Subcutaneous Route Of Administration Research Articles

Comparative analysis of semaglutide induced adverse reactions: Insights from FAERS database and social media reviews with a focus on oral vs subcutaneous administration.

Compared to alternative weight-loss strategies and medications, semaglutide stands out for its convenience and efficacy, resulting in a significant increase in prescriptions and raising public safety concerns. Furthermore, the safety profiles of its oral and subcutaneous formulations require further examination. Our goal is to investigate the potential safety risks associated with semaglutide by analyzing data from the FAERS database and social media. Additionally, we aim to compare the adverse drug reaction (ADR) signals between the oral and subcutaneous administration routes of semaglutide. We collected semaglutide-related reports from the FAERS database spanning Q1 2018 to Q2 2023, and patient reviews on WebMD and AskaPatient up to 20 July 2023. Following data extraction and cleansing, we conducted descriptive analyses of demographic characteristics. Subsequently, we calculated adverse drug reaction (ADR) signals using the reporting odds ratio (ROR). We identified 19,289 and 422 semaglutide-related adverse drug events (ADEs) reported in the FAERS database and online patient reviews, respectively. Gastrointestinal disorders emerged as the most commonly reported System Organ Class (SOC) in both datasets. Predominant Preferred Terms (PTs) included nausea, vomiting, and diarrhea. Serious outcomes constituted 3.07% and 2.25% of all cases for oral and subcutaneous semaglutide, respectively. At the SOC level, gastrointestinal disorders accounted for 30.19% of total ADEs in oral semaglutide, slightly surpassing the 27.76% in subcutaneous semaglutide. The median onset for gastrointestinal PTs was 4 days in both oral (Q1: 1, Q3: 32) and subcutaneous (Q1: 1, Q3: 35) formulations. Noteworthy, new serious adverse event (AE) signals were identified, including hemorrhagic diarrhea (ROR: 3.69), hepatic pain (ROR: 4.20), abnormal hormone levels (ROR: 6.51), and pancreatic failure (ROR: 36.34) in subcutaneous semaglutide, and Dupuytren's contracture (ROR: 46.85) in oral semaglutide. Our study delineates the safety profile of semaglutide using data from the FAERS database and social media. And identified novel ADR signals specific to oral and subcutaneous forms of semaglutide.

Comparison of subcutaneous and intravenous infliximab in patients with inflammatory bowel disease showed no differences in immunogenicity or treatment persistence at 1 year

BackgroundInfliximab (IFX) effectiveness in inflammatory bowel disease (IBD) can be impaired by antidrug antibodies (ADA). Subcutaneous IFX has a different pharmacokinetic profile compared with intravenous administration, potentially affecting immunogenicity.MethodsRetrospective audit...

Repeated subcutaneous esketamine on treatment-resistant depression: An open-label dose titration study

BackgroundKetamine has recently gained prominence as one of the most effective therapeutic options in unipolar treatment-resistant depression (TRD). However, most studies related to the antidepressant action of ketamine used intravenous (IV) or intranasal (IN) administration. The subcutaneous (SC) route of administration is a promising alternative, as it results in plasma levels comparable to IV, causes fewer side effects, and is easier and cheaper to administer than both IV and IN routes. MethodsIn this context, we conducted an open-label clinical trial for investigating the efficacy and safety of 8 weekly sessions of SC esketamine in TRD patients (n = 30). ResultsAt the end of the treatment, a partial response rate of 26.09 %, a response rate of 52.17 % and remission rate of 34.78 % were observed. The self-reported depressive symptoms, as measured by the Beck Depression Inventory II, significantly decreased from the baseline to the final session, and the improvements were sustained throughout the week. Follow-up evaluations up to the sixth month consistently showed scores lower than the baseline. LimitationsThe small sample size and the drop-out during the follow-up phase may limit the generalizability of the findings. Additionally, the absence of a control group necessitates cautious interpretation of causality. ConclusionsThis pioneering study, which addresses SC esketamine treatment for TRD, reported promising response and remission rates, as well as sustained effects. It highlights the need for further research to improve and expand our knowledge of this innovative, more accessible, and cost-effective therapeutic approach.

Preferences for diagnostic pathways and treatment choice in systemic lupus erythematosus: a patient-based discrete choice experiment.

Starting from the unmet need of early diagnosis and treatment in systemic lupus erythematosus (SLE), the study aims to explore patient preferences in diagnostic pathways and treatment modalities. It seeks to integrate clinical priorities with patient perspectives, providing an optimal approach to SLE treatment that remains uncertain. A discrete choice experiment (DCE) has been conducted to investigate whether patient preferences align while maintaining consistent attributes and levels, providing a direct assessment of relative preferences and hypothetical treatment approaches in SLE. DCE results demonstrated that obtaining an early diagnosis is the most crucial attribute for patients. Additionally, a multidisciplinary care team, capable of enhancing clinical outcomes and patient satisfaction, is essential, along with a clinical centre conveniently located within 30 minutes of the patient's home. Lastly, patients prefer the opportunity to reduce glucocorticoid to a dosage ≤5 mg/day, and eventually discontinue, aligning with the new EULAR recommendations, and favour oral and subcutaneous routes of administration for new course of treatment. Patient preferences contribute to enhancing the care pathway for SLE by optimising disease management, with a focus on multidisciplinarity and psychological support.

Immunization of BALB/c Mice against Shigella sonnei Using a Multiepitope Protein Vaccine through Intranasal and Subcutaneous Administration.

As the most common cause of bacillary dysentery or shigellosis, Shigella sonnei (S nonnei) has spread throughout the world. Invasion of the colorectal epithelial cells by this facultative intracellular bacterium occurs via various virulence factors. The increase in the resistance rate highlights the need for novel interventions, particularly increasing the urgency of the development of Shigellavaccines that may offer an effective solution. A multiepitope protein vaccine (MEPV) construct previously designed using bioinformatics tools against Shigella species, was applied in vivo in BALB/C mice. The designed vaccine construct was expressed in a bacterial host, purified, and finally confirmed by Western blot analysis. The immunogenicity of the purified MEPV was assessed against S sonnei via intranasal and subcutaneous administration routes, followed by evaluating its protective efficiency. We observed that interferon-gamma, interleukin-4, and immunoglobulin G levels were increased in all experimental groups. Therefore, The MEPV effectively protected the mice against S sonnei.

A Model-Informed Drug Development Approach to Design a Phase 3 Trial of Teverelix Drug Product in Advanced Prostate Cancer Patients with Increased Cardiovascular Risk.

Teverelix drug product (DP) is a parenteral gonadotropin-releasing hormone (GnRH) antagonist that has been successfully tested in phase 2 trials for hormone-sensitive advanced prostate cancer (APC) and benign prostatic hyperplasia (BPH). In previous APC trials, teverelix DP was administered as intramuscular (IM) and subcutaneous (SC) injections, using a loading dose and (in a single trial) a maintenance dose. Our objective was to derive an optimal dosing regimen for phase 3 clinical development, using a pharmacometrics modeling approach. Data from 9 phase 2 studies (229 patients) was utilized to develop a population pharmacokinetic (PK) model that described the concentration profile accommodating both IM and SC routes of administration. A 2-compartment model with sequential first-order absorption (slow and fast) and lag times best described the PK profiles of teverelix following SC and IM administration. An indirect response model with inhibition of production rate was fit to describe testosterone (T) concentrations based on physiological relevance. The final population PK-pharmacodynamic model was used to conduct simulations of various candidate dosing regimens to select the optimal dosing regimen to achieve clinical castration (T<0.5ng/mL by day 28) and to sustain clinical castration for 26 weeks. Model simulation showed that a loading dose of 360mg SC and 180mg IM with a maintenance dose of 360mg SC 6-weekly (Q6W) starting at day 28 can achieve a ≥95% castration rate up to 52 weeks. This dose regimen was selected for phase 3 clinical development, which includes cardiovascular safety assessment in comparison to a GnRH agonist.

Patient Preference for Subcutaneous Versus Intravenous Administration with Every-6-Week Natalizumab (Tysabri®) Dosing: NOVA Phase IIIb Extension Study (Part 2).

Following NOVA (part 1) and the approval of the subcutaneous (SC) route of administration of natalizumab by the European Medicines Agency, an extension phase of the NOVA phase IIIb study (part 2) was initiated to collect patient preference data for SC versus intravenous (IV) dosing in patients receiving every-6-week (Q6W) dosing of natalizumab. This study was performed to evaluate patient preference for SC versus IV natalizumab administration and explore the efficacy, safety, and pharmacology characteristics of both routes of administration. In part 2, participants received natalizumab (Tysabri®) 300mg via IV infusion Q6W for 36weeks and then were randomized to 48weeks of crossover treatment (24weeks SC Q6W and 24weeks IV Q6W, or vice versa). The primary endpoint was the proportion of participants who indicated a preference for natalizumab SC administration on the Patient Preference Questionnaire. A total of 153 participants were randomized in NOVA part 2. Of 123 with patient preference data, 108 (87.8%) preferred the SC route of administration for natalizumab over the IV route; 102 (82.9%) specified "requires less time in the clinic" as the reason for the SC preference. In NOVA (part 2), most participants on Q6W dosing of natalizumab preferred SC administration versus IV administration. GOV: NCT03689972. INFOGRAPHIC.

Oral Anti-Diabetic Semaglutide: A GLP-1 RA Peptide

T2DM has emerged as a global disorder. Although there are many treatment options available for T2DM patients, still several patients complaint about inadequate blood sugar levels. Diabetes management is not limited to just lowering of blood glucose level, it needs a multifactorial approach in treatment. Glucagon- like peptide-1 receptor agonists (GLP-1RA) are a new category of T2DM drugs that acts on various targets such as body weight reduction, renal and cardiovascular benefits. Despite of being so beneficial the major drawback of semaglutide has been its subcutaneous route of administration. Majority of the patients are unable to continue semaglutide for long because of their reluctance towards daily injectable. To avoid this oral semaglutide is introduced. Oral semaglutide is a GLP- 1RA which is displays high glycaemic control. However, in order to increase its bioavailability, it needs to be co formulated with sodium N-(8-[2-hydroxybenzyol] amino) caprylate (SNAC). Oral semaglutide has gone through a very intense series of clinical trials known as, Peptide Innovation for Early Diabetes Treatment (PIONEER). These trials have established benefits of oral semaglutide regarding reduction in glycaemic levels and body weight. It is deemed to be fit for regular consumption. In this review we discuss many aspects of oral semaglutide such as, its chemical structure, route of administration, challenges associated with the oral form of semaglutide, dosage, mechanism of oral bioavailability, robust indications, its placement in the line of defence, drug- drug interaction, various clinical trials (Phase trials and PIONEER studies) including their results. It also summarizes the benefits of oral semaglutide beyond glycaemic control and some future scope of research in the field.

Preclinical Pharmacokinetics in Tumors and Normal Tissues of the Antigene PNA Oligonucleotide MYCN-Inhibitor BGA002.

Although MYCN has been considered an undruggable target, MYCN alterations confer poor prognosis in many pediatric and adult cancers. The novel MYCN-specific inhibitor BGA002 is an antigene peptide nucleic acid oligonucleotide covalently bound to a nuclear localization signal peptide. In the present study, we characterized the pharmacokinetics (PK) of BGA002 after single and repeated administration to mice using a novel specific enzyme-linked immunosorbent assay. BGA002 concentrations in plasma showed linear PK, with dose proportional increase across the tested dose levels and similar exposure between male and female and between intravenous and subcutaneous route of administration. Repeated dosing resulted in no accumulation in plasma. Biodistribution up to 7 days after single subcutaneous administration of [14C]-radiolabeled BGA002 showed broad tissues and organ distribution (suggesting a potential capability to reach primary tumor and metastasis in several body sites), with high concentrations in kidney, liver, spleen, lymph nodes, adrenals, and bone marrow. Remarkably, we demonstrated that BGA002 concentrates in tumors after repeated systemic administrations in three mouse models with MYCN amplification (neuroblastoma, rhabdomyosarcoma, and small-cell lung cancer), leading to a significant reduction in tumor weight. Taking into account the available safety profile of BGA002, these data support further evaluation of BGA002 in patients with MYCN-positive tumors.

Randomised comparison of intravenous and subcutaneous routes of glucagon-like peptide-1 administration for lowering plasma glucose in hyperglycaemic subjects with type 2 diabetes.

To perform a direct, double-blind, randomised, crossover comparison of subcutaneous and intravenous glucagon-like peptide-1 (GLP-1) in hyperglycaemic subjects with type 2 diabetes naïve to GLP-1-based therapy. Ten fasted, hyperglycaemic subjects (1 female, age 63 ± 10 years [mean ± SD], glycated haemoglobin 73.5 ± 22.0 mmol/mol [8.9% ± 2.0%], both mean ± SD) received subcutaneous GLP-1 and intravenous saline, or intravenous GLP-1 and subcutaneous saline. Infusion rates were doubled every 120 min (1.2, 2.4, 4.8 and 9.6 pmol·kg-1·min-1 for subcutaneous, and 0.3, 0.6, 1.2 and 2.4 pmol·kg-1·min-1 for intravenous). Plasma glucose, total and intact GLP-1, insulin, C-peptide, glucagon and gastrointestinal symptoms were evaluated over 8 h. The results are presented as mean ± SEM. Plasma glucose decreased more with intravenous (by ~8.0 mmol/L [144 mg/dL]) than subcutaneous GLP-1 (by ~5.6 mmol/L [100 mg/dL]; p < 0.001). Plasma GLP-1 increased dose-dependently, but more with intravenous than subcutaneous for both total (∆max 154.2 ± 3.9 pmol/L vs. 85.1 ± 3.8 pmol/L; p < 0.001), and intact GLP-1 (∆max 44.2 ± 2.2 pmol/L vs. 12.8 ± 2.2 pmol/L; p < 0.001). Total and intact GLP-1 clearance was higher for subcutaneous than intravenous GLP-1 (p < 0.001 and p = 0.002, respectively). The increase in insulin secretion was greater, and glucagon was suppressed more with intravenous GLP-1 (p < 0.05 each). Gastrointestinal symptoms did not differ (p > 0.05 each). Subcutaneous GLP-1 administration is much less efficient than intravenous GLP-1 in lowering fasting plasma glucose, with less stimulation of insulin and suppression of glucagon, and much less bioavailability, even at fourfold higher infusion rates.

Clinical Outcomes of Intravenous Methylnaltrexone in Children: A Single-Arm Retrospective Cohort Study.

Constipation is a common adverse event of opioid use that is often difficult to treat. Methylnaltrexone is a therapeutic option for opioid-induced constipation (OIC) approved for oral and subcutaneous use in adults. These administration routes are not always feasible in the pediatric population. The primary objective of this research was to quantify the response rate of methylnaltrexone in pediatric patients when it was administered via the intravenous (IV) route. This retrospective study evaluated patients ages <18 years who received IV methylnaltrexone between January 1, 2013, and June 30, 2020, for OIC. Efficacy was evaluated through documentation of bowel evacuation within 4 hours of methylnaltrexone administration. Adverse events observed within 24 hours of administration were attributed to methylnaltrexone. Methylnaltrexone was administered to 134 unique patients during the study period. Of these, 46 met exclusion criteria, resulting in 88 patients being included in the study. Patients with an underlying hematology/oncology diagnosis consisted of 77% of the study population, and 23% of patients had an -underlying medical/surgical diagnosis. The response rate to IV methylnaltrexone was 25% (CI, 16-34). The results of this retrospective chart review demonstrate the potential role of IV methylnaltrexone in the pediatric population. Despite the overall lower response rate relative to that reported in adults, IV methylnaltrexone possesses a unique mechanism of action that may serve as an alternative treatment option for patients unable to use the oral and subcutaneous administration routes. There were no significant adverse events seen in the study.

Anti-Drug Antibody Incidence Comparison of Therapeutic Proteins Administered Via Subcutaneous vs. Intravenous Route.

Subcutaneous (SC) administration of therapeutic proteins is perceived to pose higher risk of immunogenicity when compared with intravenous (IV) route of administration (RoA). However, systematic evaluations of clinical data to support this claim are lacking. This meta-analysis was conducted to compare the immunogenicity of the same therapeutic protein by IV and SC RoA. Anti-drug antibody (ADA) data and controlling variables for 7 therapeutic proteins administered by both IV and SC routes across 48 treatment groups were analyzed. RoA was the primary independent variable of interest while therapeutic protein, patient population, adjusted dose, and number of ADA samples were controlling variables. Analysis of variance was used to compare the ADA incidence between IV and SC RoA, while accounting for controlling variables and potential interactions. Subsequently, 10 additional therapeutic proteins with ADA data published for both IV and SC administration were added to the above 7 therapeutic proteins and were evaluated for ADA incidence. RoA had no statistically significant effect on ADA incidence for the initial dataset of 7 therapeutic proteins (p = 0.55). The only variable with a significant effect on ADA incidence was the therapeutic protein. None of the other controlling variables, including their interactions with RoA, was significant. When all data from the 17 therapeutic proteins were pooled, there was no statistically significant effect of RoA on ADA incidence (p = 0.81). In conclusion, there is no significant difference in ADA incidence between the IV and SC RoA, based on analysis of clinical ADA data from 17 therapeutic proteins.

Patient experience of medication administration and development of a Patient Experience and Preference Questionnaire (PEPQ) for patients with advanced or metastatic cancer.

Introduction: A better understanding of patient experience of intravenous (IV) or subcutaneous (SC) routes of administration is fundamental to providing optimal administration of medical therapies to oncology patients. The objective of this study was to examine patient experiences of IV and SC treatment with nivolumab and confirm the relevance of item concepts in the Patient Experience and Preference Questionnaire (PEPQ). The PEPQ is a clinical outcomes' assessment instrument developed to obtain patient-centric data and understand the experience with IV and SC treatment administration. Methods: Embedded qualitative interviews were conducted with a subset of participants from three treatment cohorts with metastatic non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), unresectable or advanced metastatic melanoma, hepatocellular carcinoma (HCC), or colorectal cancer (CRC) from the CA209-8KX clinical trial. Concept elicitation interviews were conducted within 14days of the initial treatment cycle and patient experiences with IV and SC treatment administration were assessed. Concepts from interviews were mapped to the PEPQ version 1.0 questions to assess relevance and convergence of concepts. Results: Interviews were conducted with 43 trial participants from clinical sites opting to participate from six countries (Argentina, France, the Netherlands, Poland, Spain, and New Zealand). The mean age of sub-study participants was 66 ± 11.3years (range 24-80years), and 67.4% (N = 29) were male. Sub-study participants with experience of SC most frequently reported symptoms or signs of injection-related redness (27.9%), itching (14.0%), and pain (of needle), and described the pain as pricking, stinging, or tingling (11.0% each). The amount of pain and time burden were widely endorsed as important factors for satisfaction and related to the route of medication administration. For 11 sub-study participants with experience with both IV and SC treatments, 10 (90.9%) preferred SC over IV treatment administration. Conclusion: This study summarizes the experience and satisfaction of receiving IV or SC treatment and confirms the relevance of the PEPQ in a subgroup of CA209-8KX clinical trial participants with metastatic NSCLC, RCC, melanoma, HCC, and CRC. Participant treatment experience and satisfaction with the route of medication mapped to the PEPQ question content support the relevance of PEPQ v2.0 in clinical trials as a self-report measure.

Impact of Premedication De-Escalation on Incidence of Infusion-Related Reactions With Daratumumab.

Daratumumab is an anti-CD38 monoclonal antibody used to treat multiple myeloma and light chain amyloidosis. Because daratumumab may cause reactions after intravenous or subcutaneous (SC) administration, the manufacturer labeling recommends administration of premedications before every dose. Given incidence of infusion reactions appears to be rare after cycle 1, in April 2022, the Mayo Clinic implemented a practice change in which premedications were omitted from all daratumumab order sets after completion of cycle 1. This study investigated the safety of this practice. A retrospective chart review at the Mayo Clinic reviewed eligible patients with multiple myeloma or amyloid light-chain (AL) amyloidosis who received their first dose of daratumumab within the 4 months preceding the date of implementation (preimplementation group) or no more than 4 months after (postimplementation group) the date of implementation on April 13, 2022. Data were collected only from the first eight once per week doses of daratumumab. The primary outcome was the incidence of infusion-related reactions. Data analyzed used descriptive statistics. Nearly all patients (95.9%) received daratumumab by SC route of administration. Of the 97 patients in the preimplementation group, >90% received premedications throughout cycles 1 and 2, and five patients (5.2%) experienced infusion reactions. Of 72 patients in the postimplementation group, <20% received premedications during cycle 2 and three patients (4.2%) experienced infusion reactions. All infusion reactions occurred within the first daratumumab cycle, indicating elimination of cycle 2 premedications did not cause any infusion reactions. No patient experienced more than one infusion reaction. Omission of premedications after cycle 1 of daratumumab did not increase the incidence of infusion. Premedications may safely be omitted after cycle 1 of daratumumab when administered by the SC route.

P989 Switching from intravenous to subcutaneous vedolizumab in patients with inflammatory bowel disease in clinical remission: a multicenter study from GETECCU

Abstract Background Despite the established use of intravenous (IV) vedolizumab for treating inflammatory bowel disease (IBD), there's growing interest in exploring the advantages of the novel subcutaneous (SC) administration route. However, comprehensive real-world evidence regarding the extended safety and effectiveness of this approach remains scarce. The aim of the study was to evaluate the effectiveness and safety of vedolizumab SC among IBD patients in clinical remission. Methods Multicenter, observational, retrospective study. IBD patients on IV vedolizumab treatment across 24 Spanish hospitals who were in clinical remission were given the option to switch to SC injections or continue with IV treatment. Data encompassing clinical disease activity (assessed through partial Mayo score, and Harvey-Bradshaw Index), biochemical markers (C-reactive protein and fecal calprotectin), adverse events and treatment persistence were retrospectively gathered from prospectively maintained clinical records at baseline, and at weeks 12, 24, and 48. Non-parametric tests were used for comparisons and Kaplan-Meier for survival. Results We identified 166 patients, with 19 excluded due to not being in clinical remission and 8 excluded due to absence of follow-up data, resulting in a final inclusion of 139 patients for analysis. Of these, 36 (25.9%) remained on IV vedolizumab, while 103 (74.1%) switched to SC vedolizumab. Both groups exhibited comparable demographic characteristics including age, gender, disease type, disease duration and extension, previous therapy, presence of extra intestinal manifestations and comorbidities (Table 1). However, there were differences in Crohn’s disease behavior among groups (p=0.013). There were not significant differences in clinical, biochemical and fecal calprotectin remission at week 12, 24 and 48 neither in the overall cohort nor assessing Crohn’s disease or ulcerative colitis separately (Figure 1). At the end of follow-up, median duration 47 weeks (29-49), persistence on the same formulation was 85%,1 (2.8%) patient on IV and 4 (3.9%) on SC withdrew the drug (p=0.810), 5 (4.8%) switched back to IV from SC. Adverse events were reported in 1 (2.8%) IV vs 11 (10.7%) SC vedolizumab (p=0.292), most of them being mild skin reactions to SC injection 3 (2.9%). Conclusion In our study we found that transitioning from IV to SC vedolizumab in patients with IBD in remission showed comparable effectiveness in maintaining disease remission. Switching to SC formulation appears safe with no new safety signals identified and most adverse events being mild.

Transition from intravenous to subcutaneous biological therapies in inflammatory bowel disease: An online survey of patients.

The transition from in-hospital intravenous administration to subcutaneous therapies to treat inflammatory bowel disease (IBD) can raise some concerns among patients due to the self-administration concerns, the management of potential side effects and the overall worries related to a change of treatment. This study aimed at evaluating patients' opinion about the switch from intravenous to subcutaneous formulations and their knowledge on new available therapeutic options. We conducted a survey using a questionnaire prepared by a team of gastroenterologists and nurses working at the IBD unit. It consists of 31 items and has been divided into four sections: descriptive, commitment, knowledge and passage mode opinion. The questions were formulated in Italian and conceived according to daily consultations with patients in everyday practice, without any previous piloting or specific medical literature reference. The survey was administered to consecutive IBD patients in intravenous biological treatment; patients currently or previously treated with subcutaneous therapy were excluded. Four hundred questionnaires were distributed to participants. As many as 311 patients (77.7%) completed the survey, while the remaining were excluded from the analysis; 155 (49.8%) patients were favorable to switch from intravenous to subcutaneous therapy, while only 78 (25.1%) disagreed. In univariate and multi-variate analysis, the approval rate for home therapy was significantly associated with the distance from the IBD center and work/family/personal commitments. Surprisingly, only a quarter of the IBD patients knew that almost all available therapeutic agents have a subcutaneous administration route. Regarding patients' opinion on the efficacy of subcutaneous administration of biological agents compared to intravenous drugs, 194 (63%) had no definite idea, while 44 (14%) believed that the effectiveness could be reduced. The transition from in-hospital to subcutaneous therapeutic management of biological therapy at home was generally viewed favorably by patients, especially if they have commitments or were residents far from the IBD center.

Clinical Pharmacology Approaches to Support Approval of New Routes of Administration for Therapeutic Proteins.

Intravenous or subcutaneous routes of administration (ROAs) are common dosing routes for therapeutic proteins. Eleven therapeutic proteins with approval for one ROA have subsequently received approval for a second ROA. The clinical programs supporting the second ROA consistently leveraged data from the first ROA and included studies that characterized the pharmacokinetics (PKs) of the drug administered by the new ROA to identify an appropriate dosage regimen. The selected dosing regimen was then further evaluated in clinical trials designed with various primary end points. All programs implemented model-informed drug development approaches to ensure that the selected regimens would achieve comparable systemic exposures (PK-based bridging) or pharmacodynamic (PD) responses (PD-based bridging) as the reference ROA. To support the approval of a second ROA, these programs either demonstrated noninferiority in PK, PD, and/or clinical end points for the second ROA, or established efficacy and safety through a comparison to a placebo treatment. The accumulative examples showed that clinical trials which provided the primary evidence to support approvals of the second ROA generally demonstrated noninferiority in the systemic exposures regardless of being specified as an end point or not in the study protocols. The experience to date supports the use of PK- and PD-based bridging approaches not only in the selection of dosing regimens for a second ROA to be tested in clinical studies, but also for providing evidence of effectiveness to support approval, when appropriate.

Ketamine for Adults With Treatment-Resistant Depression or Posttraumatic Stress Disorder: A 2023 Update

What Is the Issue?&#x0D; &#x0D; Many drug treatments are available for depression, but 22% of people in Canada with the condition have treatment-resistant depression (TRD). For people with TRD, standard drug treatments do not improve their symptoms or do not work for long, and their depression persists.&#x0D; Posttraumatic stress disorder (PTSD) is a disabling mental health condition that affects about 9% of people in Canada in their lifetime. Few drugs are available for treating PTSD, none of which are considered effective.&#x0D; Ketamine is a hallucinogenic drug used primarily for anesthesia. Ketamine has also been explored for other indications, such as TRD and PTSD, generating questions about whether it could be a treatment option for these conditions.&#x0D; &#x0D; What Did We Do?&#x0D; &#x0D; We conducted a review of the clinical effectiveness, cost-effectiveness, and evidence-based guidelines on the use of ketamine in adults with TRD or PTSD, to help guide decisions on the use of ketamine for managing these conditions.&#x0D; An information specialist conducted a search of peer-reviewed and grey literature sources published in March 2022 or later. One reviewer screened citations and selected and critically appraised the included studies.&#x0D; CADTH engaged a patient with lived experience of TRD who shared their experiences and perspectives on ketamine-assisted psychotherapy. These perspectives helped us to contextualize the literature and appreciate nuances of the experience.&#x0D; &#x0D; What Did We Find?&#x0D; &#x0D; Ketamine could lead to an immediate improvement in depressive symptoms and suicidal ideation compared to placebo or midazolam in adults with TRD. The longest follow-up was 90 days, and the longest lasting effect after a dose was 28 days. Serious side effects of ketamine — such as dissociation — were rare and short-lived, lasting hours, in adults with TRD.&#x0D; It is uncertain if ketamine is an effective and safe treatment for symptoms of PTSD, due to little to no evidence suggesting its effectiveness or safety against placebo, midazolam, or opioids.&#x0D; Most studies evaluated ketamine given intravenously, and we found limited evidence on intramuscular (IM), subcutaneous, and intranasal routes of administration. We found no studies on oral or sublingual administration of ketamine and no studies comparing the different ways that ketamine can be given for TRD or PTSD.&#x0D; An economic evaluation found that IV ketamine was likely to be cost-effective compared to intranasal esketamine in adults with TRD from a health care perspective in the US. However, from a patient perspective, IV ketamine was unlikely to be cost-effective compared to esketamine, due to comparable levels of clinical effectiveness and lower costs of esketamine attributable to commercial insurance coverage and manufacturer assistance programs.&#x0D; A US guideline on TRD suggests ketamine as augmentation to antidepressants. A US guideline on PTSD does not suggest the use of ketamine as therapy.&#x0D; The patient contributor CADTH engaged for this review highlighted the benefits, stigma, and barriers of ketamine therapy, including financial implications.&#x0D; &#x0D; What Does This Mean?&#x0D; &#x0D; There is some clinical effectiveness and cost-effectiveness evidence and a guideline recommendation to support the short-term use of ketamine in adults with TRD.&#x0D; Clinical effectiveness evidence and a guideline recommendation do not support the use of ketamine in adults with PTSD.&#x0D; Future research is necessary to understand the effectiveness and safety of ketamine as therapy for TRD in larger populations over longer periods and for PTSD for any follow-up duration.&#x0D; Decision-makers should consider offering ketamine in an equitable manner.&#x0D;

Subcutaneous Marzeptacog Alfa (Activated) for On-Demand Treatment of Bleeding Events in Subjects With Hemophilia A or B With Inhibitors.

Marzeptacog alfa (MarzAA) is under development for subcutaneous treatment of episodic bleeds in patients with hemophilia A/B and was studied in a phase III trial evaluating MarzAA compared with standard-of-care (SoC) for on-demand use. The work presented here aimed to evaluate MarzAA and SoC treatment of bleeding events on a standardized four-point efficacy scale (poor, fair, good, and excellent). Two continuous-time Markov modeling approaches were explored; a four-state model analyzing all four categories of bleeding improvement and a two-state model analyzing a binarized outcome (treatment failure (poor/fair), and treatment success (good/excellent)). Different covariates impacting improvement of bleeding episodes as well as a putative relationship between MarzAA exposure and improvement of bleeding episodes were evaluated. In the final four-state model, higher baseline diastolic blood pressure and higher age (> 33 years of age) were found to negatively and positively impact improvement of bleeding condition, respectively. Bleeding events occurring in knees and ankles were found to improve faster than bleeding events at other locations. The covariate effects had most impact on early treatment success (≤ 3 hours) whereas at later timepoints (> 12 hours), treatment success was similar for all patients indicating that these covariates might be clinically relevant for early treatment response. A statistically significant relationship between MarzAA zero-order absorption and improvement of bleedings (P < 0.05) were identified albeit with low precision. No statistically significant difference in treatment response between MarzAA and intravenous SoC was identified, indicating the potential of MarzAA for treatment of episodic bleeding events with a favorable subcutaneous administration route.

Recent advances and future perspectives of T-cell engagers in lymphoid malignancies.

Bispecific antibodies (BsAbs) are monoclonal antibodies that simultaneously bind to a specific antigen on tumors and CD3 on T cells, leading to T cell activation and subsequent tumor cell lysis. Several CD20×CD3 BsAbs are being developed for B-cell lymphomas. Furthermore, multiple clinical trials to evaluate BsAbs for the treatment of multiple myeloma, with targets including BCMA, GPRC5D and FcRH5, are ongoing. Emerging evidence suggests promising efficacy in heavily pretreated patients with relapsed or refractory lymphoid malignancies, showing an overall response rate of 50-60%, with complete response rates of 30-40% for relapsed or refractory large B-cell lymphoma and 60-70% for relapsed or refractory multiple myeloma. Their toxicity profiles are generally consistent with other T-cell redirecting therapies, including cytokine release syndrome, which may be mitigated with several strategies, such as step-up dosing, pre-mediation with glucocorticoids and a subcutaneous route of administration, and very rare neurotoxicity. Several clinical trials evaluated BsAbs in combination with other agents or in earlier lines of treatment, including in front-line settings. BsAbs have the potential to change the treatment paradigm of lymphoid malignancies in the coming years; however, longer follow-ups are required to assess the durability of responses to these agents. We herein provide an overview of the findings of recent clinical trials on BsAbs, including mechanisms of action, safety profiles, and efficacy, and discuss the role of BsAbs in the treatment of B-cell lymphomas and multiple myeloma.