the 2 trials. For example, systolic BP varied 3 – 6 mm Hg from BL throughout the study. Conclusion This oral TU formulation is an option for hypogonadal men and has a safety profile consistent with other approved T products, such as a rise in hematocrit and a decrease in HDL-C. Notably, no evidence of liver toxicity was observed over 2 years. The long-term efficacy and safety profile of oral TU may provide a treatment option that avoids issues associated with other TRTs, such as injection site pain or transference to partners and children. Disclosure Work supported by industry: yes, by Clarus Therapeutics. A consultant, employee (part time or full time) or shareholder is among the authors (Clarus Therapeutics).

Two-Year Administration Data of an Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men

ABSTRACT Introduction An oral testosterone (T) replacement therapy (TRT) would be the preferred administration route for many hypogonadal men. Until recently, the only oral TRT approved in the US was methyl-T which has been associated with hepatotoxicity. Objective The safety of a novel oral T undecanoate (TU) formulation was evaluated in hypogonadal men with two-year follow up. Methods Two open-label, multicenter, dose-titration trials were conducted in hypogonadal men (serum T ≤ 300 ng/dL) age 18-75 years. Trial I was a randomized, active-controlled, 2-arm, 12-month study. Trial 2 was a long-term extension of those who completed Trial 1. Statistical analyses were only conducted with the subjects who completed Trial 1 and continued treatment in Trial 2, thus providing up to 2 full years of data. Safety was assessed by physical exam, AE reporting, and routine clinical laboratory measurements. Results Overall, 86 subjects participated in both studies. T concentration increased from 193.75 ± 9.44 ng/dL (Mean ± SEM) at baseline (BL) to 475.5 ± 49.7 ng/dL after 24 Mo of therapy with oral TU, and 84% of men achieved T in eugonadal range (300-1000 ng/dL) after 90 days of therapy. Mean T concentrations remained in the eugonadal range throughout Trial 2. There were no clinically significant changes in liver function tests – ALP (64.05 ± 1.95 to 53.74 U/L ± 1.86 U/L), ALT (27.8 ± 1.40 to 26.7 ± 1.6 U/L), AST (21.6 ± 0.76 to 22.0 ± 1.0 U/L), and bilirubin (0.58 ± 0.03 to 0.52 ± 0.03 mg/dL) throughout the two studies. At d270, one subject had an ALT level of 227 U/L, which was &amp;gt; 4x the ULN (ULN for ALT = 45 U/L). Despite continued use of oral TU, ALT was measured again on d290, and the level dropped to 87 U/L, &amp;lt; 2x ULN. This was the only instance of an LFT elevation. There was a modest initial increase in prostate-related growth endpoints (i.e. PSA and prostate volume) that stabilized over time. Although there was a slight increase in prostate-growth related endpoints, there were no significant changes in IPSS total score (-0.06 ± 3.9 vs BL). There were significant, yet modest, increases in mean HCT (44.3 ± 0.3 to 46.6 ± 0.5%, p &amp;lt; 0.001) and cuff systolic BP (127.1 ± 1.2 to 131.8 ± 1.67 mmHg vs BL, p = 0.006). The change in CV endpoints, including HDL-C, hematocrit, and BP, changed initially and stabilized throughout the 2 trials. For example, systolic BP varied 3 – 6 mm Hg from BL throughout the study. Conclusions This oral TU formulation is an option for hypogonadal men and has a safety profile consistent with other approved T products, such as a rise in hematocrit and a decrease in HDL-C. Notably, no evidence of liver toxicity was observed over 2 years. The long-term efficacy and safety profile of oral TU may provide a treatment option that avoids issues associated with other TRTs, such as injection site pain or transference to partners and children. Disclosure Yes, this is sponsored by industry/sponsor: Clarus Therapeutics Clarification Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Clarus Therapeutics

Real-World Experience with First FDA-Approved Oral Testosterone Undecanoate Formulation

ABSTRACT Introduction The diagnosis of hypogonadism (HG) in men requires both consistently low testosterone (T) levels and signs and symptoms of T deficiency. Management of HG with T replacement therapy (TRT) aims to improve both low serum T levels and patients’ symptomatic complaints. The first oral softgel formulation of testosterone undecanoate (TU) was recently approved by FDA (JATENZO®) for TRT in men with specific hypogonadal conditions and is available in 3 capsule strengths and 5 dosage combinations for necessary dose adjustments. However, dose titration may not be necessary in many patients treated with this new oral TU formulation given the wide eugonadal range. Objective Assess the ability of any given daily dosage of oral TU to restore T to eugonadal levels without dose adjustment at steady state (Css); and determine real-world dose titration experience of patients treated with oral TU. Methods Pharmacokinetic (PK) simulations were performed using a robust population PK model developed for T in 474 hypogonadal men who were treated with oral TU in prior PK studies. The model consisted of a 1-compartment model with absorption lag time and an allometric function on key allometric parameters to account for differences in body weight. This final population PK model was coded in Trial Simulator v2.3.0.6 software. T levels were simulated following oral TU BID dosing on Day 55 (i.e., at steady state) with no dose adjustments. Average T concentrations (Cavg) were derived from multiple serial blood samples collected over 24 hrs for oral TU doses of 237, 316, and 396 mg TU, BID (without dose modification). The percent of subjects with T levels within the eugonadal range (serum Cavg between 304 ng/dL-1030 ng/dL) at each of these TU dose levels was calculated. Prescription data was also accessed in the Symphony PatientSource Patient Transactional Dataset to evaluate the frequency of real-world dose titration. Results The percentage of subjects with Css T Cavg within the eugonadal range for 237, 316, and 396 mg TU, BID were 61%, 74% and 74%, respectively. These corresponded to mean [5%, 95% CI] serum T levels (ng/dL) of 398 [389, 406], 560 [549, 572] and 728 [715, 741] ng/dL, respectively. Early assessment of real-world prescribing data for JATENZO indicated 35% of patients underwent dose titration by month 5. Conclusions Simulated daily BID dosing of oral TU without dose adjustment yielded eugonadal T levels in most subjects at all 3 dose levels examined. These data are consistent with initial early real-world experience with oral TU that indicates dose titration has not been required in most patients. However, because the desired outcome of TRT therapy focuses on both T Cavg and symptomatic response, this oral TU formulation enables necessary dose adjustment when needed. Disclosure Yes, this is sponsored by industry/sponsor: Clarus Therapeutics, Inc. Clarification Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Clarus Therapeutics, Inc.

Effects of the oral testosterone undecanoate Kyzatrex™ on ambulatory blood pressure in hypogonadal men.

Testosterone replacement therapies have been shown to increase blood pressure (BP) in hypogonadal men. We studied the effects of a new formulation of testosterone undecanoate (Kyzatrex™) on ambulatory blood pressure (ABP) and heart rate, in 155 men with hypogonadism (mean age, 50.5 years, 76.8% white, 36.1% on antihypertensive therapy). The ABP, heart rate and clinical assessments were obtained at baseline and following 120 and 180 days of therapy. Mean changes from baseline in 24‐h ambulatory systolic BP of 1.7 mmHg (95% CI, 0.3, 3.1) at day 120 and 1.8 mmHg (95% CI, 0.3, 3.2) at day 180 were observed post‐treatment. For those men on antihypertensive drug therapy, increases in mean 24‐h systolic BP were greater than those not taking antihypertensive drugs (3.4 vs 0.7 mmHg at day 120 and 3.1 vs 1.0 mmHg at day 180, respectively). Changes from baseline in 24‐h diastolic BP and heart rate at day 120 were smaller (<1 mmHg and <1 beat/min, respectively). There were no relationships observed between testosterone concentration or hemoglobin levels with ABP. Multivariable analyses showed that baseline ambulatory BP and antihypertensive therapy were significantly correlated with BP changes. These data demonstrate small increases in ambulatory BP following 120 days on this oral testosterone undecanoate with no further changes at 180 days. Changes in ambulatory BP were minimal in patients not taking antihypertensive therapy.

Safety Analysis of an Oral Testosterone Undecanoate (TU) Formulation Following 2 Years of Administration in Hypogonadal Men

Introduction: An oral testosterone (T) replacement therapy (TRT) would be the preferred choice for many hypogonadal men. Until recently, the only oral TRT approved in the US was methyl-T which has been associated with hepatotoxicity. The safety of a novel oral T undecanoate (TU) formulation was evaluated in hypogonadal men for up to 2 years. Subjects and Methods: Two open-label, multicenter, dose-titration trials were conducted in hypogonadal men (serum T ≤ 300 ng/dL) age 18-75 years. Trial I was a randomized, active-controlled, 2-arm, 12-month study. Trial 2 was a long-term extension of those who completed Trial 1. Statistical analyses were only conducted with the subjects who completed Trial 1 and continued treatment in Trial 2, thus providing up to 2 full years of data. Safety was assessed by physical exam, AE reporting, and routine clinical laboratory measurements. Results: Overall, up to 81 subjects were available for evaluation. T concentration increased from 208.3 ± 102.4 ng/dL (Mean ± SD) at baseline (BL) to 470.1 ± 396.5 ng/dL after 24 Mo of therapy with oral TU, and 84% of men achieved T in eugonadal range (300-1000 ng/dL) after 90 days of therapy. Mean T concentrations remained in the eugonadal range throughout Trial 2. There were no clinically significant changes in liver function tests - ALT (28.0 ± 12.3 to 26.6 ± 12.8 U/L), AST (21.8 ± 6.8 to 22.0 ± 8.2 U/L), and bilirubin (0.58 ± 0.22 to 0.52 ± 0.19 mg/dL) throughout the two studies. At Day 270, one subject had an ALT level of 227 U/L, which was > 4x the ULN (ULN for ALT = 45 U/L). Despite continued use of oral TU, ALT was measured again on Day 290, and the level dropped to 87 U/L, < 2x ULN. This was the only instance of an LFT elevation. There was a modest initial increase in prostate-related growth endpoints (i.e. PSA and prostate volume) that stabilized over time. There were not any significant changes in IPSS total score (-0.06 ± 3.9 vs BL). There were significant, yet modest, increases in mean HCT (+2.52 ± 3.7% vs BL, p < 0.001) and cuff systolic BP (+5.6 ± 15.0 mmHg vs BL, p = 0.006). The change in prostate-related growth variables and CV endpoints changed initially and stabilized throughout the 2 trials. For example, systolic BP consistently showed a mean increase from BL between 3 - 6 mmHg. Conclusion: This oral TU formulation is an effective long-term therapy for hypogonadal men and has a safety profile consistent with other approved T products. Notably, no evidence of liver toxicity was observed. The long-term efficacy and safety profile of oral TU may provide a treatment option that avoids issues associated with other TRTs, such as injection site pain or transference to partners and children.

Novel Oral Testosterone Formulation Improves Male Well Being Without Compromising International Prostate Symptom Scores

Introduction: Male hypogonadism results from insufficient secretion of testosterone (T) and is characterized by low serum T concentrations. Common symptoms of hypogonadism include decreased libido, impotence, weakness, low energy, depression and/or loss of motivation, memory and concentrating issues, and sleep disturbances. Several forms of T replacement are available. Testosterone undecanoate (TU) is a testosterone prodrug available in oral formulations. A novel TU formulation, SOV2012-F1, has been submitted for FDA consideration under the name KYZATREX®. While TU efficacy is measured by serum total T, patientfocused endpoints such as Patient Reported Outcomes (PROs) are valuable indicators of well-being and psychosexual symptom abatement. Methods: A Phase 3, randomized, multicenter, open-label, active-controlled trial, comparing SOV2012F1 (testosterone undecanoate capsules) (n=214) with AndroGel® (1.62% topical testosterone gel) (n=100) enrolled males aged 18 to 65 years with hypogonadism (serum total T levels ≤281 ng/dL). A key exploratory endpoint was change from Baseline (ΔBL) after 52 weeks of treatment in the following PROs: International Prostate Symptom Score (IPSS), Psychosexual Daily Questionnaire (PDQ), Short Form Health Survey 36 item (SF-36), and the International Index of Erectile Function (IIEF). Results: Total or overall scores for all PROs (IPSS, PDQ, SF-36 and IIEF) showed increased improvement in the SOV2012-F1 group relative to the Androgel group, and all but IPSS demonstrated improvement relative to BL. For IPSS, due to the potential that T could worsen urinary symptoms, the ΔBL would ideally be small to reflect minimal impact. Change for the SOV2012-F1 and AndroGel groups was, respectively, 0.6 and 1.0. Further, the IPSS total score was not significantly different from BL in the patients receiving SOV20212-F1 (p = 0.5659). For PDQ, a clinically meaningful improvement of sexual desire in hypogonadal men age ≥65 years is ≥0.7; mean ΔBL was 1.6 in the SOV2012-F1 group versus 1.4 in the AndroGel group. In the SF-36, the mean ΔBL total score was 83.7 in the SOV2012-F1 group and 70.2 in the AndroGel group. Further, post hoc analysis of the Health Change category found a significant (p ≤ 0.05) improvement in patient perspectives on health over the course of the study. The overall satisfaction score of the IIEF trended towards significance for the SOV2012-F1 group with a mean ΔBL score of 2.3 versus and 1.6 in the AndroGel group. The ΔBL for the 4 domains of male sexual function were small and consistent between the SOV2012-F1 and AndroGel groups. Comparable results were noted for Early Withdrawals and All Subjects across all PROs. Conclusion: Treatment with SOV2012-F1 for 52 weeks exceeded AndroGel patient satisfaction as measured by PROs including IPSS, PDQ, SF-36 and IIEF, demonstrating clinical distinction. Further analysis of SOV2012-F1 will be forthcoming.

SAT-LB6 First Human Trial of an Oral Native Testosterone Shows Physiological Levels of Testosterone and Dht in Both Fasted and Fed State in Hypogonadal Men

Introduction: The prevalence of male hypogonadism is estimated to be 6% in the USA (1). Current therapies have limited acceptability: gels can be messy and risk inadvertent dosing of others; injections are painful; and oral testosterone undecanoate (TU) delivers variable testosterone levels, requires concurrent ingestion of a fatty meal and may produce supraphysiological dihydrotestosterone (DHT) levels. We present the first human trial of an oral native testosterone preparation formulated to deliver physiological levels of testosterone irrespective of food intake. Aim: To compare the pharmacokinetics of DITEST (Diurnal Ltd Cardiff, UK) to an oil based oral TU formulation (Andriol Testocaps MSD, UK) and explore the effect of food on DITEST bioavailability. Methods: Single centre, phase 1b study of DITEST in 25 adult males with hypogonadism, one subject withdrawn after single period and only included in safety analysis (Clinicaltrials.gov: NCT02966652). Part 1 compared the pharmacokinetics of 80mg TU with 120mg DITEST after a high fat meal. Part 2 the pharmacokinetics of 200mg of DITEST administered in either fed or fasted states. Results are baseline adjusted. Results: DITEST showed a testosterone dose response between 120mg and 200mg with Cmax 550 (19.1) and 877 (30.4) ng/dl (nmol/l) and AUC0-10h 59.5 and 88.6 h*nmol/L. DITEST 200mg gave an equivalent Cmax and AUC0-10h to TU 80mg: Cmax 877 (30.4) vs 906 (31.4) ng/dl (nmol/l) and AUC0-10h 88.6 vs 102 h*nmol/L. Fed and fasted DITEST had similar pharmacokinetics: Cmax 764 (26.5) vs 877 (30.4) ng/dl (nmol/L), AUC0-10h 87.0 vs 88.6. DITEST resulted in lower levels of DHT than TU: Cmax 84 (2.9), 131 (4.5) & 194 (6.7) ng/dl (nmol/l); AUC0-10h 11.0, 16.7 & 36.3 h*nmol/L for DITEST 120mg, 200mg & 80mg TU, respectively. There was one serious adverse event (urinary retention) in the study during TU dosing. There were no emerging safety concerns, and adverse event frequency and severity was similar between the two treatments. Discussion: These results demonstrate that 200mg DITEST provides similar testosterone exposure with more physiological DHT exposure than 80mg TU given with a high fat meal. Administration of DITEST in fed and fasted states provides similar testosterone and DHT exposure. Compared to published literature on a self-emulsifying formulation of TU at 200mg, DITEST at 200mg provides a similar testosterone Cmax and no requirement for a fatty meal (2). Conclusion: DITEST is an oral native testosterone formulation with anticipated advantages over current oral therapy of dosing without food and a lower risk of supraphysiological DHT levels.

A new oral testosterone undecanoate therapy comes of age for the treatment of hypogonadal men.

Background:A novel formulation of oral testosterone undecanoate (TU) was studied in a long- and short-term phase III trial to evaluate safety and efficacy.Methods:Hypogonadal men (age 18–65 years; two morning serum testosterone (T) <300 ng/dl with signs/symptoms) were recruited into a 365 day (trial I) or 105 day (trial II), randomized, multicenter trial. Patients were randomized 1:1 to oral TU (n = 161) or T-gel (n = 160) in trial I, and 3:1 to oral TU, twice daily (BID) JATENZO® (n = 166) or a topical T product [Axiron® (n = 56)] in trial II. Dose adjustments were based on average T concentrations (Cavg). Efficacy was assessed based on T levels, body composition and bone density. Safety was assessed by standard clinical measures.Results:Oral TU efficacy (% of patients with eugonadal T Cavg) was 84% (serum Cavg = 628 ± 343 ng/dl) and 87% (serum T equivalent Cavg ≈ 489 ± 155 ng/dl) in trials I and II, respectively. Oral TU significantly (p <0.0001) improved all Psychosexual Daily Questionnaire parameters in trials I and II. In trial I, lean mass increased 3.2 ± 2.7 kg and fat decreased by 2.4 ± 3.6 kg (both p <0.0001) and bone density improved in hip (+0.012 ± 0.0225 g/cm2) and spine (+0.018 ± 0.0422 g/cm2) after 365 days (both p <0.0001). Oral TU-associated adverse effects were consistent with other T-replacement therapies but oral TU patients experienced a greater number of mild gastrointestinal adverse effects. Oral TU subjects in both studies exhibited an increase in mean systolic blood pressure of about 3–5 mmHg. Oral TU was not associated with liver toxicity nor did it cause an elevation in high-sensitivity C-reactive protein or lipoprotein-associated phospholipase A2 (cardiovascular safety biomarkers) after 365 days of therapy.Conclusion:A new oral TU formulation was safe and effective and represents a significant therapeutic advance for the treatment of appropriate hypogonadal men.

Feasibility of poly (ε-caprolactone-co-DL-lactide) as a biodegradable material for in situ forming implants: evaluation of drug release and in vivo degradation

The purpose of this study was to evaluate the technical feasibility of poly (ε-caprolactone-co-DL-lactide), P (CL/DL-LA), for injectable in situ forming implants (ISFI). The ISFI was prepared by dissolving P (CL/DL-LA) in N-methyl-2-pyrrolidone (NMP), and Testosterone undecanoate (TU) was used as model drug. The effect of various polymer concentrations, molecular weights (Mws) and drug loads on the drug release from the TU-loaded ISFI systems was investigated in vitro. The release of TU-loaded ISFI was also evaluated in rats. In addition, a subcutaneous rabbit model was used to evaluate the degradation and foreign-body reaction of P (CL/DL-LA) ISFI. The use of higher concentration of P (CL/DL-LA) with higher molecule weight and larger CL:DL-LA monomer ratio for the TU-loaded ISFI gave a slower drug release. The ISFI of 80/20 P (CL/DL-LA) (Mw 61 753):NMP 20:80 with 16% TU formulation increased serum testosterone levels in rats over a period of three months. The in vivo degradation and biocompatibility study of ISFI shows that P (CL/DL-LA) degrades by a process of bulk degradation and that the foreign-body reaction of this biomaterial is relatively mild. In summary, our investigations demonstrate that in situ parenteral drug delivery systems can be obtained from P (CL/DL-LA) solutions.

Comparison of long-acting testosterone undecanoate formulation versus testosterone enanthate on sexual function and mood in hypogonadal men

To compare the effects of two treatment modalities of testosterone on sexual functioning and mood. Design Forty men were randomized to receive either parenteral testosterone enanthate (TE) or long-acting parenteral testosterone undecanoate (TU) over a period of 30 weeks. Thereafter, 20 men who had received TU and 16 men who had received TE continued with TU and completed another 65 weeks to study longer-term effects of TU. The following variables of sexual functioning were studied: sexual thoughts and fantasy, sexual interest and desire, satisfaction with sex life, number of erections and ejaculations per week, and number of spontaneous morning erections per week. Also variables related to mood were analyzed. Improvements in these variables were significant and were of a similar magnitude in the group treated with TU and TE for 30 weeks. Improvements were maintained at the same levels over a period of another 65 weeks when all men received TU. Effects on mood were recorded for 30 weeks, but were more difficult to establish in the study population. There were significant differences in baseline values between the two groups and scores showed wide s.d. Both TE and TU were effective in improving sexual functions in hypogonadal men. An advantage of TU over TE is its lower frequency of administration and its better tolerability and safety profile.

Comparison of a new long-acting testosterone undecanoate formulation vs testosterone enanthate for intramuscular androgen therapy in male hypogonadism

To assess the efficacy and safety of a novel long-acting im testosterone undecanoate (TU) formulation in comparison with testosterone enanthate (TE). An open-label, randomized, prospective clinical trial in 40 hypogonadal men (baseline serum testosterone levels <5 nmol/l), randomly assigned to 250 mg TE/3 weeks (no.=20) or 1000 mg TU im every 6 to 9 weeks for 30 weeks (no.=20). Subsequently, 32/40 men continued the study for another 114 weeks, now receiving TU 1000 mg/12 weeks. TU and TE produced no statistically significant improvements in grip strength over the first 30 weeks, which only occurred after approximately 90 weeks when all subjects received TU. There were no changes in body mass index with TU and TE, neither in the follow-up period when all patients received TU. But ratios of waist to hip circumferences declined in the longer term. Total serum cholesterol, LDL cholesterol, and triglycerides declined over the first 30 weeks, while plasma HDL also declined. Plasma LDL decreased further under long-term TU therapy, while HDL then increased. Hemoglobin and hematocrit values significantly increased over the first 30 weeks in both treatment groups and then no further increase was observed. Levels did not exceed the upper limit of normal. In both treatment groups, serum prostate specific antigen levels rose slightly after 30 weeks, with no further increase over the first 12 months, remaining stable within the normal range. Plasma T before the following TU injection was above the lower limit of reference values. Four injections per year are adequate. Administration of TU every 12 weeks is at least as safe and efficacious for treatment of hypogonadal men as TE, with a substantially lower frequency of administration. Follow-up over 114 weeks, when all subjects received TU, showed an excellent profile of efficacy and safety.

The effect of food composition on serum testosterone levels after oral administration of Andriol® Testocaps®

ObjectiveAndriol® Testocaps® is a new oral formulation of testosterone undecanoate (TU) for treatment of hypogonadism. As TU is taken up by the intestinal lymphatic system, both the presence and the composition of food influence the absorption. The aim of this study was to investigate the effect of food composition on the pharmacokinetics of oral TU.DesignAn open-label, single-centre, four-way crossover study. With a washout period of 6–7 days, 80 mg TU was administered in the morning 5 min after consuming each of four different meals in a randomized order (A: 230 kcal, 0·6 g lipid; B: 220 kcal, 5 g lipid; C: 474 kcal, 19 g lipid; D: 837 kcal, 44 g lipid).PatientsTwenty-four postmenopausal volunteers.MeasurementsSerial blood samples were collected until 24 h after dosing to determine testosterone and dihydrotestosterone (DHT) by gas chromatography-mass spectroscopy (GC-MS).ResultsThe bioavailability of testosterone after a low-calorie meal containing 0·6 g lipid or 5 g lipid was relatively low, the area under the concentration–time curve (AUC0–tlast) for testosterone being 30·7 and 43·5 nmol h/l, respectively. The bioavailability of testosterone after a meal containing 19 g lipid was considerably higher (AUC0–tlast = 146 nmol h/l), whereas increasing the lipid content to 44 g lipid did not further increase the bioavailability of testosterone (AUC0–tlast = 154 nmol h/l).ConclusionApproximately 19 g of lipid per meal efficiently increases absorption of testosterone from oral TU. Therefore, coadministration with a normal rather than a fatty meal is sufficient to increase serum testosterone levels when using oral TU.

Testosterone Undecanoate ??? Schering AG

Schering AG is developing a formulation of testosterone undecanoate [Nebido] for the treatment of testosterone deficiency or hypogonadism. This deficiency can lead to decreased muscle mass, impaired muscle function, osteoporosis, reduced sexual function and mental degeneration. Schering claims that its new formulation provides superior control of blood levels of the drug and permits a longer period of application. Nebido requires only four injections per year, and represents a major improvement for men with testosterone deficiency. Schering AG received approval of its testosterone undecanoate formulation in its first European country, Finland, in November 2003 for the treatment of hypogonadism in men. In July 2004, Schering's testosterone undecanoate formulation completed approval of the European mutual recognition procedure. This approval clears the way for marketing the product (as Nebido) in the large pharmaceutical markets like Germany, France and the UK. The initial phase of the product launch will occur in Finland in October 2004, and in Germany in November 2004. Other European countries will follow in 2005, and following receipt of approval, it will be introduced in the first Latin American and Asian countries. In its 2002 Annual Report, Schering predicted that testosterone undecanoate has the potential to reach peak sales of euro 100 million, 3 years after launch-launch in Europe was at the time anticipated in 2004.

A new oral testosterone undecanoate formulation.

Testosterone undecanoate has been available on the market for more than 20 years. This testosterone ester is used worldwide for oral treatment of male hypogonadism. So far, testosterone undecanoate has been dissolved in oleic acid, leading to inconvenient storage conditions. It will now be available in a new formulation with castor oil and propylene glycol laurate instead of oleic acid, thus improving storage conditions markedly (stable at room temperature for approximately 3 years). Pharmacokinetic and pharmacodynamic studies have demonstrated bioequivalence of the old and the new formulation of testosterone undecanoate. Therefore, the results of studies that were performed with the old formulation can be transferred to the clinical use of the new formulation. Controlled studies have shown its efficacy in the treatment of symptoms associated with reduced serum testosterone levels. In these cases testosterone undecanoate improves bone mineral density, quality of life, muscle mass, libido and mood. Further studies will help evaluate the efficacy and safety of the new formulation in the treatment of elderly men with late-onset hypogonadism.

The aging male project

With an increasing life expectancy and a decreasing reproduction rate, the population structure changes. A Jenapharm R &amp; D program investigates the endocrinology of aging men. In men, a decrease in production of sex steroids and other hormones with age can be observed. The typical patterns of daily rhythmicity become less distinct. This is part of a very complex picture in which not only isolated hormones are involved, but also the influence of hormones on each other. Many factors from the external and intemal environment mediated by neurotransmitters constantly affect the highly sensitive hormonal balance. Therefore, aging has also been defined as "the gradual dysfunction of homeostatic processes". Declining testosterone (T) levels are involved in 'andropausal' symptoms in men: loss of libido, erectile dysfunction, insulin receptor resistance, obesity, osteoporosis, disturbances of lipid metabolism, myocardial and circulatory disturbances, impaired well-being and mood. Data are derived from studies in hypogonadal men treated by T replacement. In such parients under T treatment libido increases, fat mass decreases, muscle strenth, bone mineral density and erythropoesis increase. Whether the symptoms of andropause in aging men could successfully be treated by T substitution remains to be investigated. Negative effects of T, especially on the prostate and the cardiovascular system, are under discussion. There is increasing evidence that low T levels seem to be a risk factor for both the prostate and the cardiovascular system. Jenapharm's new testosterone undecanoate formulation for intramuscular injection can be administered every three months. T levels remain within the physiologic range. No supraphysiologic peaks occur. In women, estrogens have beneficial non-genital effects. Studies concentrate on synthetic estrogens for men without feminizing properties such as gynecomastia and reduced testicular size. Several derivatives of 17- alpha estradiol have been synthesized some of which show selectivity for the central nervous system. CNS effects have been demonstrated in female and male animals. Cardiovascular protection by estrogens has been shown in animal and human studies. Atherosclerotic plaque size was reduced after estrogen injections in cholesterol-fed rabbits. Phytoestrogen-fed monkeys had lower total cholesterol and LDL cholesterol and higher HDL cholesterol. Apart from atherosclerotic lesions, coronary artery vascular reactivity was improved. Some of these experimental findings were confirmed in human studies in postmenopausal women with and without estrogen treatment. Whether all of the described estrogenic effects can be seen in men remains to be investigated. (Med J Indones 2001; 10: 127-33)Keywords : aging, andropause, testosterone, estrogens