Subcutaneous Route Of Administration Research Articles

Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site.

The subcutaneous administration route is widely used to administer different types of drugs given its high bioavailability and rapid onset of action. However, the sensation of pain at the injection site might reduce patient adherence. Apart from a direct effect of the drug itself, several factors can influence the sensation of pain: needle features, injection site, volume injected, injection speed, osmolality, viscosity and pH of formulation, as well as the kind of excipients employed, including buffers and preservatives. Short and thin needles, conveniently lubricated and with sharp tips, are generally used to minimize pain, although the anatomic injection site (abdomen versus thigh) also affects the sensation of pain. Large subcutaneous injection volumes are associated with pain. In this sense, the maximum volume generally accepted is around 1.5 ml, although volumes of up to 3 ml are well tolerated when injected in the abdomen. Injected volumes of up to 0.5–0.8 ml are not expected to increase substantially the pain produced by the needle insertion. Ideally, injectable products should be formulated as isotonic solutions (osmolality of about 300 mOsm/kg) and no more than 600 mOs/kg have to be used in order to prevent pain. A pH close to the physiological one is recommended to minimize pain, irritation, and tissue damage. Buffers are frequently added to parenteral formulations to optimize solubility and stability by adjusting the pH; however, their strength should be kept as low as possible to avoid pain upon injection. The data available recommend the concentration of phosphate buffer be limited to 10 mM and that the concentration of citrate buffer should be lower than 7.3 mM to avoid an increased sensation of pain. In the case of preservatives, which are required in multiple-dose preparations, m-cresol seems to be more painful than benzyl alcohol and phenol.Funding: Sandoz SA.

The development of an oral GLP-1 receptor agonist for the management of type 2 diabetes: evidence to date.

Glucagon-like peptide 1 receptor agonists (GLP1-RA) are prominent agents in the therapeutics of type 2 diabetes mellitus due to their exemplary efficacy in both preprandial and postprandial glycemia, their safety, low risk of hypoglycemia, their multilevel pathophysiological superiority, weight loss and importantly the observed benefits in cardiovascular disease reduction. Their major drawback is the subcutaneous route of administration, constituting a barrier to adoption and reason for treatment discontinuation. Thus, the development of an oral GLP1-RA agent would promote medication adherence and quality of life, further consolidating its beneficial effects in real-life clinical practice. However, this task is hampered by suboptimal gastrointestinal protein absorption. Yet, the introduction of oral semaglutide, a modified form of semaglutide with the addition of a carrier sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, may have provided a safe and effective way to reach systemic circulation while other molecules are in development. Whether this molecule still has the impressive cardiovascular effects demonstrated with the use of its precursor remains to be explored. However, to date, its efficacy and safety have already been showcased in a randomized trial. More research is warranted in order to further consolidate these findings across different type 2 diabetes mellitus (T2DM) subpopulations, and adequately powered studies with a longer follow-up that would allow the exploration of microvascular and macrovascular complications are needed. Finally, studies comparing oral semaglutide and similar molecules with other currently established antidiabetic agents to evaluate the relative efficacy, the cost-effectiveness and further understand its place in T2DM therapeutic algorithm are needed. This review focuses on the development of oral GLP1-RA agents and summarizes the challenges, milestones and expected benefits associated with a successful introduction.

Current therapeutic applications and pharmacokinetic modulations of ivermectin.

Ivermectin is considered to be a wonder drug due to its broad-spectrum antiparasitic activity against both ectoparasites and endoparasites (under class of endectocide) and has multiple applications in both veterinary and human medicine. In particular, ivermectin is commonly used in the treatment of different kinds of infections and infestations. By altering the vehicles used in the formulations, the pharmacokinetic properties of different ivermectin preparations can be altered. Since its development, various vehicles have been evaluated to assess the efficacy, safety, and therapeutic systemic concentrations of ivermectin in different species. A subcutaneous route of administration is preferred over a topical or an oral route for ivermectin due to superior bioavailability. Different formulations of ivermectin have been developed over the years, such as stabilized aqueous formulations, osmotic pumps, controlled release capsules, silicone carriers, zein microspheres, biodegradable microparticulate drug delivery systems, lipid nanocapsules, solid lipid nanoparticles, sustained-release ivermectin varnish, sustained-release ivermectin-loaded solid dispersion suspension, and biodegradable subcutaneous implants. However, several reports of ivermectin resistance have been identified in different parts of the world over the past few years. Continuous use of suboptimal formulations or sub-therapeutic plasma concentrations may predispose an individual to resistance toward ivermectin. The current research trend is focused toward the need for developing ivermectin formulations that are stable, effective, and safe and that reduce the number of doses required for complete clinical cure in different parasitic diseases. Therefore, single-dose long-acting preparations of ivermectin that provide effective therapeutic drug concentrations need to be developed and commercialized, which may revolutionize drug therapy and prophylaxis against various parasitic diseases in the near future. The present review highlights the current advances in pharmacokinetic modulation of ivermectin formulations and their potent therapeutic applications, issues related to emergence of ivermectin resistance, and future trends of ivermectin usage.

Underutilization of the Subcutaneous Route of Administration

Therapeutic proteins have become an important part of treatment, particularly for serious and chronic diseases, and the subcutaneous (SC) route of administration has become a more popular, yet still underutilized mode of delivery. The extracellular matrix of the hypodermis is composed of a network of fibrous proteins (e.g., collagen and elastin) embedded within a viscoelastic gel. The viscoelastic gel is composed of glycosaminoglycans and proteoglycans that create resistance to bulk fluid flow in the SC space. The primary glycosaminoglycan is the highly hydrated hyaluronan, a mega-dalton polymer of repeating disaccharide units of N-acetylglucosamine and glucuronic acid.

MON-152 Less Is More: Human Regular U-500 Insulin

Introduction: Human Regular U-500 Insulin is used to control high blood glucose in diabetic patients who need more than 200 units of insulin daily. High-dose insulin therapy may be limited because the volumes of insulin necessary to achieve these very high doses are difficult to administer subcutaneous and there is a decrease in the absorption rate. We report a case of a woman with DM2 and severe insulin resistance who achieved glycemic control using off-label U-500 via continuous subcutaneous insulin infusion (CSII) but with fixed bolus given manually by patient and remained controlled over the next six years. Clinical Case: A 66-year-old woman with DM2, HTN, metabolic syndrome and adiposity based chronic disease referred to endocrinologist office for glycemic control. Patient treated for diabetes with metformin and premixed insulin and HTN treated with CCB/ACE inhibitor and beta blocker/thiazide combinations. Clinical examination reveals an obese female (BMI: 37.9kg/m2) with acanthosis nigricans. Initial laboratory test showed HbA1c of 13.9%, FBS 293mg/dL, cholesterol 195mg/dL, TGs 147mg/dL and LDL 103mg/dL. Patient was treated with multiple insulin regimens, including U-500 insulin by subcutaneous route of administration and oral antihyperglycemic agents including followed up by nutritionist, where the lowest HbA1c was 9.1%. Patient total daily dose of insulin was 220 units. Although U-500 insulin is not FDA-approved for use in CSII and the ideal candidate should be intellectually able to deal with insulin pump therapy, this treatment was effective for our patient who required high insulin doses and failing other treatment regimen, achieving glycemic control and weight loss in six weeks. The only way this patient used this mode of insulin administration was on a single basal rate and fixed insulin bolus doses before each meal and with bedtime snack. All of these parameters were adjusted by 5 for the use of concentrated insulin in the pump device. HbA1c decreased from 10.5% to 8.5% with only six weeks of treatment and at one year decreased to even more 7.0%. Currently patient had been using CSII with U-500 for six years and patient HbA1c range is between 7.5-7.9% evaluated approximately every 3 months. Conclusion: The increase in the prevalence of obesity and diabetes has been an issue in treating patients who require high doses of insulin. The use of U-500 for CSII allows for better absorption of high insulin doses and improvement of glycemic control thus improving quality of life, weight loss, decreasing multiple daily injections and preventing diabetes complications. To our knowledge this is the first case report demonstrating long-term glycemic control with U-500 via CSII and on a fixed dose regimen on CSII without using carb counting or corrections to make this regimen easier for certain patients without the knowledge for complicated regimens.

Patients beliefs on intravenous and subcutaneous routes of administration of biologics for severe asthma treatment: A cross-sectional observational survey study

BackgroundUnderstanding how patients generate preferences for administration route alternatives may improve health-care delivery and clinical outcomes. Recently, novel biological therapies with subcutaneous (SC) and intravenous (IV) administration routes have been approved for severe uncontrolled asthma. The aim of our study was to assess the preferred route of biologic therapy administration and related beliefs among patients with severe uncontrolled asthma. MethodsWe conducted a cross-sectional observational survey study. Patients answered an anonymous, self-administered questionnaire after an outpatient visit in pulmonary disease clinics located throughout Italy. Socio-demographic and clinical information together with the 12-Item Short Form Survey (SF-12), Work Productivity Impairment Scale and the medical resources utilization module of the Health & Work Survey were collected. Patients beliefs and preference towards SC and IV administration were investigated by means of an ad hoc 13 item questionnaire. Results: the main findings150 patients fulfilled the inclusion criteria and completed the questionnaire (47.3% males). Preference for IV and SC administration was 18.7% and 81.3%, respectively. Compared with patients preferring SC formulation, patients that favored IV were older (p ​= ​0.04), less likely to escalate corticosteroid dose (p ​= ​0.03) and had emergency room (ER) access (p ​= ​0.009) during asthma exacerbations. Patients felt that SC was more convenient than IV, but this belief was not associated with higher likelihood of preferring SC administration. IV formulations were more likely associated with quicker and more effective drug action (p ​= ​0.0001), procedural safety and medical oversight (p ​= ​0.0002) and social support (p ​= ​0.007). Predictors of IV preference were represented by the association of worse asthma control and increased use of ER services, and by beliefs toward formulation effectiveness/efficiency in reducing symptoms (p ​= ​0.04 and p ​< ​0.0001, respectively). The model achieved excellent discrimination of administration route preference (area under the curve ​= ​0.87). ConclusionsPreference is guided by partially misleading beliefs, which may generate wrong expectations that in turn can affect treatment satisfaction and adherence. Convenience and efficacy beliefs for drugs with different routes of administration always should be discussed with patients to achieve informed shared-decision making. Trial registrationNot applicable.

Intradermal delivery of vaccine nanoparticles using hollow microneedle array generates enhanced and balanced immune response

Hollow microneedles can help overcome the skin permeation barrier imposed by the stratum corneum and facilitate transcutaneous delivery of nanoparticle delivery systems. In the present study, we investigated the use of the hollow microneedle array for intradermal delivery of polymeric nanoparticles (NPs) in rats. Compared to intravenous and subcutaneous routes of administration, intradermal delivery of polymeric NPs via a hollow microneedle array resulted in a unique pharmacokinetic profile, characterized by an early burst transit through the draining lymph nodes and a relatively limited overall systemic exposure. Based on high local lymphatic concentrations achieved, we investigated the use of this modality for vaccine delivery. A model antigen ovalbumin (OVA) and TLR agonists imiquimod and monophosphoryl Lipid A encapsulated in poly(d,l-lactide-co-glycolide) (PLGA) NPs were used as the vaccine formulation. Compared to soluble OVA-based vaccine, OVA loaded NPs demonstrated faster antibody affinity maturation kinetics. Moreover, antigen loaded NPs delivered via a hollow microneedle array elicited a significantly higher IgG2a antibody response and higher number of interferon (IFN)-γ secreting lymphocytes, both markers of Th1 response, in comparison to antigen loaded NPs delivered by intramuscular injection and soluble antigen delivered through hollow microneedle array. Overall, our results show that hollow microneedle mediated intradermal delivery of polymeric NPs is a promising approach to improve the effectiveness of vaccine formulations.

A Novel and Potent Inhibitor of E-Selectin, GMI-1687, Attenuates Thrombus Formation and Augments Chemotherapeutic Intervention of AML in Preclinical Models Following Subcutaneous Administration

Abstract Uproleselan (GMI-1271), an E-selectin antagonist, has been shown in preclinical models to disrupt activation of cell survival pathways in acute myeloid leukemia (AML), enhance chemotherapy efficacy, and improve survival. Uproleselan received FDA breakthrough therapy designation for adult relapsed/refractory AML in 2017 and Phase III studies are ongoing. In the present studies we report on the in vitro and in vivo comparative activities of an innovative high potency E-selectin antagonist, GMI-1687, a potential subcutaneously administered follow-on drug candidate to Uproleselan. The binding constant, association and dissociation rates of GMI-1687 to immobilized recombinant human (rh) E-selectin were determined by surface plasmon resonance (SPR) at 25oC. The KD of GMI-1687 was 2.4 nM, with Kon = 3 x 106 M-1s-1 and Koff = 1 x10-2 s-1. Under similar experimental conditions the KD of Uproleselan was 520 nM with Kon = 0.02 x 106 M-1s-1 and Koff = 1 x10-2 s-1. GMI-1687 was evaluated for its ability to inhibit binding of sialyl Lea to immobilized rh E-selectin. The median IC50 (n=6 independent assays) of GMI-1687 and Uproleselan in this assay was 15 and 550 nM, respectively. The in vitro activity of GMI-1687 to release adherent KG1a AML cells from E-selectin coated wells was also determined. GMI-1687 at 100 nM detached approximately 55% of adherent AML cells and was significantly different from Uproleselan at an identical concentration (38% detachment, P=0.0216). The percent bioavailability (%F) of GMI-1687 was evaluated in male Sprague-Dawley rats following intravenous (IV) and subcutaneous (SC) routes of administration at 5 mg/kg. The mean (+/- SD) SC %F for GMI-1687 was 126 +/- 3.8%. GMI-1687 also showed high bioavailability in CD-1 mice after SC administration of 0.58 mg/kg with %F = 132 +/-38. The in vivo therapeutic activity of GMI-1687 following SC administration was assessed in an acute model of inferior vena cava (IVC) thrombosis and a tumor model of AML.Immediately following the induction of a non-occlusive thrombosis via electrical stimulation (250 mAmp) of the IVC, cohorts of male C57BL/6J mice (n=5/group) were given a single SC injection of saline (0.1 mL); Uproleselan (40 mg/kg); or GMI-1687 (4 mg/kg, 0.4 mg/kg or 0.04 mg/kg), and twenty-four hrs post thrombus induction the IVC was harvested from all mice and thrombus weights were determined. Treatment with GMI-1687 decreased thrombus formation with significant inhibition at 0.04 mg/kg (92%, P&lt;0.001 compared to saline control). The inhibition of thrombus formation with GMI-1687 dosed at 0.04 mg/kg was statistically indistinguishable from Uproleselan administered SC at 40 mg/kg (97% inhibition). The therapeutic activity of SC GMI-1687 was also observed in combination with chemotherapy in a U937 tumor model. Three days post IV injection of U937 tumor cells, bone marrow ablated, female NOD/SCID mice (n=10/group) were treated with saline (0.1 mL SC QDx14); GMI-1687 (0.04 mg/kg SC QDx14) alone; cytarabine (AraC 300 mg/kg IP QDx3) + daunorubicin (DNR 3 mg/kg IV QDx1), or the combination of GMI-1687 and AraC + DNR. All treatments were well tolerated. The median survival time (MST) of mice treated with AraC + DNR was 36 days and statistically different (P&lt;0.001) to groups treated with saline (MST=22 days) or GMI-1687 alone (MST=23 days). Importantly, the therapeutic activity of AraC+DNR was significantly enhanced when combined with GMI-1687 (MST&gt;47.5 days, P=0.0153 compared to AraC+DNR alone). In summary, a highly potent innovative antagonist of E-selectin, GMI-1687, has been produced that demonstrates high bioavailability following SC administration. SC injection of GMI-1687 shows significant activity in preclinical models previously reported for parenteral administration of Uproleselan, but at approximately 250-fold lower dose. GMI-1687 is therefore well-positioned for potential use in outpatient treatment settings where an E-selectin antagonist has therapeutic relevance. IND-enabling studies with GMI-1687 are currently underway. Disclosures Peterson: GlycoMimetics: Employment, Equity Ownership. Baek:GlycoMimetics: Employment, Equity Ownership. Locatelli-Hoops:GlycoMimetics: Employment, Equity Ownership. Lee:GlycoMimetics: Employment, Equity Ownership. Deng:GlycoMimetics: Employment, Equity Ownership. Stewart:GlycoMimetics: Employment, Equity Ownership. Smith:GlycoMimetics: Employment, Equity Ownership. Fogler:GlycoMimetics: Employment, Equity Ownership. Magnani:GlycoMimetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

DEVELOPMENT OF A PATIENT-REPORTED OUTCOME MEASURING PATIENTS’ EXPERIENCE WITH IMMUNOGLOBULIN TREATMENT

Introduction The objective of this study is to assess the impact of immunoglobulin replacement therapy (IgRT) in individuals with primary immunodeficiency diseases (PIDD) and to develop a self-reported measure evaluating patients’ experiences with IgRT, the Immunoglobulin Patient Experience with Treatment (IgPET), applicable to both subcutaneous (SC) and intravenous (IV) routes of administration (ROA) and different sites of care. Methods Cognitive interviews (CIs) were conducted with patients with PIDD in the US to better understand their experiences with and impact of IgRT and to obtain feedback on draft IgPET items. IgPET concepts were identified via literature searches for concepts applicable to all PIDD patients using IgRT. Questionnaire items were tested and refined through 3 iterative sets of CIs. Results CIs were conducted with 21 participants (females=19 [90%]; mean age [range], 42.5 [17–70] years; mean [range] years since PIDD diagnosis, 8.3 [1–26]). Approximately half of the patients were treated by each RoA. Overall, patients were generally “satisfied” with their current IgRT. The most commonly reported negative impacts of IgRT were side effects following IgRT (n=11 [52%]) and impact on social/family activities (n=6 [29%]). Impacts were generally similar across subgroups regardless of ROA or site of care. 29 items were tested in round 1, 20 in rounds 2 and 3. The final 19-item IgPET was easy to understand and answer, and important to patients’ IgRT experiences. Conclusions The IgPET is a new measure assessing patients’ experiences with IgRT. It was subsequently validated in 814 IgRT patients via a cross-sectional, observational study.

Practical management of opioid rotation and equianalgesia

PurposeTo review the recent literature on opioid rotation (ie, switching from one opioid drug to another or changing an opioid’s administration route) in cancer patients experiencing severe pain and to develop a novel equianalgesia table for use in routine clinical practice.MethodsThe MEDLINE database was searched with terms “cancer pain,” “opioid rotation,” “opioid switching,” “opioid ratio,” “opioid conversion ratio,” and “opioid equianalgesia” for the major opioids (morphine, oxycodone, fentanyl, and hydromorphone) and the intravenous, subcutaneous, oral, and transdermal administration routes. Selected articles were assessed for the calculated or cited opioid dose ratio, bidirectionality, and use of the oral morphine equivalent daily dose or a direct drug-to-drug ratio.ResultsTwenty publications met our selection criteria and were analyzed in detail. We did not find any large-scale, prospective, double-blind randomized controlled trial with robust design, and most of the studies assessed relatively small numbers of patients. Bidirectionality was investigated in seven studies only.ConclusionThe updated equianalgesic table presented here incorporates the latest data and provides information on bidirectionality. Despite the daily use of equianalgesic tables, they are not based on high-level scientific evidence. More clinical research is needed on this topic.

Chitosan/alginate microparticles for the oral delivery of fowl typhoid vaccine: Innate and acquired immunity

Oral fowl typhoid (FT) vaccine is necessary for improved flock vaccinations and economic growth. This study was undertaken to evaluate the immune responses of birds given oral fowl typhoid vaccine coated with chitosan/alginate microparticles and comparing it with the conventional subcutaneous route of administration. Preliminary studies were done to evaluate the particle size, encapsulation efficiency and agglutination. Sixty day-old chicks were divided into three groups of twenty birds each. This comprised a negative control group NEG 451 (non-vaccinated and non-challenged used as control for cytokine quantification), SC 634 (live 9R vaccine by the injection route) and OCV 567 (live 9R vaccine coated with chitosan/alginate microparticles). Vaccination was done at 10 weeks and 14 weeks of age followed by challenge at 16 weeks of age. IgG was measured using ELISA. mRNA fold expression of IFN-γ in spleen was calculated using qRT-PCR. Particle sizes ranged between 0.55 µm and 10 µm. Encapsulation efficiency was above 60%. ELISA showed E-values of 0.10 ± 0.14, 0.07 ± 0.01 and 0.02 ± 0.01 for OCV 567, SC 634 and NEG 451 respectively after primary vaccination. Also E-values were 0.25 ± 0.16, 0.19 ± 0.04 and 0.0008 ± 0.005 for SC 634, OCV 567 and NEG451 respectively after boost vaccination. The expression of IFN-γin spleen using 2−ΔΔ CT calculation was upregulated with values of 1.97 and 0.75 for OCV 567 and SC 634 respectively. After challenge with the 85-kb virulence plasmid SG9, there was 100% protection of the birds in both OCV 567 and SC 634 groups with no mortality. In conclusion, there was no significant difference at p < 0.05 of the means ± SD in immune responses between the oral fowl typhoid vaccine coated with chitosan/alginate microparticles and the subcutaneous route of administration. However, it is noteworthy to mention that the protective efficacy of the oral route is due to the chitosan/alginate biopolymers which coated the vaccine preventing destruction in the gastrointestinal tract.

Subcutaneous Immunoglobulin Replacement Therapy Experience with Intravenous Preparation

Objective: Intravenous immunoglobulin preparations have been used in the treatment of primary immunodeficiency for many years. Recently, immunoglobulin administration via the subcutaneous route has become popular. Subcutaneously administered immunoglobulin provides more stable serum immunoglobulin levels and has a lower incidence of systemic adverse effects than the intravenous route. This method increases the quality of the patient’s life by self administration or parental administration at home. Immunoglobulin preparations designed for subcutaneous administration have been available in Europe and the US since 2006. Although subcutaneous immunoglobulin preparations are not available in Turkey, the subcutaneous administration route has recently been included in the instructions of the three intravenous products with 10% concentration. Our aim was to use one of these intravenous immunoglobulin preparations via the subcutaneous route and describe its advantages and disadvantages. Materials and Methods: Six primary immunodeficiency patients were selected from our clinic. The procedure was described and informed consent obtained. They had been treated with intravenous immunoglobulin for the last few years. Their monthly immunoglobulin dosage was calculated and roughly divided into weekly doses. The first few administrations took place under medical supervision at the hospital until the patients and/or their family learned the procedure. Results: They were encouraging with fewer side effects, better life quality and lower infection rates in our small sample of patients. Conclusion: In this article, we describe our experience with 6 primary immunodeficiency patients of our clinic in whom we successfully used intravenous immunoglobulin preparation via the subcutaneous route.

Mechanisms Underlying Early-Stage Changes in Visual Performance and Retina Function After Experimental Induction of Sustained Dyslipidemia.

Visual and retinal function was measured in a mouse model of chemically induced, sustained dyslipidemia to determine the contribution of dyslipidemia to the pathogenesis of retinopathy in the context of metabolic syndrome. Fifteen male C57BL/6Crl mice were divided into three groups. Poloxamer 407 (P-407), 14.5% w/w was delivered at a rate of 6µl/day by implanted osmotic mini-pumps either subcutaneously (P-407 SQ) or intraperitoneally (P-407 IP) to P-407-treated mice, whereas saline was administered at the same rate to control mice using only the subcutaneous route of administration. Total cholesterol (TC) and true triglyceride (TG) levels were quantified from plasma. Optomotor responses to stimuli of varying spatial frequency or contrast were used to measure visual acuity and contrast sensitivity. Retinal function was determined using Ganzfeld flash electroretinography (ERG). At 32 days, TC for the P-407 IP group was significantly elevated compared to saline controls (169.4 ± 16.5mg/dl, 0.001 < P < 0.01). TG levels for both the P-407 SQ (59.3 ± 22.4mg/dl, 0.01 < P < 0.05) and P-407 IP groups (67.7 ± 18.0mg/dl, 0.001 < P < 0.01) were significantly elevated relative to controls. Electroretinography demonstrated a very significant decline in the b/a ratio (1.80 ± 0.11, P < 0.01) for the P-407 IP group. The b/a ratio exhibited a moderate, significant correlation with TC levels (r = - 0.4425, P = 0.0392) and a strong, very significant correlation with TG levels (r = - 0.6190, P = 0.0021). Delivery of P-407 via osmotic mini-pump resulted in the sustained, significant elevation of plasma TC and TG levels. This elevation in plasma lipid levels was correlated with a decline in inner retinal function.

Comparison of Usability, Accuracy, Preference, and Satisfaction Among Three Once-Weekly GLP-1 Receptor Agonist Pen Devices.

Glucagon-like peptide 1 (GLP-1) receptor agonists are relatively new additions to the treatment options available for type 2 diabetes. These agents provide glycemic control by increasing glucose-dependent insulin secretion, decreasing inappropriate glucagon secretion, slowing gastric emptying, and increasing satiety (1). The GLP-1 receptor agonists are an attractive treatment option because they are associated with weight loss and have a low risk of hypoglycemia. However, their use is limited in some patients because of gastrointestinal adverse effects (nausea, vomiting, diarrhea), cost, and their subcutaneous route of administration (1). There are currently six GLP-1 receptor agonists approved for use in the United States: exenatide (Byetta), 2005; liraglutide (Victoza), 2010; exenatide XR (Bydureon), 2012; albiglutide (Tanzeum), 2014; dulaglutide (Trulicity), 2014; and lixisenatide (Adlyxin), 2016. Many differences exist within this class of medications, including efficacy and safety profiles, dosing schedules, and preparation and administration requirements, making product selection and use potentially confusing for both health care professionals (HCPs) and patients. Dosing schedule is one important consideration when comparing GLP-1 receptor agonists. Whereas three of the GLP-1 receptor agonists are available in multi-use, disposable pen devices and are given either twice daily (exenatide) or once daily (liraglutide and lixisenatide), the other three GLP-1 receptor agonists are once-weekly formulations available in single-use, disposable pen devices (albiglutide [2], dulaglutide [3], and exenatide XR [4]). Once-weekly products may offer the advantage of better adherence and ease of use compared to once- or twice-daily medications. In clinical studies, adherence to treatment and treatment satisfaction significantly increased with once-weekly GLP-1 receptor agonists compared to once- or twice-daily GLP-1 receptor agonists (5–7). In comparing efficacy and safety of the once-weekly agents, meta-analyses and head-to-head trials demonstrate that dulaglutide showed the greatest reduction in A1C compared with other once-weekly GLP-1 receptor agonists, …

PCN59 - Budget Impact of the Introduction of Subcutaneous Rituximab to U.S. Health Plans

A recent FDA-approved formulation of rituximab offers a subcutaneous (SC) route of administration. The SC product has labeled indications for the treatment of follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). We sought to estimate the financial impact of converting rituximab eligible patients from the intravenous (IV) route of administration to SC from the perspective of a commercial health insurance plan. We created a de novo budget impact model using Microsoft® Excel in order to evaluate the costs of drug, administration, and adverse events. We applied costs across several uptake scenarios of patients receiving SC and IV rituximab within a hypothetical one-million-member health plan. We forecasted budget impact at 1, 2 and 3 years. Wholesale drug acquisition costs were used for the two drugs, while infusion and SC injection costs were estimated from the Marketscan® databases. Grade 3 and 4 adverse events occurring >5% of treated patients also were included. We estimated treatment costs and annual per-member-per-month (PMPM) in each year. To assess parameter uncertainty, we developed one-way and multi-way sensitivity analyses. Using reported incidence rates for the labeled indications, we estimate that 150 newly diagnosed patients in the hypothetical health plan would be eligible for rituximab - FL (n=56), DLBCL (n=63), or CLL (n=31). We show that rituximab treated patient costs are reduced year over year, in proportion to the change in converted market share from the IV to SC formulation. In the year with the highest conversion rate, total costs were approximately $223,000 lower translating to a PMPM decrease of $0.02. Lower CLL rituximab costs and lower administration costs were the main drivers of these cost reductions. Switching patients with FL, DLBCL and CLL from IV to SC rituximab can reduce pharmacy and overall PMPM costs for commercial health plans.

Intranasal administration of a two-dose adjuvanted multi-antigen TMV-subunit conjugate vaccine fully protects mice against Francisella tularensis LVS challenge.

Tularemia is a fatal human disease caused by Francisella tularensis, a Gram-negative encapsulated coccobacillus bacterium. Due to its low infectious dose, ease of aerosolized transmission, and lethal effects, the CDC lists F. tularensis as a Category A pathogen, the highest level for a potential biothreat agent. Previous vaccine studies have been conducted with live attenuated, inactivated, and subunit vaccines, which have achieved partial or full protection from F. tularensis live vaccine strain (LVS) challenge, but no vaccine has been approved for human use. We demonstrate the improved efficacy of a multi-antigen subunit vaccine by using Tobacco Mosaic virus (TMV) as an antigen carrier for the F. tularensis SchuS4 proteins DnaK, OmpA, SucB and Tul4 (DOST). The magnitude and quality of immune responses were compared after mice were immunized by subcutaneous or intranasal routes of administration with a TMV-DOST mixture, with or without four different adjuvants. Immune responses varied in magnitude and isotype profile, by antigen, by route of administration, and by protection in an F. tularensis LVS challenge model of disease. Interestingly, our analysis demonstrates an overwhelming IgG2 response to SucB after intranasal dosing, as well as a robust cellular response, which may account for the improved two-dose survival imparted by the tetravalent vaccine, compared to a previous study that tested efficacy of TMV-DOT. Our study provides evidence that potent humoral, cellular and mucosal immunity can be achieved by optimal antigen combination, delivery, adjuvant and appropriate route of administration, to improve vaccine potency and provide protection from pathogen challenge.

Population pharmacokinetics and probability of target attainment of ertapenem administered by subcutaneous or intravenous route in patients with bone and joint infection.

Ertapenem is a therapeutic option in patients with Gram-negative bone and joint infection (BJI). The subcutaneous (sc) route of administration is convenient in the outpatient setting and has shown favourable pharmacokinetics (PK), but available data on ertapenem are limited. To perform population PK analysis and pharmacokinetic/pharmacodynamic (PK/PD) simulation of ertapenem administered by the intravenous (iv) or sc route to patients with BJI. This was a retrospective analysis of PK data collected in patients with BJI who received iv or sc ertapenem. Measured ertapenem concentrations were analysed with a non-parametric population approach. Then, simulations were performed based on the final model to investigate the influence of ertapenem route of administration, dosage and renal function on the probability of achieving a pharmacodynamic (PD) target, defined as the percentage of time for which free plasma concentrations of ertapenem remained above the MIC (fT>MIC) of 40%. Forty-six PK profiles (13 with iv and 33 with sc ertapenem) with a total of 133 concentrations from 31 subjects were available for the analysis. A two-compartment model with linear sc absorption and linear elimination best fitted the data. Creatinine clearance was found to significantly influence ertapenem plasma clearance. Simulations showed that twice daily dosing, sc administration and renal impairment were associated with an increase in fT>MIC and target attainment. Our results indicate that 1 g of ertapenem administered twice daily, by the iv or sc route, may optimize ertapenem exposure and achievement of PK/PD targets in patients with BJI.

Lymphatic delivery of etanercept via nanotopography improves response to collagen-induced arthritis

BackgroundEvidence suggests lymphatic function mediates local rheumatoid arthritis (RA) flares. Yet biologics that target the immune system are dosed systemically via the subcutaneous (SC) administration route, thereby inefficiently reaching local lymphatic compartments. Nanotopography has previously been shown to disrupt tight cellular junctions, potentially enhancing local lymphatic delivery and potentially improving overall therapeutic efficacy.MethodWe first characterized nanotopography (SOFUSA™) delivery of an anti-TNF drug, etanercept, by comparing pharmacokinetic profiles to those obtained by conventional SC, intravenous (IV), and intradermal (ID) routes of administration, and assessed uptake of radiolabeled etanercept in draining lymph nodes (LNs) in single dosing studies. We then compared etanercept efficacy in a progressive rat model of collagen-induced arthritis (CIA), administered systemically via SC route of administration; via the regional lymphatics through ID delivery; or through a nanotopography (SOFUSA™) device at 10, 12, and 14 days post CIA induction. Measurements of hind limb swelling and near-infrared fluorescence (NIRF) imaging of afferent lymph pumping function and reflux were conducted on days 11, 13, and 18 post CIA induction and compared to untreated CIA animals. Univariate and multivariate analysis of variance were used to compare the group differences for percentage swelling and lymphatic contractile activity.ResultsEven though all three modes of administration delivered an equal amount of etanercept, SOFUSA™ delivery resulted in increased lymphatic pumping and significantly reduced swelling as compared to untreated, ID, and SC groups. Pharmacokinetic profiles in serum and LN uptake studies showed that using the nanotopography device resulted in the greatest uptake and retention in draining LNs.ConclusionsLocoregional lymphatic delivery of biologics that target the immune system may have more favorable pharmacodynamics than SC or IV administration. Nanotopography may provide a more efficient method for delivery of anti-TNF drugs to reverse impairment of lymphatic function and reduce swelling associated with RA flares.

Pharmacokinetic and pharmacodynamic modelling after subcutaneous, intravenous and buccal administration of a high-concentration formulation of buprenorphine in conscious cats.

BackgroundThe aim of this study was to describe the joint pharmacokinetic-pharmacodynamic model and evaluate thermal antinociception of a high-concentration formulation of buprenorphine (Simbadol™) in cats.MethodsSix healthy cats (4.9 ± 0.7 kg) were included in a prospective, randomized, blinded, crossover study. Simbadol™ (1.8 mg mL-1) was administered by the subcutaneous (SC; 0.24 mg kg-1), intravenous (IV; 0.12 mg kg-1) or buccal (OTM; 0.12 mg kg-1) route of administration and thermal thresholds (TT) were compared with a saline group (SAL). Thermal threshold testing and blood sampling were performed at predetermined time points up to 72 hours including a placebo group. Plasma buprenorphine and norbuprenorphine concentrations were measured using liquid chromatography mass spectrometry. A bespoke bicompartmental pharmacokinetic model simultaneously fitted data from two analytes/three routes of administration. Temporal changes in TT were analyzed using one-way ANOVA followed by Dunnett’s test and treatment comparisons using two-way ANOVA with Bonferroni’s correction (P < 0.05).ResultsThermal thresholds were significantly increased after SC, IV and OTM from 1–24 hours (except 2 hours), 0.5–8 hours (except 6 hours), and 1–8 hours (except 6 hours), respectively, when compared with baseline. Thermal thresholds were significantly increased after SC (1–30 hours), IV (1–8 hours) and OTM (1–12 hours) when compared with SAL, but not different among buprenorphine-treated cats. The absolute buprenorphine clearance was 0.98 L kg-1 hour-1, volume of distribution at steady state was 7.9 L kg-1 and the elimination-half-life was 12.3 hours. Bioavailability for SC and OTM was 94% and 24%, respectively. Subcutaneous absorption was biphasic. An initial peak (0.08 hours) was followed by a slow (half-life 11.2 hours) and progressive (peak acceleration at 2.8 hours) uptake.ConclusionThe SC administration of Simbadol™ was characterized by prolonged absorption half-life and sustained plasma concentrations yielding long-lasting antinociception (≥ 24 hours) when compared with the IV and OTM routes.

Are abatacept and tocilizumab intravenous users willing to switch for the subcutaneous route of administration? A questionnaire-based study.

Choosing the subcutaneous (SC) route of administration of abatacept and tocilizumab is more cost-effective than the intravenous (IV) route. The objective of this study was to examine patients' reasons for choosing to keep with their IV infusions or to switch to subcutaneous SC injections. This study was based upon a self-administered questionnaire given to consecutive rheumatoid arthritis patients treated with abatacept or tocilizumab. Patients were asked to express their opinions concerning reasons explaining why they chose to keep the IV route or switch to the SC route. A total of 201 questionnaires completed by 127 patients treated by tocilizumab and 74 by abatacept were analysed. Overall, 45.8% of the patients chose to keep the IV route of administration. Another ongoing SC treatment was noted more often in patients choosing the SC route (15.9 versus 4.3%, p<0.05). Reasons guiding the choice of the SC route were concerns about repeated hospital day-care (72%), greater autonomy with SC injections (38.7%) and economic considerations (21.5%). Reasons associated with choosing to maintain the IV route were worries about a lack of follow-up (72.1%), the absence of medical assistance during the SC injection (61.2%), maintaining social relationships with other patients developed at the hospital (40.5%), lower frequency of injection (32.9%), fear of adverse events (27.7%) and fear of SC injections (17.9%). Patients reject the SC switch from the IV route of tocilizumab and abatacept mainly because of fears about the unknown SC route, while those who accept it find it more convenient.