A New Oral Testosterone Undecanoate Formulation Restores Testosterone to Normal Concentrations in Hypogonadal Men

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

e19009 Background: Ibrutinb is approved for treatment of CLL. Hypertension (HTN) has been reported as a side effect of ibrutinib in 1-23% of patients. We previously reported HTN in CLL patients after 6 months of treatment with ibrutinib. In this study we describe the effects of long-term treatment with ibrutinib on blood pressure (BP). Methods: We performed a retrospective study, evaluating 150 CLL patients on ibrutinib-based clinical trials from 2010 to 2015. Patient demographics, co-morbidities, tobacco use, anti-HTN therapy were recorded. BP was evaluated at baseline and sequentially for up to 5 yrs. New onset HTN was defined as systolic BP (SBP) of ≥ 130 mmHg and/or diastolic BP (DBP) ≥ 80 on two separate visits with no prior HTN or anti-HTN therapy. An increase in baseline SBP by ≥10 and/or increase in DBP by ≥10 was considered significant regardless of the absolute BP. Univariate logistic regression analysis was performed to assess relationship of HTN risk factors and new HTN. Results: Patients’ median age was 65 yrs (68% male and 88% white). Median follow-up was 3 yrs. Pre-existing HTN was present in 44% of patients, 40% were on anti-HTN therapy prior to ibrutinib. New HTN developed in 65% of patients without prior diagnosis of HTN; 32 % of patients were started on anti-HTN therapy or received additional anti-HTN therapy. Of the patients who experienced an increase in BP, 33% experienced isolated systolic HTN. Median SBP was 130 at baseline, 132 at 1mo, 137 at 3mo, 135 at 6mo, 139 at 12mo, 138 at 3yrs, 144 at 5yrs (mean increase in SBP: 7.2, P < 0.001). In patients whose SBP was < 130 at baseline the median SBP was 119 at baseline, 122 at 1mo, 134 at 3mo, 130 at 6mo, 134 at 12mo, 135 at 3yrs and 141 at 5yrs (mean increase in SBP: 15.7, p < 0.001). 74% of patients experienced and increase in SBP ≥10. New HTN on ibrutinib was not associated with: tobacco use, obesity, chronic kidney disease or obstructive sleep apnea (p > 0.05). Conclusions: In this study we demonstrated a high rate of new HTN in patients on prolonged ibrutinib treatment. HTN in these patients is persistent, linear and independent of other risk factors. The increase in BP remained despite initiation of anti-HTN therapy. Additional studies are ongoing to define cardiovascular and renal complications associated with HTN in these patients.

Background:A novel formulation of oral testosterone undecanoate (TU) was studied in along- 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 (trialI) or 105 day (trial II), randomized, multicenter trial. Patients wererandomized 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 onaverage T concentrations (Cavg). Efficacy was assessedbased on T levels, body composition and bone density. Safety was assessed bystandard clinical measures.Results:Oral TU efficacy (% of patients with eugonadal T Cavg) was84% (serum Cavg = 628 ± 343 ng/dl) and 87% (serum Tequivalent Cavg ≈ 489 ± 155 ng/dl) in trials I and II,respectively. Oral TU significantly (p <0.0001) improvedall Psychosexual Daily Questionnaire parameters in trials I and II. In trialI, lean mass increased 3.2 ± 2.7 kg and fat decreased by 2.4 ± 3.6 kg (bothp <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 (bothp <0.0001). Oral TU-associated adverse effects wereconsistent with other T-replacement therapies but oral TU patientsexperienced a greater number of mild gastrointestinal adverse effects. OralTU subjects in both studies exhibited an increase in mean systolic bloodpressure of about 3–5 mmHg. Oral TU was not associated with liver toxicitynor did it cause an elevation in high-sensitivity C-reactive protein orlipoprotein-associated phospholipase A2 (cardiovascular safetybiomarkers) after 365 days of therapy.Conclusion:A new oral TU formulation was safe and effective and represents a significanttherapeutic advance for the treatment of appropriate hypogonadal men.

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

Hypertension Development, Management, and Cardiovascular Events Following Ibrutinib Initiation for Hematologic Malignancies

Hypertension, Cardiovascular and Renal Complications Observed in Patients with Chronic Lymphocytic Leukemia Receiving Long-Term Therapy with Ibrutinib

BackgroundUse of alemtuzumab in relapsing multiple sclerosis (RMS) is limited by safety concerns, notably risk of rare, serious vascular events. Along with other vital sign (VS) changes, acute increase in systolic blood pressure (SBP) is monitored as a marker of vascular risk. Peri-infusion prophylaxis is used to manage clinical risk by moderating cytokine release; protocols are not fully specified and vary across sites. Here, we report a modified prophylaxis regimen developed at Maritime Neurology. This single-center observational cohort study (NCT04633967) aimed to examine acute responses (VS events and infusion-associated reactions) in RMS patients receiving alemtuzumab infusion under this regimen. In a post hoc analysis, we examined incidence of acute SBP increase at this clinic versus the Bayshore network of Canadian infusion centers, where a standard prophylaxis regimen is used. MethodsAlemtuzumab was infused on 5 consecutive days (Course 1; n = 29) and 3 consecutive days one year later (Course 2; n = 28). In addition to intravenous methylprednisolone 500mg on each infusion day, patients received daily prophylactic treatment with oral prednisone 50mg from 5 days before to 5 days after treatment (infusion days excepted) and oral H1 and H2 antihistaminics from 7 days before to 7 days after treatment. Excursions in SBP and other VS were relative to prespecified ranges; persistent excursions were those for which two sequential measurements were outside these ranges. In comparing VS events at Maritime Neurology and the Bayshore centers, acute SBP increase was defined as ≥20 mmHg increase in mean SBP, or any SBP reading ≥20% over patient's pre-course baseline. ResultsMean (SD) VS were within range at pre-course and all other daily baselines. VS changes, including persistent excursions, were generally subclinical; all infusion-associated reactions were mild. One patient discontinued treatment after Course 1 due to immune thrombocytopenia purpura. Acute SBP increase occurred in 11/28 (39%) Maritime Neurology versus 367/610 (60%) Bayshore (p = 0.028). ConclusionThe modified peri-infusion prophylaxis regimen was well tolerated and may reduce incidence of acute SBP increase. FundingThis project was funded by Sanofi, Canada.

Orthostatic hypertension in normotensives and borderline hypertensive patients

Orthostatic hypertension: An underestimated cause of orthostatic intolerance

Therapeutic induction of puberty using oral testosterone (T) undecanoate (TU) 40 mg daily was performed in 4 pubertal boys aged 12.7-17.1 yr with constitutional delayed puberty and/or short stature. Single-dose pharmacokinetics study was performed on matched plasma and saliva samples obtained half-hourly for 10 h after the first dose and then repeated 3 and 6 months later. Treatment was continued for 15-21 months. Peak plasma total T concentration was achieved at 255 +/- 51 (SEM) min after the first 40 mg dose of TU, 300 +/- 76 min at 3 months, and 293 +/- 103 min at 6 months, the levels remaining elevated above baseline for at least 8 h after a single oral dose. Total T levels were initially high (mean 13.0 +/- 2.5; peak 38.7 +/- 4.2 nmol/L) but dropped significantly at 3 months (mean 8.3 +/- 1.8; peak 23.6 +/- 5.6 nmol/L) and at 6 months (mean 9.2 +/- 1.6; peak 24.8 +/- 3.5 nmol/L) paralleled by a dramatic fall in sex hormone binding globulin (73.9 +/- 18.0 to 35.1 +/- 9.7 at 3 month and 29.2 +/- 6.0 nmol/L at 6 month). Mean concentrations of unbound and free T (non-sex hormone binding globulin-bound T, free T, and salivary T) were below the normal adult range and remained unchanged over the same period. Plasma dihydrotestosterone concentrations were elevated after the first dose (mean 5.4 +/- 1.3; peak 11.0 +/- 2.5 nmol/L), the extent of this rise being less after 6 months (mean 4.1 +/- 0.8; peak 7.1 +/- 1.1 nmol/L) as was the case with mean estradiol (51.5 +/- 8.9 to 38.1 +/- 3.7 pmol/L). Signs of virilization progressed to Tanner stage G3 PH2-3 with testicular volumes increasing to 3-4 mL at 12 months, and G4 PH4-5 with further testicular growth to 6-10 mL at 24 months. Height velocity rose from 3.2 +/- 0.3 cm/yr (pretreatment) to 7.2 +/- 1.0 cm/yr in the first year and was maintained at 7.3 +/- 0.4 cm/yr despite cessation of therapy during the second year. Bone age advanced by 1.1 +/- 0.1 yr at 12 months and a further 0.8 +/- 0.3 yr at 24 months. Predicted adult height remained unchanged. No side effects were observed. Our preliminary data suggest that oral TU is a well accepted, effective, and safe treatment for the initiation of male puberty without disproportionate skeletal maturation. Continued pubertal advance was evident after cessation of treatment in all patients.(ABSTRACT TRUNCATED AT 400 WORDS)

To examine whether insulin, leptin and adiponectin are independent correlates of blood pressure (BP) in a large population-based sample of children and adolescents. We studied 655 boys and 667 girls aged 9, 13 and 16 years who participated in the Quebec Child and Adolescent Health and Social Survey, a province-wide school-based survey conducted in 1999. Strong, positive univariate associations between BMI, insulin and leptin Z-scores, and both systolic and diastolic BP were found in both sexes. Adiponectin Z-scores were negatively associated with systolic BP in girls only. In multivariate analyses only BMI and insulin Z-scores were significantly associated with systolic BP. In boys, each 1 SD increase in BMI was associated with a 4 mmHg increase in mean systolic BP; each 1 SD increase in insulin was associated with a 1 mmHg increase in mean systolic BP. Only insulin Z-scores were independently associated with diastolic BP in both sexes. For each 1 SD increase in insulin, there was a 1 mmHg increase in mean diastolic BP in boys. Similar to systolic BP, the magnitude of the effect of insulin Z-scores on diastolic BP increased as a function of BMI Z-scores in girls. Independently of BMI, insulin is a strong correlate of systolic and diastolic BP in youth. Although animal studies support a role for leptin and adiponectin in controlling BP, they are not independently associated with BP in youth.

(394) Effects of Age, Body Mass Index (BMI) and Diabetic Status on Testosterone Levels, Testosterone Dosing and Safety in Hypogonadal Men Treated with an Oral Testosterone Undecanoate (JATENZO)

The diagnosis and management of systemic hypertension in cats requires a reliable method for measurement of systemic arterial blood pressure (BP) in clinical patients. Unfortunately, the setting of a clinical practice and the act of measuring BP might raise BP and heart rate (HR), an effect referred to as the white‐coat effect in human patients. The purpose of the present study was to determine if a white‐coat effect was experienced by cats. Radiotelemetric implants were used to measure BP and HR in 13 conscious cats in a research colony while undisturbed in their cages and while subjected to simulated visits to a veterinarian's office. The white‐coat effect was taken to be the difference between the overall 24‐hour average value for parameters of BP and HR and the corresponding value during the simulated office visit. A white‐coat effect was observed in cats. In healthy cats, the systolic BP measured during the examination period of the simulated office visit exceeded the 24‐hour average systolic BP by 17.6 ± 1.5 mm Hg. However, marked heterogeneity occurred in the pattern and magnitude of the increase in systolic BP above the 24‐hour baseline and the increase varied between 75.3 and —27.2 mm Hg for the healthy cats. Variation in response to the simulated office visit was observed among cats and among visits by the same cat. During an office visit, the magnitude of the white‐coat effect tended to decrease, but not disappear, over time. The magnitude of the white‐coat effect varied when cats were subjected to 5 repeat office visits, but did not diminish in the group as a whole. The mean increase in systolic BP during the examination (22.3 ± 0.9 mm Hg) was greater (P&lt; .05) in cats with renal insufficiency. Although the heterogeneity of response expected from companion animals might be greater than that observed in these colony cats, these results indicate that veterinarians should carefully consider the white‐coat effect in evaluation of BP in cats. A quiet, undisturbed environment and adequate time for acclimation should be included in the standard protocol for measurements of BP. Because of day‐to‐day variation in the white‐coat effect in individual cats, multiple serial measurements following a standard protocol should provide the best estimate of BP in cats.

The diagnosis and management of systemic hypertension in cats requires a reliable method for measurement of systemic arterial blood pressure (BP) in clinical patients. Unfortunately, the setting of a clinical practice and the act of measuring BP might raise BP and heart rate (HR), an effect referred to as the white-coat effect in human patients. The purpose of the present study was to determine if a white-coat effect was experienced by cats. Radiotelemetric implants were used to measure BP and HR in 13 conscious cats in a research colony while undisturbed in their cages and while subjected to simulated visits to a veterinarian's office. The white-coat effect was taken to be the difference between the overall 24-hour average value for parameters of BP and HR and the corresponding value during the simulated office visit. A white-coat effect was observed in cats. In healthy cats, the systolic BP measured during the examination period of the simulated office visit exceeded the 24-hour average systolic BP by 17.6+/-1.5 mm Hg. However, marked heterogeneity occurred in the pattern and magnitude of the increase in systolic BP above the 24-hour baseline and the increase varied between 75.3 and -27.2 mm Hg for the healthy cats. Variation in response to the simulated office visit was observed among cats and among visits by the same cat. During an office visit, the magnitude of the white-coat effect tended to decrease, but not disappear, over time. The magnitude of the white-coat effect varied when cats were subjected to 5 repeat office visits, but did not diminish in the group as a whole. The mean increase in systolic BP during the examination (22.3+/-0.9 mm Hg) was greater (P < .05) in cats with renal insufficiency. Although the heterogeneity of response expected from companion animals might be greater than that observed in these colony cats, these results indicate that veterinarians should carefully consider the white-coat effect in evaluation of BP in cats. A quiet, undisturbed environment and adequate time for acclimation should be included in the standard protocol for measurements of BP. Because of day-to-day variation in the white-coat effect in individual cats, multiple serial measurements following a standard protocol should provide the best estimate of BP in cats.

Background: Obesity is a chronic, relapsing, neurochemical disorder controlled by the autonomic nervous system. It is an imbalance in the energy homeostasis that leads to cardiovascular conditions such as hypertension, ischemic heart disease, atherosclerosis, and stroke. The sympathetic nervous system (SNS) plays an important role in the regulation of metabolic and cardiovascular homeostasis. SNS activation is characteristic of a number of metabolic and cardiovascular diseases that occur more frequently in obese individuals. Aims and Objective: This study aims to assess the relationship between cardiac autonomic function (handgrip and cold pressor test [CPT]) and obesity in adults. Materials and Methods: This is an experimental analytical non-randomized study. Body mass index was calculated by Quetelet’s index. Cardiac autonomic function tests employed were handgrip test (HGT) and CPT. Results: In HGT, the mean increase in systolic blood pressure (SBP) and diastolic BP (DBP) was 9.85 mmHg and 8.54 mmHg in obese and 15.88 mmHg and 14.15 mmHg in non-obese. While in CPT, the mean increase in SBP and DBP was 11.2 mmHg and 9.12 mmHg in obese and 17.00 mmHg and 14.62 mmHg in non-obese. Conclusion: The increase in SBP and DBP was significantly less in obese as compared to non-obese during autonomic function tests.