Safety, efficacy, and pharmacokinetics of oral testosterone undecanoate in males with hypogonadism.

BACKGROUND: Testosterone deficiency results from insufficient testosterone production. Testosterone therapy may require dose titration to reach eugonadal serum testosterone concentrations. OBJECTIVE: The primary objective was the efficacy of oral testosterone undecanoate (TLANDO; Antares Pharma Inc.) in male patients with documented hypogonadism. Secondary objectives included a comparison of oral testosterone undecanoate safety and quality-of-life assessments to 1.62% topical testosterone gel (AndroGel 1.62%; AbbVie). MATERIALS AND METHODS: In this phase 3 study, 315 patients were randomized 2:1 to oral testosterone undecanoate or 1.62% topical testosterone gel (NCT02081300). Patients received 225 mg oral testosterone undecanoate twice daily, and doses were adjusted by 75 mg/dose at weeks 4 and 8 based on average serum total testosterone concentration and maximum observed serum concentration. The primary endpoint was the proportion of patients receiving oral testosterone undecanoate with serum total testosterone concentration within the eugonadal reference range (300-1140 ng/dL). Secondary endpoints included the proportion of patients with maximum serum total testosterone concentrations within predetermined limits, safety parameters, and quality-of-life endpoints including the Short Form-36v2 Health Survey, Psychosexual Daily Questionnaire, and International Prostate Symptom Score. RESULTS: Overall mean ± SD baseline testosterone was 205.7 ± 71.6 ng/dL. For patients receiving oral testosterone undecanoate, 87.4% demonstrated a 24-h average serum total testosterone concentration within the reference range following titration. Oral testosterone undecanoate demonstrated a nominal statistically significantly greater mean change from baseline than 1.62% topical testosterone gel for Short Form-36v2 Health Survey measures of mental health (2.91 vs. -0.10; p = 0.035), and mental component summary (3.82 vs. 0.55; p = 0.009); and Psychosexual Daily Questionnaire measure of weekly negative mood (-0.57 vs. -0.20; p = 0.021). Safety endpoints were comparable between therapies. No deaths or treatment-related serious adverse events were reported. DISCUSSION AND CONCLUSION: Male patients with hypogonadism receiving oral testosterone undecanoate 225 mg twice daily demonstrated improvements in libido and sexual frequency. Serum testosterone concentrations were within the reference range in 87% of patients without dose titration.

Newer formulations of oral testosterone undecanoate: development and liver side effects.

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.

A new oral testosterone (TLANDO) treatment regimen without dose titration requirement for male hypogonadism.

BACKGROUND: Male hypogonadism (testosterone level < 300 ng/dl) is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone. Most marketed testosterone replacement therapy products often require multiple dose adjustment clinic visits to achieve the desired, eugonadal testosterone levels. OBJECTIVE: To evaluate the efficacy and safety of a novel oral testosterone undecanoate therapy for the treatment of hypogonadism. MATERIAL AND METHODS: Ninety-five (N = 95) hypogonadal men were enrolled in this open-label, single-arm, multicenter study in the United States (NCT03242590). Subjects received 225 mg of oral testosterone undecanoate (TLANDO) twice a day for 24 days without dose adjustment. Primary efficacy was percentages of subjects who achieved mean 24-h testosterone levels within the eugonadal range and secondary efficacies were evaluated based on the upper limit of lab normal range of testosterone concentration. RESULTS: Subjects enrolled were on average age of 56 years, with about 17% of subjects older than 65 years. The mean body mass index was 32.8 kg/m2 . The baseline mean total testosterone values were below the normal range (202 ± 74 ng/dl). Post-treatment with 450 mg testosterone undecanoate daily dose without dose adjustment, 80% of subjects (95% confidence interval of 72%-88%) achieved a testosterone Cavg in the normal range and restored testosterone levels to mean testosterone Cavg of 476 ± 184 ng/dl at steady state. Testosterone restoration was comparable to other approved testosterone replacement therapy products. TLANDO was well tolerated with no deaths, no drug-related serious adverse events, and no hepatic adverse events. DISCUSSION AND CONCLUSIONS: TLANDO restored testosterone levels to the normal range in the majority of hypogonadal males. This new oral testosterone replacement therapy can provide an option for no-titration oral testosterone replacement therapy. This therapy has the potential to improve patient compliance in testosterone replacement therapy.

Effects of a Novel Oral Testosterone Undecanoate on Ambulatory Blood Pressure in Hypogonadal Men.

BACKGROUND: Testosterone replacement therapies may increase blood pressure (BP) with chronic use but the mechanism is not clear. TLANDO™ is a new oral testosterone undecanoate (TU) under development for the treatment of male hypogonadism. METHODS: We studied the effects of the TU at 225 mg twice daily on ambulatory BP (ABP) and heart rate, in 138 men with hypogonadism (mean age, 54 years, 79% white, 48% with hypertension). Ambulatory BP and heart rate and hematologic assessments were obtained at baseline and following 4-months of therapy. RESULTS: Changes from baseline in ambulatory 24-hour, awake, and sleep systolic BP (SBP) of 3.8 (P < 0.001), 5.2 (P < 0.001), and 4.3 mmHg (P = 0.004) were observed post-treatment, respectively. Lesser changes in the diastolic BP (DBP) were observed (1.2 (P = 0.009), 1.7 (P = 0.004), and 1.7 mmHg (P = 0.011) for 24-hour, awake, and sleep, respectively). Hematocrit and hemoglobin were increased by 3.2% and 0.9 g/dL (P < 0.001), respectively. In those men in the top quartile of changes in hematocrit (range of 6% to 14%), the largest increases in ambulatory SBP (mean, 8.3 mmHg) were observed, whereas the changes in ambulatory SBP in the lower 3 quartiles were smaller (mean, 1.9, 3.3, and 2.1 mmHg in 1st, 2nd and 3 rd quartiles, respectively). CONCLUSION: These data demonstrate that small increases in ABP occurred following 4 months of the oral TU. For those men whose hematocrit rose by >6%, BP increases were of greater clinical relevance. Hence, hematocrit may aid in predicting the development of BP increases on testosterone therapy. CLINICALTRIALS.GOV IDENTIFIER: NCT03868059.

LPCN 1144 Resolves NAFLD in Hypogonadal Males.

Hypogonadism affects hepatic lipid metabolism and is expected to promote nonalcoholic fatty liver disease (NAFLD). The aims of this study were to determine (1) the prevalence of NAFLD in hypogonadal males and (2) the impact of correction of hypogonadism by LPCN 1144 (Lipocine, Inc., Salt Lake City, UT), an oral testosterone prodrug, on NAFLD in this population. Data were derived from a multicenter open-label single-arm trial of LPCN 1144 for hypogonadal males, in which a subset (n = 36) had serial magnetic resonance imaging-proton density fat fraction measurements (National Clinical Trial 03868059). NAFLD prevalence, defined by magnetic resonance imaging-proton density fat fraction ≥5%, was 66%. Eighty-one percent of those with baseline liver fat (BL) ≥5% had improvement in liver fat content, and NAFLD resolved in 33% of subjects at 8 weeks (mean relative reduction: 45%) and 48% (mean relative reduction: 55%) after 16 weeks of LPCN 1144 therapy. The reduction in liver fat was greater in those with higher BL (BL ≥5%: 71%; BL ≥8%: 80%; and BL ≥10%: 75%). Normalization rate of alanine aminotransferase and gamma-glutamyltransferase greater than the upper limit of normal range were 100% and 50% of treated patients, respectively. LPCN 1144 was not associated with major adverse events. Conclusion: Treatment with LPCN 1144 (oral T prodrug) in hypogonadal males with NAFLD resolved NAFLD in approximately half of the affected patients without any safety signals. Further studies are needed to validate its use in hypogonadal males with nonalcoholic steatohepatitis.

High-aspect-ratio nanoimprint process chains.

Different methods capable of developing complex structures and building elements with high-aspect-ratio nanostructures combined with microstructures, which are of interest in nanophotonics, are presented. As originals for subsequent replication steps, two families of masters were developed: (i) 3.2 µm deep, 180 nm wide trenches were fabricated by silicon cryo-etching and (ii) 9.8 µm high, 350 nm wide ridges were fabricated using 2-photon polymerization direct laser writing. Both emerging technologies enable the vertical smooth sidewalls needed for a successful imprint into thin layers of polymers with aspect ratios exceeding 15. Nanoridges with high aspect ratios of up to 28 and no residual layer were produced in Ormocers using the micromoulding into capillaries (MIMIC) process with subsequent ultraviolet-curing. This work presents and balances the different fabrication routes and the subsequent generation of working tools from masters with inverted tones and the combination of hard and soft materials. This provides these techniques with a proof of concept for their compatibility with high volume manufacturing of complex micro- and nanostructures.

Comparison of lead zirconate titanate thin films for microelectromechanical energy harvester with interdigitated and parallel plate electrodes.

Lead zirconate titanate (PZT) thin films on insulator- buffered silicon substrates with interdigitated electrodes (IDEs) have the potential to harvest more energy than parallel plate electrode (PPE) structures because the former exploit the longitudinal piezoelectric effect, which is about twice as high as the transverse piezoelectric effect used by PPE structures. In this work, both options are compared with respect to dielectric, ferroelectric, and piezoelectric properties, leakage currents, and figure of merit (FOM) for energy harvesting. The test samples were silicon beams with {100} PZT thin films in the case of the PPE geometry, and random PZT thin films for the IDE geometry. Both films were obtained by an identical sol-gel route. Almost the same dielectric constants were derived when the conformal mapping method was applied for the IDE capacitor to correct for the IDE geometry. The dielectric loss was smaller in the IDE case. The ferroelectric loops showed a higher saturation polarization, a higher coercive field, and less back-switching for the IDE case. The leakage current density of the IDE structure was measured to be about 4 orders of magnitude lower than that of the PPE structure. The best FOM of the IDE structures was 20% superior to that of the PPE structures while also having a voltage response that was ten times higher (12.9 mV/µ strain).

Measurement of effective piezoelectric coefficients of PZT thin films for energy harvesting application with interdigitated electrodes.

Interdigitated electrode (IDE) systems with lead zirconate titanate (PZT) thin films play an increasingly important role for two reasons: first, such a configuration generates higher voltages than parallel plate capacitor-type electrode (PPE) structures, and second, the application of an electric field leads to a compressive stress component in addition to the overall stress state, unlike a PPE structure, which results in tensile stress component. Because ceramics tend to crack at relatively moderate tensile stresses, this means that IDEs have a lower risk of cracking than PPEs. For these reasons, IDE systems are ideal for energy harvesting of vibration energy, and for actuators. Systematic investigations of PZT films with IDE systems have not yet been undertaken. In this work, we present results on the evaluation of the in-plane piezoelectric coefficients with IDE systems. Additionally, we also propose a simple and measurable figure of merit (FOM) to analyze and evaluate the relevant piezoelectric parameter for harvesting efficiency without the need to fabricate the energy harvesting device. Idealized effective coefficients e(IDE) and h(IDE) are derived, showing its composite nature with about one-third contribution of the transverse effect, and about two-thirds contribution of the longitudinal effect in the case of a PZT film deposited on a (100)-oriented silicon wafer with the in-plane electric field along one of the <011> Si directions. Randomly oriented 1-µm-thick PZT 53/47 film deposited by a sol-gel technique, was evaluated and yielded an effective coefficient e(IDE) of 15 C·m(-2). Our FOM is the product between effective e and h coefficient representing twice the electrical energy density stored in the piezoelectric film per unit strain deformation (both for IDE and PPE systems). Assuming homogeneous fields between the fingers, and neglecting the contribution from below the electrode fingers, the FOM for IDE structures with larger electrode gap is derived to be twice as large as for PPE structures, for PZT-5H properties. The experiments yielded an FOM of the IDE structures of 1.25 × 10(10) J/m(3) and 14 mV/µ strain.