Subcutaneous Research Articles

The safety and efficacy of treprostinil for the treatment of pulmonary arterial hypertension: a systematic review and meta-analysis of randomized controlled trials

Abstract Introduction Pulmonary arterial hypertension (PAH) is a severe and life-threatening condition characterized by increased pulmonary vascular resistance and elevated mean pulmonary artery pressure. Treprostinil, a prostacyclin analog, has vasodilatory and anti-remodeling effects on pulmonary arterial smooth muscle cells, indicating promising benefits in enhancing exercise capacity, improving hemodynamics, and reducing morbidity in patients with PAH. Aim The primary objective of this systematic review and Meta-analysis is to assess the efficacy and safety of Treprostinil in patients with PAH. Methods We systematically searched PubMed, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov from inception until July 2023. Randomized controlled trials comparing Treprostinil with Placebo were selected. We used the mean values to compare continuous data and odds ratio (OR) for dichotomous outcomes with their 95% confidence interval (CI). Results We included 7 studies with a total of 2,447 patients. The Treprostinil group was favored over the control group in terms of 6-minute walk distance (6MWD) (Mean difference (MD), meters (m)) (MD = 15.16 m, 95% confidence interval (CI) (10.42 – 19.90 )). Subgroup analysis based on the route of administration revealed a 6MWD of (MD = 13.55 m (95% CI (7.82 – 19.28)) for oral administration and (MD = 17.49 m, 95% CI (6.01 – 28.89)) for intravenous (IV)/subcutaneous (SC) administration, indicating enhanced exercise capacity. When evaluating the efficacy of Treprostinil for oral administration, there was a slight but non-significant trend toward functional improvement (Odds Ratio (OR): 1.36; 95% CI: 0.95 to 1.93) and no significant change in maintaining functional status (OR: 0.94; 95% CI: 0.59 to 1.51). In terms of functional deterioration, the risk was also not significantly reduced (OR: 0.84; 95% CI: 0.36 to 1.98). Safety assessment of the drug was based on clinical, mortality, and adverse events outcomes. Clinically, Treprostinil demonstrated a protective effect against disease progression, evidenced by a reduced risk of clinical worsening (OR: 0.69; 95% CI: 0.52 to 0.91). Mortality rates were not significantly impacted by Treprostinil addition (OR: 0.95; 95% CI: 0.57 to 1.58 for oral, 0.80; 95% CI: 0.32 to 1.98 for IV/SC). However, the incidence of adverse events was notably higher among Treprostinil-treated patients, particularly with oral administration. Conclusion The addition of Treprostinil therapy for patients with PAH significantly improved exercise capacity, as evidenced by an increase in the 6MWD compared to control groups and demonstrated a reduced risk of clinical worsening. The incidence of adverse events was higher among Treprostinil-treated patients, especially with oral administration, potentially impacting quality of life.Forest plot of the 6MWD

Clinical assessment of the potential use of a novel single-dose prefilled injection device for the administration of Acthar Gel in children: a narrative review.

Acthar® Gel (repository corticotropin injection; Mallinckrodt Pharmaceuticals, NJ, USA) is indicated for the treatment of myriad inflammatory disorders and is currently administered manually via a vial and syringe. The administration of Acthar via a single-dose prefilled injector (SelfJect™) is intended to simplify its subcutaneous (SC) delivery. The purpose of this review was to determine whether SelfJect is suitable for use in pediatric patients through a literature assessment of various factors, including skin depth, needle length and gauge, dosage, force required for injection, and potential harms. Infants and young children, who commonly have skin-to-muscle distances less than the minimum depth of SelfJect administration, may have risk of unintentional intramuscular (IM) injection; however, an inadvertent IM injection poses no additional risk to children because of the bioequivalence between SC and IM administration of Acthar. The needle gauge of SelfJect is acceptable for pediatric patients and aligns with the Centers for Disease Control and Prevention recommendations for SC injections. The dosage delivered by SelfJect is only appropriate for children over 2years of age. Although adolescents would likely be able to achieve the minimum force required to remove the protective cap and deliver a full dose of Acthar with SelfJect, an adult (18years of age and older) should administer SelfJect to pediatric patients. In addition to the commonly reported postmarketing adverse events (AEs) from Acthar administration (e.g., asthenic conditions, fluid retention, insomnia, headache and increased blood glucose), injection site-related AEs common to injection devices may occur with SelfJect use. The risk of needlestick injury from SelfJect is mitigated by a needle guard. In summary, this review of injection device considerations demonstrates that SelfJect is appropriate for use in the pediatric population.

Fabrication and Optimization of a Silodosin In Situ-Forming PLGA Implants for the Treatment of Benign Prostatic Hyperplasia: In Vitro and In Vivo Study

Objectives: Lower urinary tract symptoms (LUTSs) related to benign prostatic hyperplasia (BPH) are common in older men, and alpha-adrenoceptor blockers continue to be a key part of managing these symptoms. This study aimed to formulate injectable poly (lactic-co-glycolic acid) (PLGA) in situ-forming implants (ISFIs) loaded with silodosin (SLD) to address symptoms associated with BPH. This method, which ensures prolonged therapeutic effects of SLD, is intended to decrease dosing frequency and improve treatment outcomes, leading to better patient adherence. Methods: An appropriate solvent with favorable PLGA solubility, viscosity, and in vitro release profile was selected. Additionally, an I-optimal design was employed as an optimization technique. An in vivo study in albino male rats was conducted to investigate prostate-specific antigens (PSAs), prostate weight and prostatic index, histopathology, and SLD pharmacokinetics. Results: The optimized formulation showed experimental values of 29.25% for the initial burst after 2 h and 58.23% for the cumulative release of SLD after 10 days. Pharmacokinetic data revealed that the SLD–ISFI formulation had lower Cmax and higher AUC values than subcutaneous (SC) pure SLD and oral commercial SLD capsule, indicating the controlled-release impact and improved bioavailability of the ISFI systems. SLD–ISFI produced a marked drop in the prostatic index by 2.09-fold compared to the positive control. Serum PSA level decreased significantly from 0.345 ± 0.007 to 0.145 ± 0.015 ng/mL after SLD–ISFI injection compared to the positive control. Conclusions: This study indicated that the optimized SLD–ISFI formulation proved its efficacy in managing BPH.

Cost-effectiveness analysis of denosumab versus alendronate for improving bone mineral density in renal transplant recipients: a comparative study

BackgroundDenosumab and alendronate had a positive impact on bone mineral density (BMD) preservation after kidney transplantation. However, the cost-effectiveness of these agents in the context of kidney transplantation remains largely unexplored. We have conducted a cost-effectiveness analysis to compare the cost and the clinical outcomes of adding subcutaneous (SC) 60 mg denosumab every 6 months vs. oral weekly 70 mg Alendronate, to the standard care therapy (vitamin D and calcium) in renal transplant recipients (RTRs). The impact of both drugs on BMD t-score improvement and fracture prevention was investigated. A decision-analysis model from a health care payer perspective was applied.ResultsThe cost-effectiveness analysis has shown that alendronate add-on to the standard therapy was the most cost-effective regimen, in terms of BMD improvement and fracture prevention with an incremental cost-effectiveness ratio (ICER) of $154/patient/year. The one-way sensitivity analyses have delineated the change in cost-effectiveness when alendronate retail unit price was increased by 25% and 50%, or when denosumab retail unit price was decreased by 25% and 50%. The model was sensitive to the uncertainties (95% confidence interval) in the probabilities of fracture prevention and the probabilities of attaining the desired outcome.ConclusionThe model suggests that oral once weekly alendronate add-on regimen to standard therapy seems to be substantially more cost effective than twice yearly SC denosumab in terms of BMD improvement and fracture prevention in RTRs. Longer time horizon models with longer follow-up periods for fracture risks and adverse events are warranted to validate these data.

Differences Between Intravenous and Subcutaneous Modes of Administration in Oncology from the Patient, Healthcare Provider, and Healthcare System Perspectives: A Systematic Review.

While patients with cancer have traditionally received oncology treatments through intravenous (IV) administration, some therapies are becoming available via alternative modes of administration, such as subcutaneous (SC). This study aimed to evaluate IV versus SC therapy administration from the perspectives of the patient, healthcare provider (HCP), and healthcare system. A systematic review was conducted, searching MEDLINE and Embase databases from 2000 to 2022. This was supplemented with grey literature searches of additional sources such as conference proceedings. Observational studies and clinical trials were included if they assessed adult patients with any cancer type who were treated with pharmacologic therapies administered via IV or SC and included patient- or HCP-reported outcomes or healthcare system perspectives on the mode of administration. Records identified by the literature search were screened by two independent reviewers. Included studies were data extracted by a single reviewer and validated by a second reviewer and synthesized using a narrative approach. After screening, 33 unique studies were included in the systematic review. Patients and HCPs reported substantially more favorable preference rates for SC over IV treatment. Additionally, from the patient perspective there were reductions in treatment time and economic burden for SC compared with IV therapy. From the HCP's perspective, treatment time was consistently reduced by SC compared with IV treatment administration. Although information on the impact of SC and IV treatments for oncology on healthcare systems was limited, the use of SC formulations showed consistent cost savings (direct costs) and time savings from this perspective considering various uptake scenarios compared with IV administration. Compared with IV administration, SC oncology treatment is a preferred option by patients and HCPs, increasing optionality and reducing treatment time while simultaneously increasing capacity and reducing the financial burden on healthcare systems.

Toxicological screening of zinc oxide nanoparticles in mongrel dogs after seven days of repeated subcutaneous injections

Zinc oxide nanoparticles (ZnO NPs) have recently been applied in various veterinary and medical fields, however, the toxicological evaluations of these NPs in dogs are lacking. Therefore, the current study is designed to assess the impact of exposure to daily subcutaneous (SC) injections of ZnO NPs at different concentrations on various organs of mongrel dogs. Nine dogs were randomly divided into three groups (n = 3 for each) as follows: group (1) served as the control group, whereas groups (2&3) received SC injections of 50 and 100 ppm ZnO NPs (8 and 16 μg/kg bwt), respectively, once/day for 7 days. Our results revealed that ZnO NPs disrupted the oxidant/antioxidant balance in the lungs, liver, and kidneys of dogs in a dose-dependent manner. ZnO NPs induced dose-dependent radiological, ultrasonographical, and histopathological alterations in various organs especially lungs, spleen, liver, and kidneys along with disturbance in both liver and kidney biomarkers levels. Most organs of both ZnO NPs receiving groups displayed strong caspase-3 protein expression. Additionally, it upregulates the transcriptase levels of TNF-α and VEGF, as well as downregulates the antiapoptotic gene IL-10 in lung, kidney, and liver tissue homogenates. It was concluded that the daily SC injections of dogs with ZnO NPs at concentrations of 50 and 100 ppm caused extensive oxidative stress damage in various organs which provoked serious pathological processes such as apoptosis and inflammation.

Effectiveness of switching to subcutaneous infliximab in inflammatory bowel disease patients with inadequate biochemical response during intravenous administration

Infliximab (IFX) has transformed the management of inflammatory bowel diseases (IBD). While intravenous (IV) IFX has been effective, a subcutaneous (SC) formulation offers advantages in convenience and cost. However, there is lack of evidence regarding the transition from IV to SC-IFX, especially for patients with inadequate responses. This study investigates the effectiveness of switching from IV to SC-IFX in patients with inadequate responses during IV maintenance therapy. A retrospective study enrolled IBD patients who transitioned to SC-IFX after demonstrating inadequate responses during IV maintenance therapy. The study collected data of demographics of patients and dose and therapies administered prior to the IV-IFX. Primary outcomes included improvements in C-reactive protein (CRP) or fecal calprotectin (FC) levels. This study evaluated the trough levels and its differences between pre- and post-switching. Among 44 patients included, 10 exhibited CRP elevation before the switch, with 6 showing normalization post-switch. Similarly, 42 patients had elevated FC levels pre-switch, with 26 experiencing reductions post-switch. Trough levels increased after the switch. However, there were no significant differences between responders and non-responders. This study is the first study to investigate the transition therapy of IV to SC-IFX in patients with inadequate response. This suggests that SC-IFX could be a viable alternative in the management of IBD. However, further research is necessary to evaluate its efficacy in a larger population of patients who exhibit inadequate responses during IV-IFX maintenance therapy.

Model-Informed Drug Development-Based Approval of Intravenous Secukinumab for the Treatment of Adult Patients with Active Psoriatic Arthritis, Active Ankylosing Spondylitis, and Active Non-Radiographic Axial Spondyloarthritis.

On October 6, 2023, the US Food and Drug Administration (FDA) approved an intravenous (IV) formulation and dosage of Cosentyx® (secukinumab), for the treatment of adult patients with active psoriatic arthritis (PsA), active ankylosing spondylitis (AS), and active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation. Clinical pharmacokinetics (PK), efficacy, and short-term placebo-controlled safety data were available from clinical studies (NCT04156620 and NCT04209205) with the to-be-marketed IV formulation using a maintenance dosage 3 mg/kg every 4 weeks (q4w), which was different from the dose approved (1.75 mg/kg q4w). The IV dosage of 3 mg/kg utilized in these two trials resulted in exposures (Cmax,ss) significantly higher than those for the approved subcutaneous (SC) regimens. Further, there is limited long-term safety information available for this 3 mg/kg q4w IV dose. To address this important limitation, a model-informed drug development (MIDD) approach was employed to leverage available clinical PK, efficacy, and safety data from the secukinumab development program to identify a maintenance IV dosing regimen, 1.75 mg/kg IV q4w, that better approximated the relevant SC secukinumab exposures for which efficacy and safety have been established. The MIDD analyses were used to support approval of this IV dosing regimen not directly studied in the indications sought for licensure, PsA, AS, and nr-AxSpA.

Exogenous ketones exert antiseizure effects and modulate the gut microbiome and mycobiome in a clinically relevant murine model of epilepsy.

Despite growing interest in the potential use of exogenous ketones for the treatment of epilepsy, their impact on seizures and the gut microbiome and mycobiome remain unclear. Here, we examined the effects of both oral gavage and subcutaneous (SC) injection of a ketone ester (KE) in spontaneously epileptic Kcna1-null (KO) mice that model seminal aspects of human temporal lobe epilepsy. Electroencephalographic recordings and biochemical analyses were performed in KE-treated KO mice. Fecal microbial and fungal communities were profiled to determine whether the antiseizure activity of KE involves changes in the gut microbiome. We found that exogenous KE administration by SC injection was more effective than oral gavage in terms of rendering antiseizure effects while generating similar degrees of ketonemia. However, reductions in mean daily seizure counts were accompanied by overall alterations in the fecal bacterial microbiome. Either oral or SC injection imposed a greater impact on the microbiome in male than female mice. In males, oral KE decreased Bacteroidota phylum and genera of Ligilactobacillus and Muribaculaceae, whereas SC injection decreased Bacteroides, Lactobacillus, and Lachnospiraceae. The fecal mycobiome was affected by KE injection to a greater degree than by oral gavage, and more in females than in males, as reflected by an increase in Ascomycota and Saccharomyces. Correlation analysis between microbiome and seizure counts revealed that in mice receiving KE injection, the seizure count was positively correlated with an amplicon sequencing variant of Lactobacillus (Spearman rho = .64, p = .03) and tended toward a negative correlation with Saccharomyces (Spearman rho = -.57, p = .057). Our findings demonstrate that exogenous ketone administration alone can induce antiseizure effects equally via different routes of administration, and that they induce differential shifts in both the bacterial microbiome and mycobiome.

Human-factors validation study for a wearable, single-use injector for patients with paroxysmal nocturnal hemoglobinuria

Pegcetacoplan is a complement component 3 inhibitor approved to treat adults with paroxysmal nocturnal hemoglobinuria, a rare disease characterized by life-threatening complement-mediated hemolysis (often leading to anemia) and thrombosis. Pegcetacoplan is self-administered as a subcutaneous (SC) injection with an at-home infusion pump. A newly approved, more convenient, wearable, single-use automatic injector was evaluated in a human factors study for the safe and effective SC delivery of pegcetacoplan in the abdominal area. Adult patients with anemia (representative of PNH) and caregivers (n=15 each) received formal injector use training (2-hour session followed by 1-hour decay) and reviewed the instructions for use (IFU), whereas health care providers (HCPs; n=15) only received the IFU. Participants completed a use test, knowledge-based assessment (KBA), and interviews. Forty-four of 45 participants (98%) passed the use test. Residual risks from observed errors (17 critical use and 6 KBA errors) were deemed acceptable. This study validated the injector for ease of use and safe and effective SC delivery of pegcetacoplan at home, which may potentially reduce treatment burden for patients with PNH.

9224 Evaluation of Safety and Efficacy of Administration of Estradiol by Subcutaneous Injection in Transgender Women

Abstract Disclosure: H. Perkins: None. H. Moreau: None. J. LaBudde: None. W. Craig: None. D.I. Spratt: None. Background: Off-label use of subcutaneous (SC) estradiol (E2) by transgender women for gender-affirming hormone therapy is becoming increasingly widespread, despite a lack of published data regarding its efficacy and safety. Methods: This retrospective cohort study used manual data extraction from electronic medical records for patients ages 18-79 years, currently or previously receiving oral (PO) 17-beta E2 or SC E2 valerate therapy at Maine Medical Center Reproductive Endocrinology and Infertility and Gender Clinics between 5/30/14-5/30/23, who completed E2 dose adjustments aimed at obtaining a serum E2 of 75-250 pg/mL. SC E2 was administered weekly and PO E2 daily. Serum testosterone (T), estrone (E1), and sex hormone binding globulin (SHBG) levels were recorded if drawn within 90 days of E2 measurement on an optimized dose. In a subset of patients receiving SC E2, serum E2 levels were drawn 1-2 days post- and pre-injection. All patient-reported local or systemic reactions were recorded. Data are expressed as median (full range) or mean ± standard deviation (full range). Results: 45 patients were included with no significant differences in demographics between PO (n=20) and SC (n=25) groups. Both groups achieved therapeutic E2 levels after dose adjustment without statistical difference in mean serum E2 (pg/mL) between SC and PO groups: 148.7 ± 41.0 (78-226) vs. 151.6 ± 31.7 (97-208); p=0.79 by t-test. In patients without orchiectomy, both SC and PO groups had T (ng/dL) suppressed to normal adult female range (10-55) in 11/12 SC patients and in 17/17 PO patients; median T was 14.0 (7.7-86) for SC vs. 20.6 (3.4-42) for PO; p=0.98 by Mann-Whitney U test. Median E2 dose (mg/week) in the SC group was 3.0 (1.4-6.0) and in the PO group was 42.0 (28-84). Median serum E1 (pg/mL) was lower in the SC group than the PO group: 73.5 (29-115), n=12 vs. 907 (596-1601), n=5, p<0.001 by Mann-Whitney U test. E1/E2 ratio was lower in the SC group than the PO group: 0.4 ± 0.1 vs. 8.0 ± 2.9; p<0.001 by t-test. There was no significant difference in median serum SHBG (nmol/L) between SC and PO groups: 71.7 (19.3-146.7), n=15 vs. 73.4 (51.0-187.4), n=14; p=0.20 by Mann-Whitney U test. Mean post- and pre-dose serum E2 levels in 5 patients were 138.0 ± 24.0 and 88.0 ± 57.6, respectively. There was one transient local reaction and no systemic allergic or inflammatory reactions in the SC group with no systemic reactions in the PO group. Conclusion: These results demonstrate that SC E2 at doses of 1.4-6 mg/week can be administered safely to achieve therapeutic serum E2 levels and suppress serum T levels to within the normal female range. Our preliminary data reveal lower serum E1 levels in the SC group than in the PO group suggesting reduced hepatic first-pass metabolism with SC administration; this pattern was not seen with serum SHBG levels. Post- and pre-dose serum E2 levels revealed only a mild decline in E2 levels between injections. Presentation: 6/3/2024

6961 Evaluation of Safety and Efficacy of Administration of Estradiol by Subcutaneous Injection in Transgender Women

Abstract Disclosure: H. Perkins: None. H. Moreau: None. J. LaBudde: None. W. Craig: None. D.I. Spratt: None. Background: Off-label use of subcutaneous (SC) estradiol (E2) by transgender women for gender-affirming hormone therapy is becoming increasingly widespread, despite a lack of published data regarding its efficacy and safety. Methods: This retrospective cohort study used manual data extraction from electronic medical records for patients ages 18-79 years, currently or previously receiving oral (PO) 17-beta E2 or SC E2 valerate therapy at Maine Medical Center Reproductive Endocrinology and Infertility and Gender Clinics between 5/30/14-5/30/23, who completed E2 dose adjustments aimed at obtaining a serum E2 of 75-250 pg/mL. SC E2 was administered weekly and PO E2 daily. Serum testosterone (T), estrone (E1), and sex hormone binding globulin (SHBG) levels were recorded if drawn within 90 days of E2 measurement on an optimized dose. In a subset of patients receiving SC E2, serum E2 levels were drawn 1-2 days post- and pre-injection. All patient-reported local or systemic reactions were recorded. Data are expressed as median (full range) or mean ± standard deviation (full range). Results: 45 patients were included with no significant differences in demographics between PO (n=20) and SC (n=25) groups. Both groups achieved therapeutic E2 levels after dose adjustment without statistical difference in mean serum E2 (pg/mL) between SC and PO groups: 148.7 ± 41.0 (78-226) vs. 151.6 ± 31.7 (97-208); p=0.79 by t-test. In patients without orchiectomy, both SC and PO groups had T (ng/dL) suppressed to normal adult female range (10-55) in 11/12 SC patients and in 17/17 PO patients; median T was 14.0 (7.7-86) for SC vs. 20.6 (3.4-42) for PO; p=0.98 by Mann-Whitney U test. Median E2 dose (mg/week) in the SC group was 3.0 (1.4-6.0) and in the PO group was 42.0 (28-84). Median serum E1 (pg/mL) was lower in the SC group than the PO group: 73.5 (29-115), n=12 vs. 907 (596-1601), n=5, p<0.001 by Mann-Whitney U test. E1/E2 ratio was lower in the SC group than the PO group: 0.4 ± 0.1 vs. 8.0 ± 2.9; p<0.001 by t-test. There was no significant difference in median serum SHBG (nmol/L) between SC and PO groups: 71.7 (19.3-146.7), n=15 vs. 73.4 (51.0-187.4), n=14; p=0.20 by Mann-Whitney U test. Mean post- and pre-dose serum E2 levels in 5 patients were 138.0 ± 24.0 and 88.0 ± 57.6, respectively. There was one transient local reaction and no systemic allergic or inflammatory reactions in the SC group with no systemic reactions in the PO group. Conclusion: These results demonstrate that SC E2 at doses of 1.4-6 mg/week can be administered safely to achieve therapeutic serum E2 levels and suppress serum T levels to within the normal female range. Our preliminary data reveal lower serum E1 levels in the SC group than in the PO group suggesting reduced hepatic first-pass metabolism with SC administration; this pattern was not seen with serum SHBG levels. Post- and pre-dose serum E2 levels revealed only a mild decline in E2 levels between injections. Presentation: 6/3/2024

9224 Evaluation of Safety and Efficacy of Administration of Estradiol by Subcutaneous Injection in Transgender Women

Abstract Disclosure: H. Perkins: None. H. Moreau: None. J. LaBudde: None. W. Craig: None. D.I. Spratt: None. Background: Off-label use of subcutaneous (SC) estradiol (E2) by transgender women for gender-affirming hormone therapy is becoming increasingly widespread, despite a lack of published data regarding its efficacy and safety. Methods: This retrospective cohort study used manual data extraction from electronic medical records for patients ages 18-79 years, currently or previously receiving oral (PO) 17-beta E2 or SC E2 valerate therapy at Maine Medical Center Reproductive Endocrinology and Infertility and Gender Clinics between 5/30/14-5/30/23, who completed E2 dose adjustments aimed at obtaining a serum E2 of 75-250 pg/mL. SC E2 was administered weekly and PO E2 daily. Serum testosterone (T), estrone (E1), and sex hormone binding globulin (SHBG) levels were recorded if drawn within 90 days of E2 measurement on an optimized dose. In a subset of patients receiving SC E2, serum E2 levels were drawn 1-2 days post- and pre-injection. All patient-reported local or systemic reactions were recorded. Data are expressed as median (full range) or mean ± standard deviation (full range). Results: 45 patients were included with no significant differences in demographics between PO (n=20) and SC (n=25) groups. Both groups achieved therapeutic E2 levels after dose adjustment without statistical difference in mean serum E2 (pg/mL) between SC and PO groups: 148.7 ± 41.0 (78-226) vs. 151.6 ± 31.7 (97-208); p=0.79 by t-test. In patients without orchiectomy, both SC and PO groups had T (ng/dL) suppressed to normal adult female range (10-55) in 11/12 SC patients and in 17/17 PO patients; median T was 14.0 (7.7-86) for SC vs. 20.6 (3.4-42) for PO; p=0.98 by Mann-Whitney U test. Median E2 dose (mg/week) in the SC group was 3.0 (1.4-6.0) and in the PO group was 42.0 (28-84). Median serum E1 (pg/mL) was lower in the SC group than the PO group: 73.5 (29-115), n=12 vs. 907 (596-1601), n=5, p<0.001 by Mann-Whitney U test. E1/E2 ratio was lower in the SC group than the PO group: 0.4 ± 0.1 vs. 8.0 ± 2.9; p<0.001 by t-test. There was no significant difference in median serum SHBG (nmol/L) between SC and PO groups: 71.7 (19.3-146.7), n=15 vs. 73.4 (51.0-187.4), n=14; p=0.20 by Mann-Whitney U test. Mean post- and pre-dose serum E2 levels in 5 patients were 138.0 ± 24.0 and 88.0 ± 57.6, respectively. There was one transient local reaction and no systemic allergic or inflammatory reactions in the SC group with no systemic reactions in the PO group. Conclusion: These results demonstrate that SC E2 at doses of 1.4-6 mg/week can be administered safely to achieve therapeutic serum E2 levels and suppress serum T levels to within the normal female range. Our preliminary data reveal lower serum E1 levels in the SC group than in the PO group suggesting reduced hepatic first-pass metabolism with SC administration; this pattern was not seen with serum SHBG levels. Post- and pre-dose serum E2 levels revealed only a mild decline in E2 levels between injections. Presentation: 6/3/2024

6961 Evaluation of Safety and Efficacy of Administration of Estradiol by Subcutaneous Injection in Transgender Women

Abstract Disclosure: H. Perkins: None. H. Moreau: None. J. LaBudde: None. W. Craig: None. D.I. Spratt: None. Background: Off-label use of subcutaneous (SC) estradiol (E2) by transgender women for gender-affirming hormone therapy is becoming increasingly widespread, despite a lack of published data regarding its efficacy and safety. Methods: This retrospective cohort study used manual data extraction from electronic medical records for patients ages 18-79 years, currently or previously receiving oral (PO) 17-beta E2 or SC E2 valerate therapy at Maine Medical Center Reproductive Endocrinology and Infertility and Gender Clinics between 5/30/14-5/30/23, who completed E2 dose adjustments aimed at obtaining a serum E2 of 75-250 pg/mL. SC E2 was administered weekly and PO E2 daily. Serum testosterone (T), estrone (E1), and sex hormone binding globulin (SHBG) levels were recorded if drawn within 90 days of E2 measurement on an optimized dose. In a subset of patients receiving SC E2, serum E2 levels were drawn 1-2 days post- and pre-injection. All patient-reported local or systemic reactions were recorded. Data are expressed as median (full range) or mean ± standard deviation (full range). Results: 45 patients were included with no significant differences in demographics between PO (n=20) and SC (n=25) groups. Both groups achieved therapeutic E2 levels after dose adjustment without statistical difference in mean serum E2 (pg/mL) between SC and PO groups: 148.7 ± 41.0 (78-226) vs. 151.6 ± 31.7 (97-208); p=0.79 by t-test. In patients without orchiectomy, both SC and PO groups had T (ng/dL) suppressed to normal adult female range (10-55) in 11/12 SC patients and in 17/17 PO patients; median T was 14.0 (7.7-86) for SC vs. 20.6 (3.4-42) for PO; p=0.98 by Mann-Whitney U test. Median E2 dose (mg/week) in the SC group was 3.0 (1.4-6.0) and in the PO group was 42.0 (28-84). Median serum E1 (pg/mL) was lower in the SC group than the PO group: 73.5 (29-115), n=12 vs. 907 (596-1601), n=5, p<0.001 by Mann-Whitney U test. E1/E2 ratio was lower in the SC group than the PO group: 0.4 ± 0.1 vs. 8.0 ± 2.9; p<0.001 by t-test. There was no significant difference in median serum SHBG (nmol/L) between SC and PO groups: 71.7 (19.3-146.7), n=15 vs. 73.4 (51.0-187.4), n=14; p=0.20 by Mann-Whitney U test. Mean post- and pre-dose serum E2 levels in 5 patients were 138.0 ± 24.0 and 88.0 ± 57.6, respectively. There was one transient local reaction and no systemic allergic or inflammatory reactions in the SC group with no systemic reactions in the PO group. Conclusion: These results demonstrate that SC E2 at doses of 1.4-6 mg/week can be administered safely to achieve therapeutic serum E2 levels and suppress serum T levels to within the normal female range. Our preliminary data reveal lower serum E1 levels in the SC group than in the PO group suggesting reduced hepatic first-pass metabolism with SC administration; this pattern was not seen with serum SHBG levels. Post- and pre-dose serum E2 levels revealed only a mild decline in E2 levels between injections. Presentation: 6/3/2024

6461 VRDN-003, A Full Antagonist Antibody To The IGF-1 Receptor For Thyroid Eye Disease (TED): Safety And Pharmacokinetic Results Of Subcutaneous Administration In Healthy Volunteers

Abstract Disclosure: K. Foster: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. B. Dickinson: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. A. Matthew: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. J. Vijayaraghavan: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. C. Michalsky: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. V. Bedian: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. Introduction: While VRDN-001 is a full antagonist antibody to the IGF-1 receptor (IGF-1R) with phase 2 proof-of-concept data showing clinically meaningful improvements in thyroid eye disease (TED) symptoms after 2 intravenous (IV) infusions, VRDN-003 is a next-generation half-life extended version of VRDN-001. VRDN-003’s half-life extension has the potential to provide sustained pharmacokinetics (PK) and pharmacodynamics (PD) with less frequent administration. We present results from an ongoing study to assess the safety, PK, PD, and bioavailability of VRDN-003 for subcutaneous (SC) administration. Methods: Healthy volunteers (HVs) were randomized to receive a single dose of VRDN-003 or placebo in the following 4 IV or SC dose cohorts: IV 5.0 mg/kg, IV 15.0 mg/kg, SC 300 mg, or SC 600 mg. Preliminary treatment-emergent adverse events (AEs) were assessed through December 12, 2023, and will continue to be assessed through study exit (120 days). Preliminary PK parameters including bioavailability were assessed by noncompartmental analysis, and a 2-compartment Population PK model was employed to simulate exposures following repeat SC dosing. Results: Twenty-eight HVs received either VRDN-003 IV (n=8), VRDN-003 SC (n=12), placebo IV (n=4), or placebo SC (n=4). AEs were reported by 25% (2/8) of participants who received VRDN-003 IV, 25% (3/12) who received VRDN-003 SC, and 13% (1/8) who received placebo. Of the AEs, 3 were deemed treatment related, all occurring in VRDN-003 SC-treated patients and all grade 1/mild as follows: injection site reaction, insomnia, and hepatic enzyme increased. No serious AEs were reported. VRDN-003 half-life was estimated at 40-50 days, 4-5 times longer than VRDN-001; bioavailability is currently estimated to be approximately 60% after SC administration. Simulated dosing regimens show the potential for VRDN-003 to be administered SC Q4W or Q8W and reach exposure levels observed with the VRDN-001 parent molecule in its prior phase 2 study. Conclusions: A single dose of VRDN-003 administered IV or SC to HVs was well tolerated and showed favorable PK for SC administration including a half-life of 40-50 days, 4-5 times longer than its parent molecule, VRDN-001. These results show the potential for VRDN-003 SC dosing regimens with the goal of reducing the treatment burden associated with achieving IGF-1R blockade in TED. Safety and efficacy of VRDN-003 SC will be further assessed in planned clinical studies enrolling patients with TED. Presentation: 6/1/2024

Pharmacokinetics, Pharmacodynamics, and Safety of Intravenous Efgartigimod and Subcutaneous Efgartigimod PH20 in Healthy Chinese Participants.

Efgartigimod, a human immunoglobulin G (IgG)1-derived Fc fragment targeting the neonatal Fc receptor, has been developed into intravenous (IV) and subcutaneous (SC) formulations for treating generalized myasthenia gravis (gMG) and other autoimmune diseases. Data in the Chinese population were not available to date, and while both formulations have been approved in the USA, the EU, Japan and Chinafor the treatment of gMG. We present the pharmacokinetic, pharmacodynamic, and safety of IV and SC PH20 efgartigimod in healthy Chinese participants. In two independent, double-blinded, placebo-controlled, phase I studies of the IV and SC formulations of efgartigimod, healthy Chinese adults were randomized 3:1 to receive active treatment or matching placebo once every 7 days for four doses. Primary endpoints were pharmacokinetic parameters. After the fourth IV infusion, a mean maximum observed concentration (Cmax) of 194 µg/mL was reached at the end of the 1 h infusion; the mean area under concentration-time curve from time zero to 168 h (AUC0-168h) was 5300 µg × h/mL. After the fourth SC injection, a mean Cmax of 42.1 µg/mL was achieved with a median Tmax of 47.74 h; the mean AUC0-168h was 4790 µg × h/mL. Maximal mean reductions from baseline in total IgG levels were reached approximately 24 days after the first dose (60.7%, IV formulation; 66.4%, SC formulation). Treatment-related adverse events (TRAEs) were reported in seven (58.3%) participants receiving SC efgartigimod, mostly injection-site reactions. No TRAEs or AEs of special interest were reported in the IV study. The efgartigimod IV and SC pharmacokinetic, pharmacodynamic, and safety profiles in Chinese participants were similar to the known profiles in non-Chinese participants. Both formulations effectively reduced total IgG levels by a similar percentage. CTR20211952 and CTR20211805.

7227 Acute Hyponatremia Following Initiation of Antidepressant in Patient on Desmopressin Treatment for AVP Deficiency

Abstract Disclosure: M.E. Horowitz: None. Y. Gao: None. S.B. Abraham: None. P. Kishore: None. Introduction: Intranasal desmopressin (DDAVP) is indicated as antidiuretic replacement therapy in arginine vasopressin (AVP) deficiency. It increases water permeability in the distal nephron, reducing urine output, increasing urine osmolality, and decreasing serum osmolality. Treatment is titrated to normalize serum sodium and urine output (UOP). Initiation of medications affecting sodium balance or fluid status may lead to abnormalities in these markers. One of these is escitalopram, an antidepressant which can cause hyponatremia attributed to inappropriate AVP secretion. We report a case of acute hyponatremia in a patient with previously stable sodium on chronic DDAVP who was started on escitalopram. Clinical Case: A 44-year-old female with history of a craniopharyngioma resection in 2007 complicated by AVP deficiency on chronic DDAVP, bipolar disorder, and depression presented with nausea, vomiting, and dizziness for two days. Patient was found to be hyponatremic to 118 mEq/L (135-145 mEq/L). Sodium checked one month prior was 135 mEq/L, and historically was never less than 130 mEq/L since 2008. DDAVP was prescribed since resection with few dose changes, at this time four 10mcg sprays in each nostril three times daily since 2020. Escitalopram 5mg daily was initiated two months prior. Desmopressin was held in the setting of hyponatremia, which resolved appropriately to 135 mEq/L over the first five days. During this time, the patient complained of large volume diuresis at ∼three liters daily. On day six, sodium acutely increased to 146 mEq/L; subcutaneous (SC) DDAVP was given and sodium normalized. UOP decreased significantly over the next 24 hours, but large volume diuresis resumed thereafter. On day 10, DDAVP SC was given, again decreasing UOP for 24 hours. Psychiatry recommended continuing escitalopram given improvement in psychiatric symptoms since initiation. Upon discharge, the patient was prescribed DDAVP two 10mcg sprays in each nostril nightly, a significant reduction compared to her prior dose. Sodium rechecked one week later remained within normal limits. Clinical Lessons: This effect of combination DDAVP and escitalopram has not been reported previously. Prescribers should be aware of the potential for hyponatremia and the need to adjust DDAVP dose in combined use. To avoid these risks in patients on chronic DDAVP, the side effects of antidepressants and antipsychotics should be reviewed prior to initiation. Presentation: 6/2/2024

Patient and Healthcare Professional Satisfaction, Acceptability, and Preference Experiences With Mirikizumab Administration for Ulcerative Colitis: An International Survey

Abstract Background There is a need to better understand ulcerative colitis (UC) patient and healthcare provider (HCP) treatment satisfaction, acceptability, and preferences. Methods Two international, cross-sectional, web-based surveys were conducted among participants of a phase 3 mirikizumab study (NCT03519945). The questions captured moderate-to-severe UC patients’ experience, HCPs’ perception of patients’ experience, and HCPs’ own experience with mirikizumab administration through intravenous (IV) infusions and subcutaneous (SC) injections. Results Respondents included 93 patients and 42 HCPs from 11 countries. The majority of patients had UC >4 years (74.2%), were bionaive (68%), in remission at the time of the survey (63%). HCPs were primarily from the United States (57%), generally nurses (41%) or gastroenterologists (26%) with ≥6 years of experience in treating UC (57%). Most patients were “very satisfied/satisfied” (IV, 83%; SC, 91%), “completely/somewhat” accepting of mirikizumab administration (IV, 87%; SC, 97%), and agreed that improvement to their UC outweighed any administration dissatisfaction (90%). HCPs’ perspectives of patients’ experiences were higher: “very satisfied/satisfied” (IV, 93%; SC, 100%); “completely/somewhat” accepting (IV, 90%; SC, 98%). HCPs themselves were “very satisfied/satisfied” (IV, 81%; SC, 95%); gastroenterologists were “very satisfied” (IV, 82%; SC, 82%) more than nurses (IV, 29%; SC, 65%) who were generally at least “satisfied” (IV, 53%; SC, 35%). Two SC and monthly SC injections were “completely acceptable” by the patients (76% and 85%) and per HCPs’ perceptions of patients’ preferences (69% and 100%). Conclusions Both patients and HCPs were satisfied with and accepted mirikizumab IV induction followed by monthly maintenance SC injections. UC improvement outweighed any administration dissatisfaction.

Jet injection through microneedles for large volume subcutaneous delivery

Subcutaneous (SC) drug delivery offers several advantages over intravenous (IV) delivery including: self-administration, improved patient experience, and reduced treatment costs. Unfortunately, each SC delivery is currently limited to ∼ 2.25 mL with IV administration required when the delivery volume exceeds this value. In this work, we explore a new technique for large volume subcutaneous drug delivery that uses microneedles to break through the epidermis then forms the liquid drug into many small jets that penetrate past the ends of the microneedles and into the subcutaneous (or muscle) tissue. By performing multiple simultaneous injections, this delivery approach avoids the volume limitations of SC delivery, and thus may be able to greatly increase the volume we can deliver to this space. Here, we present a novel multi-jet prototype that forms seven simultaneous jets through 30G needles that have been shortened to have an exposed length of just ∼ 1mm. The jet speed, shape, and volume of jets formed through these microneedles are measured to assess the consistency of jet production through the microneedles. We then perform jet injections of volumes up to 3.9 mL into ex vivo porcine tissue. The results demonstrate the successful delivery (>95 %) of 3.9 mL in just 0.3 s using jet injection performed through microneedles. This volume is almost double the maximum volume of current autoinjectors and the perceived limit for subcutaneous injection (2.25 mL). We also find that jet speeds of 70 m/s and below do not achieve complete delivery of 3.9 mL with our prototype system, and that the addition of microneedles leads to more consistent large volume delivery than equivalent needle-free injections. These results demonstrate the promise of multi-jet injection through microneedles to accommodate volumes much greater than current autoinjectors, and thus potentially allow patient self-administration in many more delivery applications.

The Role of Subcutaneous Furosemide in Heart Failure Management: A Systematic Review.

Acute decompensated heart failure (ADHF) patients with symptomatic congestion often require in-hospital admission for intravenous (IV) diuretic, impacting both patient well-being and healthcare expenses. Subcutaneous (SC) furosemide has a potential to facilitate outpatient management of ADHF patients. Thus, this study aims to assess the efficacy and safety of SC furosemide utilization, offering a potential alternative to traditional IV administration. A systematic search was conducted until April 14 2024 across scientific databases. This review included studies comparing SC furosemide with oral and IV formulations in adult HF patients. This study analyzed 687 patients from 20 studies. The results demonstrate that SC furosemide can effectively manage symptomatic congestion in HF patients and results in significant cost reductions, symptom relief, and improved quality of life. Although further investigation into mortality rates is needed, SC furosemide demonstrates efficacy comparable to IV furosemide in diuresis and weight loss, with similar bioavailability and natriuretic effects. Adverse events are generally minor, predominantly related to skin irritation. Innovative strategies, such as developing isotonic alkaline solutions and improved infusion devices, are being explored to address these challenges. SC furosemide offers a promising alternative for managing ADHF, particularly in symptomatic HF patients with volume overload. The integration of SC furosemide into routine clinical practice and future guidelines, could optimize the management of HF, reducing hospital admission and improving patient outcomes.