BACKGROUND: The non-inferiority of the efficacy of subcutaneous (SC) vs intravenous (IV) administration of natalizumab (NTZ) once every 4 weeks in relapsing-remitting multiple sclerosis (RRMS) was recently demonstrated on the primary outcome of the REFINE study, i.e. MRI \"combined unique active lesions number\" (CUAL). To provide further evidence on the comparative efficacy of the two NTZ formulations, the effect of NTZ-SC vs NTZ-IV on annualized relapse rate (ARR) was investigated re-analysing the REFINE dataset.
METHODS: Post-hoc analysis of the REFINE study dataset aimed at exploring the non-inferiority of the efficacy of NTZ-SC vs NTZ-IV on ARR, i.e. the main secondary outcome of the REFINE study. Robustness of the non-inferiority analysis on CUAL with respect to the presence of cases from the SC arm who received a rescue treatment, including NTZ-IV, was also assessed by sensitivity analyses. Three non-inferiority margins were selected, corresponding to 25 %, 33 %, and 50 % fractions of the effect size of NTZ-IV vs placebo observed in the AFFIRM study on ARR (i.e. 0.125, 0.170, and 0.250).
RESULTS: Ninety-nine RRMS patients were included. The mean difference in the effect of NTZ-SC vs NTZ-IV on ARR was close to 0. The lower bound of the 95 % confidence interval (worst case scenario) was -0.119, corresponding to 25 % (p = 0.025) of the effect of NTZ-IV vs placebo on ARR. Sensitivity analyses confirmed the results of the primary non-inferiority analysis on the outcome CUAL.
CONCLUSIONS: NTZ-SC resulted not inferior to NTZ-IV on ARR for all the non-inferiority margins. The non-inferiority analysis of the efficacy of NTZ-SC vs NTZ-IV on CUAL was demonstrated to be robust with respect to rescued patients.

OBJECTIVE: While there are compelling arguments for developing subcutaneous allergen-specific immunotherapy for alleviation of food allergies, there is a limited number of studies in the public domain. The review seeks to present the approaches taken, to explain the paucity of studies, and to identify new roads for development.
RESULTS: A literature search revealed clinical trials of immunotherapy of food allergies to fish and peanut, but studies had limited patient numbers, short treatment courses and follow-up periods. Indications, but no clearcut effects, were seen with both classical allergen extracts and hypo-allergenic preparations. A special case is the influence on cross-reactive food allergies, when subcutaneously administered birch-pollen extracts are used for treatment of birch pollen hayfever and/or asthma. Again indications, but no convincing efficacy has been registered. Newer developments include recombinant hypoallergens and DNA-technologies. Subcutaneous immunotherapy for food allergies has not matured to provide clinically relevant treatment opportunities.

Bermekimab is a human-derived recombinant monoclonal antibody that exhibits immunoregulatory activity by specifically blocking interleukin-1α activity. Four phase 2 studies evaluated efficacy and safety of bermekimab in patients with moderate-to-severe atopic dermatitis (AD). In addition, a novel human skin explant model was developed to assess bermekimab pharmacokinetics/pharmacodynamics and proteomic/transcriptomic effects. Study 1 (NCT03496974, N = 38) was an open-label, dose escalation study of subcutaneous bermekimab (200 mg or 400 mg). Study 2 (NCT04021862, N = 87) was a double-blind, placebo-controlled, randomized (1:1:1) study of subcutaneous bermekimab (400 mg every week (qw) or every 2 weeks) or placebo. GENESIS (NCT04791319, N = 198) was a double-blind, placebo- and active-comparator-controlled, randomized (1:1:2:2) study of placebo, subcutaneous bermekimab (350 mg or 700 mg qw), or dupilumab. LUNA (NCT04990440, N = 6) was a double-blind, placebo-controlled, randomized (4:1) study of intravenous bermekimab 800 mg qw or placebo. A novel human ex vivo skin pharmacodynamic assay supported phase 0 (NCT03953196) and phase 1 (NCT04544813) studies. In Study 1, 400 mg subcutaneous bermekimab showed improvement in efficacy assessments (e.g., ≥ 75% improvement of EASI over baseline, IGA 0/1, and worst itch); however, efficacy was not confirmed in Study 2 or GENESIS. Consequently, GENESIS and LUNA were terminated early. The novel human ex vivo skin pharmacodynamic assay demonstrated that bermekimab reduced downstream skin injury responses. Although bermekimab showed potential as an AD treatment in preclinical and early open-label trials, larger controlled studies (Study 2 and GENESIS) did not confirm those initial results.

BACKGROUND: Subcutaneous (SC) administration of fentanyl allows for rapid dose titration to treat urgent cancer-related pain. After establishing the optimal fentanyl dose, patients typically rotate towards transdermal (TD) fentanyl patches. Continuing the SC fentanyl up to 12h after application of the patch led to elevated fentanyl concentrations and fentanyl-related toxicities. Based on these findings, and simulations using a pharmacokinetic (PK) model, SC fentanyl administration was discontinued immediately following the application of the patch.
OBJECTIVE: To validate the fentanyl rotation schedule by assessing the PK equivalence in fentanyl exposure before and after rotation.
METHODS: PK samples and clinical data were prospectively collected from 12 hours prior to rotation until 12 hours after rotation in patients with cancer-related pain undergoing fentanyl rotation.
RESULTS: Between December 2021 and September 2023, 29 evaluable patients were enrolled in the study. The 90% confidence interval (CI) of the geometric mean ratio between the post- over pre-rotation area under the curve (AUC) fell within the prespecified 0.8 - 1.25 equivalence interval (90% CI: 1.05 - 1.16). Patient-reported intensity of both nausea (p = 0.047) and transpiration (p= 0.034) decreased post-rotation. Pain intensity and other adverse events did not differ significantly pre- and post-rotation. One patient needed adjustment of opioid therapy 40 hours after rotation due to fentanyl-related toxicities.
CONCLUSIONS: The updated rotation scheme, implying a 1:1 dose conversion and discontinuation of SC fentanyl directly after rotation, resulted in equivalent fentanyl exposure pre- and post-rotation. Moreover, the dosing regimen showed to be safe and efficacious during rotation. The new dosing regimen when rotating from SC to TD fentanyl can be effectively and safely implemented in routine palliative care.

BACKGROUND: Lenacapavir is a long-acting HIV-1 capsid inhibitor for treatment of HIV-1 infection. We evaluated the efficacy and safety of lenacapavir in combination with an investigator-selected optimized background regimen (OBR) after 104 weeks in adults with multidrug-resistant HIV-1.
METHODS: This ongoing, international, Phase 2/3 trial at 42 sites included 72 adults living with multidrug-resistant HIV-1. Following a 2-week oral lenacapavir loading phase, participants received subcutaneous lenacapavir every 26 weeks with an OBR. HIV-1 RNA, CD4 cell counts, and adverse events were assessed over 104 weeks. One participant did not enter the extension phase.
RESULTS: At Week 104, 44 of 71 participants (62%, 95% CI 50; 73) had HIV-1 RNA <50 copies/mL via US Food & Drug Administration (FDA) snapshot algorithm. When missing data (including discontinuations) were excluded, 44 of 54 participants (82%) had HIV-1 RNA <50 copies/mL at Week 104, mean CD4 cell count increased by 122 cells/µL (95% CI 80; 165), and the proportion of participants with CD4 cell count <200 cells/µL decreased from 64% (46 of 72) at Baseline to 29% (16 of 55). Fourteen participants had treatment-emergent lenacapavir resistance; seven resuppressed (HIV-1 RNA <50 copies/mL) while maintaining lenacapavir use. There were no Grade 4 or serious treatment-related adverse events. One participant discontinued study drug due to an injection site reaction.
CONCLUSIONS: Treatment with subcutaneous lenacapavir in combination with an OBR was well tolerated and resulted in a high rate of virological suppression over 104 weeks. Lenacapavir represents an important treatment option in people with multidrug-resistant HIV-1.

This study\'s goal was to evaluate the biocompatibility of two composite cements over a 90-day period by analyzing the individuals\' behavior as well as conducting macroscopic and histological examinations and Computed Tomography (CT) scans. We conducted the cytotoxicity test by placing the materials subcutaneously and peri/intramuscularly. Days 30 and 90 were crucial for our research. On those days, we harvested the implants, kidneys and liver to search for any toxic deposits. The biomaterial\'s uniformity, color and texture remained unaltered despite being in intimate contact with the tissue. Although a slight inflammatory response was observed in the placement location, we observed an improved outcome of the interaction between the material and its insertion area. There were no notable discoveries in the liver and kidneys. According to the obtained results, the biomaterials did not produce any clinical changes nor specific irritation during the research, demonstrating that they are biocompatible with biological tissues.

This narrative review aims to summarise the information available on the use of subcutaneous (SC) levetiracetam (LEV) in the adult palliative care setting using clinical texts, databases, journals, and grey literature. A search strategy utilising Embase, Medline CINALH and Cochrane databases, as well as Google Scholar, was conducted with the mapped search terms \"levetiracetam\", \"subcutaneous\" and \"palliative\". LEV intravenous (IV) proprietary products are used subcutaneously, including as continuous subcutaneous infusions (CSCIs), in the adult palliative care setting. The total LEV daily dose ranged from 250 mg to 5000 mg and LEV was administered with various diluents at varying volumes. The data identified a clinical desire to mix LEV with other medications; however, the current evidence on combination compatibility is observational only and drug stability in combinations is lacking. The majority of information in the literature on SC LEV use is based on case reports and retrospective audits. Case reports, whilst at times offering more clinical detail, represent specific circumstances not necessarily applicable to a larger patient cohort. The findings of retrospective audits are limited by the documentation and detail reported at the time of patient care that may not be designed for data collection.

Subcutaneous (SC) injection is a common route of administration for drug compounds with poor oral bioavailability. However, bioavailability is often variable and incomplete, and there is as yet no standard accepted medium for simulation of the human SC environment. In this work we evaluate a FRAP based method for quantitative determination of local self-diffusion coefficients within extracellular matrix (ECM) mimetic hydrogels, potentially useful as in vitro models for drug transport in the ECM after SC injection. Gels were made consisting of either agarose, cross-linked collagen (COL) and hyaluronic acid (HA) or cross-linked HA. The diffusivities of uncharged FITC-dextran (FD4), the highly charged poly-lysine (PLK20) and poly-glutamic acid (PLE20) as well as the GLP-1 analogue exenatide were determined within the gels using FRAP. The diffusion coefficients in uncharged agarose gels were in the range of free diffusion in PBS. The diffusivity of cationic PLK20 in gels containing anionic HA was substantially decreased due to strong electrostatic interactions. Peptide aggregation could be observed as immobile fractions in experiments with exenatide. We conclude that the FRAP method provides useful information of peptides\' interactions and transport properties in hydrogel networks, giving insight into the mechanisms affecting absorption of drug compounds after subcutaneous injection.

OBJECTIVE: Switching from the intravenous to the subcutaneous biosimilar infliximab (SC-IFX) has been shown to safely maintain clinical remission and increase drug levels in patients with Crohn\'s disease (CD) and ulcerative colitis (UC). The aim of this study was to evaluate long-term outcomes after switching from intravenous IFX (IV-IFX) to SC-IFX, the drug concentration thresholds for maintaining remission and other predictors for loss of response after the switch.
METHODS: Multicenter observational study involving CD and UC patients who were in clinical remission for at least 24 weeks and scheduled to switch from IV-IFX to SC-IFX.
RESULTS: Two hundred and twenty patients were included [74 UC (34%) and 146 (66%) CD]. IV-IFX was administered for 52.5 months [range 25-89]. Pre-switch, 106 (49%) patients were receiving intensified IV-IFX. While SC-IFX levels significantly increased following the switch from IV to SC-IFX, clinical parameters, C-reactive protein and faecal calprotectin remained unchanged during follow-up. SC-IFX levels were significantly higher between patients receiving the standard IV-IFX dose than those with the intensified dose. Immunomodulator therapy at baseline and perianal disease had no effect on IFX trough levels, whereas higher body mass index was associated with increased levels. The suggested optimal SC-IFX cut-off concentration for clinical and biochemical remission based on ROC analysis was 12.2 μg/mL (AUC: 0.62) at week 12 and 13.2 μg/mL (AUC: 0.57) at week 52. Drug persistence was 92% at week 52, with a good safety profile.
CONCLUSIONS: Switching from IV-IFX to SC-IFX safely maintains long-term remission in patients with CD and UC. In maintenance, the optimal cut-off point associated with remission was 12-13 μg/mL.

In recent decades, subcutaneous (SC) administration of monoclonal antibodies (mAbs) has emerged as a promising alternative to intravenous delivery in oncology, offering comparable therapeutic efficacy while addressing patient preferences. This perspective article provides an in-depth analysis of the technological landscape surrounding SC mAb administration in oncology. It outlines various technologies under evaluation across developmental stages, spanning from preclinical investigations to the integration of established methodologies in clinical practice. Additionally, this perspective article explores emerging trends and prospective trajectories, shedding light on the evolving landscape of SC mAb administration. Furthermore, it emphasizes key checkpoints related to quality attributes essential for optimizing mAb delivery via the SC route. This review serves as a valuable resource for researchers, clinicians, and healthcare policymakers, offering insights into the advancement of SC mAb administration in oncology and its implications for patient care.