Real-world evidence and patient preference for subcutaneous versus intravenous natalizumab in the treatment of relapsing-remitting multiple sclerosis - initial results from the observational SISTER study.

Background: The consideration of patient preference for a certain drug route of administration (RoA) plays an important role in promoting patient adherence in chronic diseases. Natalizumab is an established treatment for relapsing-remitting multiple sclerosis (RRMS) and can be administered as intravenous (IV) infusion or subcutaneous (SC) injection developed to enable a shorter and easier administration versus IV RoA. Study objectives: Primary objective is to compare patients' preference for RoA and satisfaction with SC versus IV natalizumab at baseline and subsequent visits up to 12 months. Secondary objectives include drug utilization, clinical outcomes, safety, and treatment satisfaction in a usual care setting. Design and methods: SISTER (Subcutaneous: Non-Interventional Study for Tysabri Patient Preference - Experience from Real World) is an ongoing, prospective, observational study where natalizumab is utilized according to local label. RRMS patients are included in three natalizumab cohorts: Patients switching from current IV to SC administration (switcher) and patients newly starting natalizumab on either SC or IV route (starter SC/IV). This interim analysis includes 262 patients (184 switchers, 39 SC starters, and 39 IV starters), median observation period was 9 months. Results: 80.8% IV starters and 93.9% SC starters reported at baseline that they prefer the assigned RoA. Although initial satisfaction with chosen RoA was maintained over time from baseline through Month 12 in all three cohorts, the wish for change of the current RoA after 6 and 12 months was more frequently expressed among IV starters than in either SC cohort. Consistently, six patients (23.1%) starting with IV changed their RoA from IV to SC route.Mean global treatment satisfaction according to TSQM-II score at baseline remained high in the switcher group and increased through Month 12 in both IV and SC starter cohorts. Conclusion: Based on current data, there is a trend toward patients' preference for the natalizumab SC route over the IV route, which provides valuable insights into patients' preference for natalizumab RoA in routine care and complements available data from clinical studies with real-world data on SC natalizumab. Trial registration: This observational (non-interventional) study was registered in the local German PEI register for non-interventional studies (NIS-No. 611) and in the international CTgov register (NCT05304520).

Innovative strategies for effective paclitaxel delivery: Recent developments and prospects.

PURPOSE: Paclitaxel is an effective chemotherapeutic agent against a variety of cancer types. However, the clinical utility of paclitaxel is restricted by its poor solubility in water and high toxicity, resulting in low drug tolerance. These difficulties could be resolved by using suitable pharmacological carriers. Hence, it is essential to determine innovative methods of administering this effective medication to overcome paclitaxel's inherent limitations. METHODS: An extensive literature search was conducted using multiple electronic databases to identify relevant studies published. RESULTS: In this comprehensive analysis, many different paclitaxel delivery systems are covered and discussed, such as albumin-bound paclitaxel, polymeric micelles, paclitaxel-loaded liposomes, prodrugs, cyclodextrins, and peptide-taxane conjugates. Moreover, the review also covers various delivery routes of conventional paclitaxel or novel paclitaxel formulations, such as oral administration, local applications, and intraperitoneal delivery. CONCLUSION: In addition to albumin-bound paclitaxel, polymeric micelles appear to be the most promising formulations for innovative drug delivery systems at present. A variety of variants of polymeric micelles are currently undergoing advanced phases of clinical trials.

Physicochemical and biological stability of diluted vedolizumab in intravenous infusion bags.

INTRODUCTION: Intravenous vedolizumab is a widely used monoclonal antibody for outpatients with inflammatory bowel disease. Drug preparation is performed on the day of administration, but is time consuming, causing unnecessary in-hospital patient delay and inefficient logistics for preparation and distribution. Storage of vedolizumab ready-to-administer infusions and distribution via pneumatic air tubes could streamline logistics in the outpatient setting. The aim of this study was to test the shelf life and stability of ready-to-administer intravenous infusion bags containing vedolizumab. METHODS: For assessing in-use shelf life, the reconstituted product (300 mg fixed dose) was diluted to a concentration of 1.2 mg/mL in 0.9% NaCl under aseptic conditions, and stored in polyolefin infusion bags at 2-8°C prior to analysis. On replicate samples, we measured concentration, physical and chemical stability using sodium dodecyl sulphate polyacrylamide gel electrophoresis, size exclusion chromatography, and multi-angle laser light scattering, as well as biological activity using a biolayer interferometry assay to study target engagement, and endotoxin content to assess microbiological stability. Stability of ready-to-use vedolizumab was assessed also after transportation via pneumatic tube system. Samples were taken at different time points over an observation period of 30 days on four replicate samples. RESULTS: For all parameters assessed, the ready-to-use solution of vedolizumab remained stable over a period of at least 30 days. There were no signs of protein aggregation, chemical instability, or loss of binding of the antibody to the α4ß7 integrin target. There was no increase in endotoxin concentration over time. No significant difference was seen in antibody structural stability and protein aggregation between samples before and after transportation via pneumatic tube system. CONCLUSION: When prepared under aseptic conditions, dissolved ready-to-administer vedolizumab infusion bags can be stored long term at 2-8°C and transported via pneumatic air tube, without observable loss of antibody stability or binding activity.

Falsely elevated serum testosterone measurements resulting from testosterone topical gel contamination of the venipuncture site: Case Series and retrospective review.

Testosterone as replacement therapy for male hypogonadism or as gender-affirming hormone therapy for transgender and non-binary patients has increased worldwide. Commonly used formulations of testosterone include intramuscular, transdermal patch, and topical gel, each of which has differing pharmacokinetics and practical challenges. In monitoring testosterone serum concentrations, contamination of the phlebotomy site by testosterone topical gel can lead to supraphysiologic (>1000 ng/dL or 34.7 nmol/L) serum concentrations of testosterone, as demonstrated in a few published case reports. The frequency of this issue is currently not known. The present study involves a retrospective search over a 13-year period across all clinical sites at an academic medical center. Out of 578 unique patients using testosterone topical gel, a total of 48 patients had at least 1 testosterone serum concentration exceed 1000 ng/dL. Documentation in the electronic health record revealed 7 patients where contamination of the phlebotomy site by topical gel was strongly supported as the cause of supraphysiologic testosterone serum concentrations. These included 5 males with primary hypogonadism, 1 male with panhypopituitarism, and a non-binary patient with gender dysphoria. The high testosterone concentrations prompted further work-up, including retesting and endocrinology consultation. There were additional cases of high testosterone serum concentration that may have been falsely elevated due to gel contamination but without sufficient supporting evidence available in the health record. Overall, we present 7 cases of spuriously high testosterone concentrations strongly suspected to be due to venipuncture performed near or at the location of prior testosterone gel application. Gel contamination should be considered as a possible cause of otherwise unexplained high testosterone serum concentration in patients receiving topical testosterone gel formulations. Patient counseling and provider awareness of this potential cause of spuriously high testosterone serum concentrations is important.

Budget impact analysis: comparing the costs of nusinersen and risdiplam in the treatment of type 3 spinal muscular atrophy patients.

OBJECTIVES: The aim of the budget impact analysis (BIA) was to determine the economic impact of introducing risdiplam in the treatment of type 3 spinal muscular atrophy (SMA) patients in a rare diseases reference centre on a 3-year time horizon, as compared with nusinersen. METHODS: Public databases were used to estimate the target population. Two market scenarios were assessed over a 3-year time horizon: with nusinersen and with the introduction of risdiplam. Drug acquisition and administration costs were considered. BIA is calculated as the difference between scenarios with nusinersen - scenario with risdiplam. RESULTS: The introduction of risdiplam would generate a 3-year saving of €3411.50. There could be a saving in the administration of risdiplam in the treatment of patients under the age of 2 with a weight of 5 kg (€26 382.08). CONCLUSION: The BIA shows the overlapping costs of these therapies, although the oral administration of risdiplam could be a decisive factor for the therapeutical switch from nusinersen.

Y-site simulation compatibility study of 10% calcium salts with various injectable solutions during toxicological resuscitation.

PURPOSE: To determine the physical compatibility of 10% calcium chloride and 10% calcium gluconate in combination with injectable solutions, administered in the paediatric and adult intensive care unit setting during toxicological resuscitation involving calcium channel blockers and beta-blockers. METHODS: Forty-eight combinations were prepared at room temperature, including the following products: calcium chloride, calcium gluconate, insulin, epinephrine, norepinephrine, highly concentrated dextrose solution, sodium chloride, Plasma-Lyte A and Ringer's lactate. A visual evaluation at times 0, 1, 4, 24, 48 and 72 hours and a particle count test with the LS-20 particle counter at times 0, 4, 24 and 72 hours were performed. The admixtures were considered incompatible if there was a precipitate, a colour change, turbidity, viscosity or a gas formation. The stability of calcium salts was also tested in empty IV bags and syringes by the particle count test. RESULTS: All drug mixtures were found to be compatible by visual evaluation and using the particle counter based on United States Pharmacopoeia chapter 788 (USP<788>) specifications. Calcium salts were compatible with insulin and vasopressors in the tested combinations. The stability of 10% calcium salts in empty IV bags and polypropylene syringes was demonstrated for up to 48 hours at room temperature. CONCLUSION: All the combinations tested were physically compatible for up to 72 hours at room temperature. Clinical use of calcium salt infusions, at an undiluted concentration, in combination with these injectable solutions in a toxicological resuscitation context is considered clinically acceptable.

Hydrogel-Forming Microneedles with Applications in Oral Diseases Management.

Controlled drug delivery in the oral cavity poses challenges such as bacterial contamination, saliva dilution, and inactivation by salivary enzymes upon ingestion. Microneedles offer a location-specific, minimally invasive, and retentive approach. Hydrogel-forming microneedles (HFMs) have emerged for dental diagnostics and therapeutics. HFMs penetrate the stratum corneum, undergo swelling upon contact, secure attachment, and enable sustained transdermal or transmucosal drug delivery. Commonly employed polymers such as polyvinyl alcohol (PVA) and polyvinyl pyrrolidone are crosslinked with tartaric acid or its derivatives while incorporating therapeutic agents. Microneedle patches provide suture-free and painless drug delivery to keratinized or non-keratinized mucosa, facilitating site-specific treatment and patient compliance. This review comprehensively discusses HFMs' applications in dentistry such as local anesthesia, oral ulcer management, periodontal treatment, etc., encompassing animal experiments, clinical trials, and their fundamental impact and limitations, for example, restricted drug carrying capacity and, until now, a low number of dental clinical trial reports. The review explores the advantages and future perspectives of HFMs for oral drug delivery.

Creating an evidence-based economic model for prefilled parenteral medication delivery in the hospital setting.

OBJECTIVES: Prefilled syringes (PFS) may offer clinical and economic advantages over conventional parenteral medication delivery methods (vials and ampoules). The benefits of converting from vials and ampoules to PFS have been explained in previous drug-specific economic models; however, these models have limited generalisability to different drugs, healthcare settings and other countries. Our study aims to (1) present a comprehensive economic model to assess the impact of switching from vials to PFS delivery; and (2) illustrate through two case studies the model's utility by highlighting important features of shifting from vials to PFS. METHODS: The economic model estimates the potential benefit of switching to PFS associated with four key outcomes: preventable adverse drug events (pADE), preparation time, unused drugs, and cost of supplies. Model reference values were derived from existing peer-reviewed literature sources. The user inputs specific information related to the department, drug, and dose of interest and can change reference values. Two hypothetical case studies are presented to showcase model utility. The first concerns a cardiac intensive care unit in the United Kingdom administering 30 doses of 1 mg/10 mL atropine/day. The second concerns a coronavirus (COVID-19) intensive care unit in France that administers 30 doses of 10 mg/25 mL ephedrine/day. RESULTS: Total cost savings per hospital per year, associated with reductions in pADEs, unused drugs, drug cost and cost of supplies were £34 829 for the atropine example and €104 570 for the ephedrine example. Annual preparation time decreased by 371 and 234 hours in the atropine and ephedrine examples, respectively. CONCLUSIONS: The model provides a generalisable framework with customisable inputs, giving hospitals a comprehensive view of the clinical and economic value of adopting PFS. Despite increased costs per dose with PFS, the hypothetical case studies showed notable reductions in medication preparation time and a net budget savings owing to fewer pADEs and reduced drug wastage.

Outcomes of Intravenous Push versus Intermittent Infusion Administration of Cefepime in Critically Ill Patients.

The equivalence of intravenous push (IVP) and piggyback (IVPB) administration has not been evaluated in the critically ill population for most medications, but it is especially relevant for antibiotics, such as cefepime, that exhibit time-dependent bactericidal activity. A single center, retrospective, observational pre/post-protocol change study included critically ill adults who received cefepime as empiric therapy between August 2015 and 2021. The primary outcome was treatment failure, which was defined as a composite of escalation of antibiotic regimen or all-cause mortality. Secondary outcomes included adverse drug events, days of cefepime therapy, total days of antibiotic therapy, and ICU and hospital length of stay. Outcomes were compared using Chi-squared, Mann Whitney U, and binary logistic regression as appropriate. A total of 285 patients were included: 87 IVPB and 198 IVP. Treatment failure occurred in 18% (n = 16) of the IVPB group and 27% (n = 54) of the IVP group (p = 0.109). There were no significant differences in secondary outcomes. Longer duration of antibiotics (odds ratio [OR] 1.057, 95% confidence interval [CI] 1.013-1.103), SOFA score (OR 1.269, 95% CI 1.154-1.397) and IVP administration of cefepime (OR 2.370, 95% CI 1.143-4.914) were independently associated with treatment failure. Critically ill patients who received IVP cefepime were more likely to experience treatment failure in an adjusted analysis. The current practice of IVP cefepime should be reevaluated, as it may not provide similar clinical outcomes in the critically ill population.

Physicochemical stability of ready-to-administer mitomycin C solutions for intravesical instillation.

OBJECTIVE: The aim of the study was to investigate the physicochemical stability of mitomycin-containing medicinal products for bladder instillation, formulated with urea as excipient (mito-medac®, Mitomycin medac). For comparison, the stability of reconstituted Urocin® and Mitem® bladder instillation was studied. METHODS: Mitomycin-containing medicinal products were either reconstituted with the prepackaged 0.9% NaCl solution, nominal volume 20 mL (mito-medac®, Mitem®, Urocin®) or with 20 mL water for injection (Mitomycin medac, Mitem®, Urocin®) to a nominal concentration of 1 mg/mL and stored at room temperature (20-25°C). Samples were taken immediately after reconstitution and after 24 hours. Physicochemical stability was determined by reverse-phase high performance liquid chromatography with photodiode array detection, measurement of pH and osmolarity, and inspection for visible particles or colour changes. RESULTS: The initial pH values of the test solutions reconstituted with prepackaged 0.9% NaCl (5.2-5.6) were significantly lower than those reconstituted with water for injection (6.6-7.4). Solutions reconstituted with 0.9% NaCl solutions rapidly degraded and concentrations fell below the 90% limit after 24 hours of storage. When reconstituted with water for injection, degradation was less rapid. Concentrations of Mitomycin medac and Urocin remained above the 90% limit after 24 hours. CONCLUSIONS: The physicochemical stability of mitomycin 1 mg/mL bladder instillation prepared with prepackaged 0.9% NaCl in prefilled PVC bags is less than 24 hours at room temperature. Unfavourable pH values of the solvents cause rapid degradation of mitomycin. Mitomycin solutions reconstituted at the point of care should be administered immediately to avoid degradation and loss of efficacy. Urea added as excipient did not accelerate degradation.

A new function in the Stabilis database: physical compatibility and incompatibility of injectable drugs to secure Y-site administration.

OBJECTIVES: In intensive care units, the mixing of injectable drugs via Y-site administration is often necessary. However, some mixtures can lead to physical incompatibility or chemical instability. To assist healthcare professionals, several databases such as Stabilis compile compatibility and stability data. The objectives of this study were to update the online database Stabilis by adding physical compatibility data to the website and to characterise the incompatibility data already present in the database by specifying the phenomenon at the origin of the incompatibility and its time of occurrence. METHODS: Bibliographic sources referenced in Stabilis were evaluated using several criteria. After the evaluation, studies were rejected or the data they contain were added to the database. Data entries contained the following information: name of the two injectable drugs involved in the mixture and their concentration if available, the dilution solvent and the phenomenon at the origin of the incompatibility and its time of occurrence for incompatibility data. Three functions of the website were modified, including the 'Y-site compatibility table' function, which allows creation of customised compatibility tables. RESULTS: A total of 1184 bibliographic sources were evaluated, 77.3% (n=915) of which were scientific articles, 20.5% (n=243) were Summaries of Product Characteristics and 2.2% (n=26) were communications in a pharmaceutical congress. After evaluation, 28.9% (n=342) of the sources were rejected. From the 71.1% (n=842) sources selected, 8073 (70.2%) compatibility data entries and 3433 incompatibility data entries (29.8%) were made. With the addition of these data, the database contained compatibility and incompatibility data for 431 injectable drugs. CONCLUSIONS: Since the update, the 'Y-site compatibility table' function has seen its traffic increased by about 66% (∼1500 tables per month compared with ∼2500 tables per month). Stabilis is now more complete to offer significant help to healthcare professionals with their problems of drug stability and compatibility.

Factors influencing the acceptability of different devices for subcutaneous drug delivery: a cross-sectional observational study from the patient's point of view.

BACKGROUND: In recent years, an increasing number of patient-reported outcome assessment tools (PROs) have been developed specifically to ascertain patients' perceptions of different drug treatments. Among them, the injection process has been analysed, especially in patients chronically treated with chronic biological therapies. One of the main advantages of most current biological therapies is the possibility to self-administer medication at home through the use of a variety of devices, including prefilled syringes (PFS) and prefilled pens (PFP). OBJECTIVES: The aim of this study was to conduct qualitative research to assess the degree of preference between the different pharmaceutical forms PFS and PFP. METHODS: We performed a cross-sectional observational study in patients on biological drug therapy through the compilation of a web-based questionnaire at the time of routine delivery of biological therapy. Questions regarding primary diagnosis, adherence to therapy, the preferred pharmaceutical form and the main reason for preference among five possibilities already reported in the scientific literature were included. RESULTS: During the study period, data were collected from 111 patients and 68 (58%) indicated PFP as their preference. From the analysis of reasons that led a patient to choose one device over another, PFSs are chosen mainly out of habit (n=13 (28.3%) PFS vs n=2 (3.1%) PFP) while PFPs are chosen to avoid needle vision (n=15 (23.1%) PFP vs n=1 (2.2%) PFS). Both differences were found to be statistically significant (p<0.001). CONCLUSION: As biological subcutaneous drugs are increasingly prescribed for a wide variety of long-term therapies, further research focused on identifying patient factors which may enhance adherence to treatment will become even more valuable.

Alzheimer's and Parkinson's disease therapies in the clinic.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent neurodegenerative diseases, affecting millions and costing billions each year in the United States alone. Despite tremendous progress in developing therapeutics that manage the symptoms of these two diseases, the scientific community has yet to develop a treatment that effectively slows down, inhibits, or cures neurodegeneration. To gain a better understanding of the current therapeutic frontier for the treatment of AD and PD, we provide a review on past and present therapeutic strategies for these two major neurodegenerative disorders in the clinical trial process. We briefly recap currently US Food and Drug Administration-approved therapies, and then explore trends in clinical trials across the variables of therapy mechanism of disease intervention, administration route, use of delivery vehicle, and outcome measures, across the clinical phases over time for "Drug" and "Biologic" therapeutics. We then present the success rate of past clinical trials and analyze the intersections in therapeutic approaches for AD and PD, revealing the shift in clinical trials away from therapies targeting neurotransmitter systems that provide symptomatic relief, and towards anti-aggregation, anti-inflammatory, anti-oxidant, and regeneration strategies that aim to inhibit the root causes of disease progression. We also highlight the evolving distribution of the types of "Biologic" therapies investigated, and the slowly increasing yet still severe under-utilization of delivery vehicles for AD and PD therapeutics. We then briefly discuss novel preclinical strategies for treating AD and PD. Overall, this review aims to provide a succinct overview of the clinical landscape of AD and PD therapies to better understand the field's therapeutic strategy in the past and the field's evolution in approach to the present, to better inform how to effectively treat AD and PD in the future.

Medication adherence reporting in pivotal clinical trials: overview of oral oncological drugs.

OBJECTIVES: To assess how and to what extent adherence to medication is reported in pivotal clinical trials of oral cancer drugs. METHODS: All drugs authorised by the European Medicines Agency from 1 January 2014 to 31 December 2019 were considered for analysis. For each pivotal trial we extracted the journal of publication, phase of the study, posology, mention of adherence within the main text of the published article or additional material and the terms in which the adherence was reported. RESULTS: Thirty drugs were included in the analysis from 56 clinical trials. Eleven articles (19.6%) contained a mention of medication adherence in the main document, 26 (46.4%) in the supplementary material and 19 (33.9%) did not contain any reference to adherence. Seven studies reported medication adherence between the results, expressed as number of patients discontinuing treatment for non-compliance and mean or median percentage. CONCLUSIONS: Medication adherence in pivotal clinical trials of oral oncological drugs is poorly represented. There should be a greater level of reporting in the results and it should be included among the minimum set of recommendations in reporting health research.

Widening the net: a literature review of antimicrobial agents with potential suitability for outpatient parenteral antimicrobial therapy services-the importance of storage and stability.

OBJECTIVES: Outpatient parenteral antimicrobial therapy (OPAT) services using continuous infusions (CIs) of antimicrobial agents in elastomeric devices require evidence of acceptable stability of the agent over the infusion period. A period of refrigerated storage of filled devices, followed by the CI period, is useful for OPAT services but can present a significant challenge to the stability of drugs. The aims of this study were to review fresh-filled stability data on antimicrobials which would be useful for OPAT services and to identify suitable candidates for further assessment. METHODS: Searches identified papers relating to stability assessments of antimicrobials for immediate use tested above 31°C using a stability-indicating method. RESULTS: We identified 18 stability studies published in 12 papers between 2015 and 2020, assessing the stability of 10 agents. Aminopenicillins like ampicillin and amoxicillin appear too unstable for CI, while benzylpenicillin may benefit from buffering to improve its stability. Cephalosporins vary in their stability and CI periods of 24 hours may not be achievable. Of the carbapenems, there are insufficient data for doripenem but meropenem has been extensively studied and is unsuitable for CI longer than 6 hours. Voriconazole may be suitable for CI but needs further investigation. CONCLUSIONS: Some drugs identified in our review are unlikely to be suitable for continuous infusion in OPAT services due to instability. Using a 'fresh-fill' approach, without refrigerated storage, may make some drugs useful while other agents should be considered for further assessment to Yellow Cover Document standards. The impact of buffering for penicillins should be assessed further.

Crushing lopinavir/ritonavir tablets does not result in lower exposure to lopinavir/ritonavir in adult patients with COVID-19.

OBJECTIVE: Lopinavir/ritonavir (LPV/RTV) exposure is decreased in children after crushing the tablets. Whether exposure is also decreased in adult patients is not known. This study evaluated the exposure of LPV/RTV in adult patients after administration of crushed LPV/RTV tablets. METHODS: Blood samples were drawn from patients with COVID-19 who were receiving crushed LPV/RTV 400/100 mg tablets twice daily. RESULTS: Plasma concentrations for 11 patients with COVID-19 (eight men, mean age 62.6 years) were included. The measured plasma concentrations of LPV were substantially higher than reported for patients with HIV. CONCLUSIONS: There is adequate exposure from crushed LPV/RTV tablets, but because of limited experience, therapeutic drug monitoring is still advised.