Abstract Context A novel formulation of oral testosterone (T) undecanoate (TU) was evaluated in a phase 3 clinical trial. Objective Determine efficacy, short-term safety, and alignment of new oral TU formulation with current US approval standards for T replacement therapy. Design Randomized, active-controlled, open-label study. Setting and Patients Academic and private clinical practice sites; enrolled patients were clinically hypogonadal men 18 to 65 years old. Methods Patients were randomized 3:1 to oral TU, as prescribed (JATENZO®; n = 166) or a topical T product once daily (Axiron®; n = 56) for 3 to 4 months. Dose titration was based on average T levels (Cavg) calculated from serial pharmacokinetic (PK) samples. T was assayed by liquid chromatography–mass spectrometry/mass spectrometry. Patients had 2 dose adjustment opportunities prior to final PK visit. Safety was assessed by standard clinical measures, including ambulatory blood pressure (BP). Results 87% of patients in both groups achieved mean T Cavg in the eugonadal range. Sodium fluoride-ethylenediamine tetra-acetate plasma T Cavg (mean ± standard deviation) for the oral TU group was 403 ± 128 ng/dL (~14 ± 4 nmol/L); serum T equivalent, ~489 ± 155 ng/dL (17 ± 5 nmol/L); and topical T, 391 ± 140 ng/dL (~14 ± 5 nmol/L). Modeling/simulation of T PK data demonstrated that dose titration based on a single blood sample 4 to 6 h after oral TU dose yielded efficacy (93%) equivalent to Cavg-based titration (87%). Safety profiles were similar in both groups, but oral TU was associated with a mean increase in systolic BP of 3 to 5 mm Hg. Conclusion A new oral TU formulation effectively restored T to mid-eugonadal levels in hypogonadal patients.

INTRODUCTION AND OBJECTIVE: A new, first-in-class oral testosterone (T) replacement therapy product [T-undecanoate (TU) capsules] was recently approved by FDA to treat appropriate hypogonadal men. Two clinical trials were conducted to evaluate, in part, the impact of oral TU therapy on important secondary efficacy endpoints: a) Psycho-sexual and/or general health/well-being (Trial I and II) and; b) Body composition (Trial II). METHODS: Hypogonadal men (AM serum T ≤ 300 ng/dL) age 18 to 65 (Trial I) or 75 years old (Trial II) were randomized into open-label, active-comparator (T-gel/solution) trials. Subjects received: Trial 1: Either oral TU (n=166) or a topical T solution (Axiron®; n=55) for 4-6 mos.; or Trial II: Oral TU (n=162) or T-gel (AndroGel® 1%; n=163) for 12 mos. The starting oral TU dose (with food) was 237 mg TU, BID in Trial I and 316 mg TU, BID in Trial II; up to 2 dose-titration opportunities were available to achieve eugonadal T concentrations (Cavg; assayed by LC-MS/MS). In Trial I, Psycho-sexual Daily Questionnaires (PDQ) were completed by study subjects for 7 days at baseline and prior to final clinic visit (Day 105-180). In Trial II, the SF-36 well-being questionnaire was completed on Days 0, 30, 90, 180, 270 and 365 and PDQs were completed for 7 days prior to clinic visits on these same days. Body composition was assessed by DEXA scan on Days 0, 180 and 365. Safety was monitored by physical exam and standard clinical laboratory tests. RESULTS: Serum T Cavg in response to oral TU was 489 ± 155 ng/dL (mean ± SD) (Trial I) and 628 ± 342 ng/dL (Trial II); 84% of subjects in each trial achieved T Cavg in the eugonadal range. Mean changes from baseline for SF-36 well-being parameters increased significantly in both oral TU and topical T groups. Psycho-sexual questionnaire results also demonstrated statistically significant improvement (p<0.0001) in each parameter at Day 30 and all time points thereafter. At Day 365, oral TU was associated with a statistically significant reduction in fat mass [-2.4 ± 3.6 (SD) kg] and increase in lean mass (+3.2 ± 2.7 kg). Oral TU also significantly increased mean BMD over baseline in hip [+0.01 ± 0.04 (SD) g/cm2] and spine (+0.01 ± 0.02 g/ cm2]. Oral TU exhibited a safety profile consistent with other available T-replacement products -- including the potential to increase blood pressure in some men. CONCLUSIONS: Treatment of hypogonadal men with oral TU yielded circulating T Cavg concentrations in the mid-eugonadal range and significantly improved psycho-sexual, general well-being and body composition parameters. Source of Funding: Clarus Therapeutics, Inc.

Abstract Introduction and Objective: A new, first-in-class oral testosterone (T) replacement therapy product [T-undecanoate (TU) capsules] was recently approved by FDA to treat hypogonadal men. Clinical trials were conducted to evaluate, in part, the impact of oral TU therapy on important secondary efficacy endpoints: Psychosexual and/or general well-being (Trial I and II); and body composition and bone mineral density (BMD) (Trial II). Subject and Methods: Hypogonadal men (AM serum T ≤ 300 ng/dL) age 18 to 65 (Trial I) or 75 years old (Trial II) were randomized into open-label, active-comparator (T-gel/solution) trials. Subjects received: Trial 1: Oral TU (n=166) or a topical T solution (n=55) for 4-6 mos.; or Trial II: Oral TU (n=162) or T-gel (n=163) for 12 mos. The starting oral TU dose (with food) was 237 mg, BID in Trial I and 316 mg, BID in Trial II; up to 2 dose-titration opportunities were available to achieve eugonadal T concentrations (assayed by LC-MS/MS). In Trial I, Psychosexual Daily Questionnaires (PDQ) were completed by study subjects for 7 days at baseline and prior to final clinic visit (Day 105-180). In Trial II, the SF-36 well-being questionnaire was completed on Days 0, 30, 90, 180, 270 and 365 and PDQs were completed for 7 days prior to clinic visits on these same days. In Trial II body composition and BMD was assessed by DEXA scan on Days 0, 180 and 365. Safety was monitored by physical exam and standard clinical lab tests. Results: Mean serum T in response to oral TU was 489 ± 155 ng/dL (mean ± SD) (Trial I) and 628 ± 342 ng/dL (Trial II); 84% of subjects in each trial achieved mean T concentrations in the eugonadal range. Statistically significant mean changes from baseline (p<0.0001) for most SF-36 well-being parameters were observed in both oral TU and T-gel groups. Psychosexual questionnaire results also demonstrated statistically significant improvement over baseline (p<0.0001) in most parameters at Day 30 and all timepoints thereafter in both trials. On Days 180 and 365 (v. baseline) oral TU was associated with a significant reduction in fat mass [-1.92 ± 2.79 (SD) and -2.4 ± 3.6 kg, respectively] (p<0.0001) and an increase in lean body mass [+2.87 ± 2.73 and +3.15 ± 2.69 kg, respectively] (p<0.0001). Oral TU increased mean BMD over baseline on Days 180 and 365 in spine [+0.013 ± 0.035 and +0.018 ± 0.042 g/cm2, respectively (p<0.0001)] and hip [+0.006 ± 0.019 and +0.012 ± 0.023 g/cm2, respectively (p<0.0001)]. Oral TU exhibited a safety profile consistent with commonly prescribed topical T-comparators. Modest increases in cuff sBP of 2.8 ± 11.84 (SD) mm Hg and 1.8 ± 10.76 mm Hg were observed in Trial I for both oral TU and the comparator T-solution. Conclusions: Treatment of hypogonadal men with oral TU yielded circulating mean T concentrations in the mid-eugonadal range and significantly improved psychosexual, general well-being, body composition and BMD parameters comparable to transdermal T administration.

You have accessJournal of UrologySexual Function/Dysfunction: Medical, Hormonal & Non-surgical Therapy III (MP58)1 Apr 2019MP58-17 MONITORING TESTOSTERONE (T) LEVELS IN MEN RECEIVING ORAL TESTOSTERONE UNDECANOATE (TU): DEALING WITH POST-COLLECTION CONVERSION OF TU TO T Jed Kaminetsky*, Marc Gittelman, Ronald Swerdloff, James Longstreth, Robert Dudley, and Theodore Danoff Jed Kaminetsky*Jed Kaminetsky* More articles by this author , Marc GittelmanMarc Gittelman More articles by this author , Ronald SwerdloffRonald Swerdloff More articles by this author , James LongstrethJames Longstreth More articles by this author , Robert DudleyRobert Dudley More articles by this author , and Theodore DanoffTheodore Danoff More articles by this author View All Author Informationhttps://doi.org/10.1097/01.JU.0000556709.56920.43AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVES: Measuring T levels during T replacement therapy is critical to guide dosing decisions. Post-collection conversion of TU to T by esterases in blood from men receiving oral TU can raise measured T levels substantially above actual levels and result in inappropriate titration decisions. We identified a method for T monitoring to address this problem. METHODS: We evaluated post-collection conversion of TU to T in blood drawn from men who had received a new oral TU and in blood spiked with TU after collection. Blood was collected in Plain, EDTA or NaF-EDTA tubes and then incubated for periods between 0 and 3 hours, at room temperature (RT) or on ice. After incubation, blood was centrifuged and the matrix (serum or plasma) isolated. T and TU concentrations were measured by LC/MS-MS. Regression analysis of rate of changes of T concentration during incubation v. TU concentration was used to develop algorithms to correct for T overestimation. Algorithm accuracy was tested using results from the Phase 3 inTUne Trial of Clarus' oral TU. RESULTS: T concentrations increase in blood samples containing TU as they await centrifugation. The rate of TU to T conversion depends on TU concentration, incubation temperature, and presence of NaF, an esterase inhibitor. Incubation temperature impacted TU to T conversion the most - rate at RT >5-fold faster than on ice; NaF had less effect than temperature. Most clinic T levels are measured in serum; however, titration in the inTUne Trial of oral TU was based on T in NaF-EDTA plasma. Equations were derived to convert the T concentration measured in one matrix to another. Based on regression analysis of T concentrations in serum and NaF-EDTA plasma, a conversion factor of 1.214 was derived to convert a NaF-EDTA plasma T value to an equivalent serum T value for samples collected 6 hours post-dose (optimal dose-titration sample point for our oral TU). When this conversion factor was tested using T data collected from the inTUne PK visit where both NaF-EDTA plasma and serum were collected, comparing measured serum T values with values derived from plasma T demonstrated a mean error of only 3.1% (N=155; 95% CI 0.4%, 5.8%). CONCLUSIONS: Post-collection conversion of TU to T can cause overestimation of circulating T levels in men dosed with oral TU. By accounting for the conversion with different tube types / handling conditions, a conversion factor was derived such that T concentrations in our oral TU patients can be monitored using serum T levels. This conversion factor was validated using in TUne data. Source of Funding: Clarus Therapeutics, Inc. New York, NY; Adventura, FL; Torrance, CA; Mundelein, IL; Northbrook, IL© 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 201Issue Supplement 4April 2019Page: e859-e859 Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jed Kaminetsky* More articles by this author Marc Gittelman More articles by this author Ronald Swerdloff More articles by this author James Longstreth More articles by this author Robert Dudley More articles by this author Theodore Danoff More articles by this author Expand All Advertisement PDF downloadLoading ...

Introduction: Measuring T levels, in addition to monitoring symptoms, during T replacement therapy is critical to guide dosing decisions. T levels in blood samples from men receiving oral TU can be elevated substantially above actual circulating T levels due to post-collection conversion of TU to T by esterases in blood. Because erroneous T values can result in inappropriate dose-titration decisions, we identified a method for monitoring T that addresses this problem. Methods: Post-collection conversion of TU to T was evaluated in blood drawn from men who had received oral TU (either JATENZO®, Clarus’s oral TU, or Andriol®) and in blood spiked with TU after collection. Blood was collected in Plain, EDTA or NaF-EDTA tubes and then incubated for selected times (up to 3 hours) at room temperature (RT) or on ice. After incubation, blood was centrifuged and the matrix (serum or plasma) was used for measurement of T and TU concentrations by LC/MS-MS. Regression analysis of rate of change of T concentration during incubation versus TU concentration was used to develop algorithms to correct for T overestimation. Algorithm accuracy was tested using results from the Phase 3 inTUne Trial of JATENZO. Results: T concentrations increase in blood containing TU as the blood sits pre-centrifugation, regardless of whether the TU is in the blood when collected or spiked post-collection. The rate of TU conversion depends on the TU concentration, incubation temperature, and presence of NaF, an esterase inhibitor. Incubation temperature had the greatest impact on conversion - rate at RT >5-fold faster than on ice; NaF had a smaller effect. Most clinic T levels are routinely measured in serum from Plain tubes; however, titration in the inTUne Trial of oral TU was based on T in NaF-EDTA plasma. Based on regression analysis of the TU to T conversion rates measured in serum and NaF-EDTA plasma and the NaF effect on measured T levels, a conversion factor of 1.214 was derived to convert a NaF-EDTA plasma T value to an equivalent serum T value for samples collected 6 hours post-dose (the optimal dose-titration sample point for JATENZO). This conversion factor was tested against T data collected during the final PK Visit of the inTUne Trial (87% of subjects attained eugonadal range based on NaF-EDTA plasma T levels) where serum T levels were also measured. Using the conversion factor to compare the measured serum T value with its matched plasma value, we observed a mean error of only 3.1% (n=155 sample pairs; 95% CI 0.4%, 5.8%). Conclusion: Post-collection conversion of TU to T can cause overestimation of circulating T levels in men dosed with oral TU. By accounting for the conversion with different tube types / handling conditions, a conversion factor was derived to allow monitoring of T concentration in JATENZO patients using serum. This conversion factor was validated for JATENZO against the Phase 3 inTUne data.

Although gonadotropin-releasing hormone agonists (GnRHa) have been the standard of care of central precocious puberty (CPP) management for many years, there are still questions about the long-term consequences of treatment. With increased utilization of GnRHa treatment, it is now possible to assess posttreatment outcomes in the immediate posttreatment period and into adulthood. This literature review reports on the long-term effects of GnRHa therapy in girls with CPP after therapy has been discontinued. Published reports confirm the reversibility of hypothalamic-pituitary-ovarian axis suppression in females after cessation of GnRHa therapy, with the majority of patients achieving ovulatory menstrual cycles of normal timing and duration. GnRHa therapy does not appear to induce polycystic ovary syndrome or have long-term negative repercussions on either bone mineral density or body composition. Evidence is currently insufficient to identify agent-specific differences in outcomes, reproductive function, and health of offspring.

Gonadotropin-releasing hormone agonist (GnRHa)-stimulated luteinizing hormone (LH) is the standard hormonal assessment for both diagnosis and therapeutic monitoring of children with central precocious puberty (CPP). Use of unstimulated (random) LH levels may be helpful in diagnosis and has gained popularity in monitoring GnRHa therapy despite lack of validation against stimulated values. The objective of this investigation was to assess the suitability of random LH for monitoring pubertal suppression during GnRHa treatment.

Background: Anaphylaxis is a serious allergic reaction that can cause death; however, the actual risk of death is unclear.Objective: We sought to estimate the case fatality rate among hospitalizations or emergency department (ED) presentations for anaphylaxis and the mortality rate associated with anaphylaxis for the general population.Methods: This was a population-based epidemiologic study using 3 national databases: the Nationwide Inpatient Sample (NIS; 1999-2009), the Nationwide Emergency Department Sample (NEDS; 2006-2009), and Multiple Cause of Death Data (MCDD; 1999-2009). Sources for these databases are hospital and ED discharge records and death certificates, respectively.Results: Case fatality rates were between 0.25% and 0.33% among hospitalizations or ED presentations with anaphylaxis as the principal diagnosis (NIS+NEDS, 2006-2009). These rates represent 63 to 99 deaths per year in the United States, approximately 77% of which occurred in hospitalized patients. The rate of anaphylaxis-related hospitalizations increased from 21.0 to 25.1 per million population between 1999 and 2009 (annual percentage change, 2.23%; 95% CI, 1.52% to 2.94%), contrasting with a decreasing case fatality rate among hospitalizations (annual percentage change, -2.35%; 95% CI, -4.98% to 0.34%). Overall mortality rates ranged from 0.63 to 0.76 per million population (186-225 deaths per year, MCDD) and appeared stable in the last decade (annual percentage change, -0.31%; 95% CI, -1.54% to 0.93%).Conclusion: From 2006 to 2009, the overwhelming majority of hospitalizations or ED presentations for anaphylaxis did not result in death, with an average case fatality rate of 0.3%. Anaphylaxis-related hospitalizations increased steadily in the last decade (1999-2009), but this increase was offset by the decreasing case fatality rate among those hospitalized; both inpatient and overall mortality rates associated with anaphylaxis appeared stable and were well under 1 per million population. Although anaphylactic reactions are potentially life-threatening, the probability of dying is actually very low. With the prevalence of anaphylaxis on the increase, practitioners need to stay vigilant and follow the treatment guidelines to further reduce anaphylaxis-related deaths.

Digibind and DigiFab are commercial formulations of polyclonal, ovine, digoxin-specific Fabs in clinical use for treatment of digoxin intoxication. Of interest for extending its use to other clinical indications, Digibind has also been reported to neutralize the effect of endogenous digoxin-like molecules, including ouabain, that are linked to clinical disorders ranging from preeclampsia to congestive heart failure. Although Digibind and DigiFab are equivalent in their digoxin-binding activity, the antigens used to produce these Fabs are different. We therefore explored, using native 3H-digoxin and 3H-ouabain in four different types of solution-phase binding methods, whether they might exhibit different profiles with respect to ouabain and other digoxin-like factors. Consistent with previous results, both Fab preparations bound digoxin with the same affinities and capacities. However, 3H-ouabain was found to bind with high affinity only to Fab sub-populations present in both products. Interestingly, this sub-population was twice as large for Digibind compared to DigiFab. Competition experiments also showed differences in specificity within Fab sub-populations. Therefore, the equivalence in digoxin-binding activity of the two Fab preparations does not extend to ouabain-binding capacity and Fab specificity, with implications for clinical differentiation between the preparations in treatment of disorders related to control of non-digoxin cardenolides. The existence of a small but perhaps clinically relevant sub-population of antibodies was detected using specific radioligands. This sub-population could not have been detected nor quantified using standard cross-reactivity in an ELISA assay.