Modeling drug transport and absorption in subcutaneous injection of monoclonal antibodies: Impact of tissue deformation, devices, and physiology.

The pharmaceutical industry has experienced a remarkable increase in the use of subcutaneous injection of monoclonal antibodies (mAbs), attributed mainly to its advantages in reducing healthcare-related costs and enhancing patient compliance. Despite this growth, there is a limited understanding of how tissue mechanics, physiological parameters, and different injection devices and techniques influence the transport and absorption of the drug. In this work, we propose a high-fidelity computational model to study drug transport and absorption during and after subcutaneous injection of mAbs. Our numerical model includes large-deformation mechanics, fluid flow, drug transport, and blood and lymphatic uptake. Through this computational framework, we analyze the tissue material responses, plume dynamics, and drug absorption. We analyze different devices, injection techniques, and physiological parameters such as BMI, flow rate, and injection depth. Finally, we compare our numerical results against the experimental data from the literature.

Pharmacokinetics and safety of candidate tocilizumab biosimilar CT-P47 administered by auto-injector or pre-filled syringe: a randomized, open­label, single-dose phase I study.

BACKGROUND: This study compared the pharmacokinetics (PK), immunogenicity, and safety of candidate tocilizumab biosimilar, CT-P47, administered via auto-injector (CT-P47 AI) or pre-filled syringe (CT-P47 PFS), in healthy Asian adults. RESEARCH DESIGN AND METHODS: In this phase I, multicenter, open-label study, participants were randomized 1:1 to receive a single 162 mg/0.9 mL dose of CT-P47 via AI or PFS. Primary endpoints were area under the concentration - time curve from time zero to infinity (AUC0-inf) and maximum serum concentration (Cmax). PK equivalence was determined if 90% confidence intervals (CIs) for the ratios of geometric least-squares means (gLSMs) were within the predefined 80-125% equivalence margin. Secondary PK parameters, immunogenicity, and safety outcomes were also assessed. RESULTS: Of 314 participants randomized (155 CT-P47 AI; 159 CT-P47 PFS), 310 received the study drug (153 CT-P47 AI; 157 CT-P47 PFS). Primary and secondary PK results, immunogenicity and safety were similar between groups. Ninety percent CIs for the ratio of gLSMs were within the predefined equivalence margin for AUC0-inf (85.87-102.94) and Cmax (82.98-98.16). CONCLUSIONS: PK equivalence between CT-P47 AI and CT-P47 PFS was demonstrated in healthy Asian adults, with comparable immunogenicity and safety between the two devices. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05617183.

Tocilizumab is a biologic medicine used to treat inflammatory diseases, such as rheumatoid arthritis. A biosimilar is a drug that is an almost identical copy of an approved original ('reference') biologic medicine; it has identical efficacy and safety to the original medicine but is typically less expensive. CT­P47 is in development as a possible tocilizumab biosimilar.Some patients prefer injections using an auto-injector (AI) rather than a pre-filled syringe (PFS), for reasons including ease of use and convenience. With an AI, medicine is delivered automatically by firmly pressing the device against the skin, whereas, with a PFS, a needle is inserted into the skin and medicine delivered by depressing the plunger. The injection of CT­P47 using a PFS has shown comparable pharmacokinetics (i.e., the uptake, metabolism and excretion of the drug by the body) and safety to tocilizumab. Therefore, if the pharmacokinetics and safety of CT­P47 administered via AI and PFS were shown to be similar, this might expand the choice of administration devices available to patients.In this study, 310 healthy adults received a single injection of CT­P47 via AI or PFS. Blood samples were taken over 43 days to analyze pharmacokinetics. The uptake, metabolism and elimination of CT­P47 by the body was similar when administered by each device, suggesting that CT­P47 can be administered by either AI or PFS.

Evaluation of a video training program's impact on primary teachers' knowledge of allergies and skills in using an adrenaline autoinjector during the 2021-2022 school year.

AIM: The aim of the study was to assess the impact of a video training program (VTP) on primary school teachers' skills in using an adrenaline auto-injector (AAI), in correlation with knowledge regarding allergies, in cases of anaphylaxis. METHODS: A questionnaire on teachers' knowledge of allergies and on their level of confidence in using an AAI was distributed in primary schools in the French department of Manche (2173 teachers). A VTP followed this questionnaire. A second questionnaire was then distributed. Theoretical knowledge was assessed with a score out of 20. The confidence level was rated on a scale from 1 to 4. RESULTS: We collected 218 responses to the first questionnaire (10.0 % of the population included). The response rate to the second questionnaire was 4.7 % (103 participants), and from this group, 93 of the 103 participants viewed the video (90.3 %). Overall, 76 of the 218 (34.9 %) participants who completed the first questionnaire also completed the second questionnaire and watched the VTP. The number of participants who completed the whole survey was 76 (out of 2173, 3.5 %). The VTP significantly improved teachers' knowledge of the subject of allergies (the average score increased by 2.11 points, p < 0.001) as well as their confidence in recognizing the signs of a severe allergic reaction and in using an AAI: 85.4 % (n = 88) of self-confident teachers after the VTP versus 42.3 % (n = 92) before the VTP (p < 0.001). CONCLUSION: The VTP improved teachers' level of knowledge and confidence in using an AAI in cases of anaphylaxis. A similar VTP could be circulated more widely in schools to offer easy access to training tools about allergies.

Relative Bioavailability Study of Midazolam Intramuscularly Administered with the Needle-Free Auto-Injector ZENEO® in Healthy Adults.

INTRODUCTION: Intramuscular (IM) midazolam is indicated for the treatment of status epilepticus. Administration must be efficient to rapidly terminate prolonged seizures and prevent complications. The objective of this study was to compare, in terms of relative bioavailability and bioequivalence, IM midazolam injection by needle-free auto-injector, in different settings, to IM midazolam injection by a conventional syringe and needle. METHODS: In this open-label, randomized, four-period crossover study, healthy adults received single doses of midazolam (10 mg) under fasting conditions. The reference treatment (conventional syringe) was administered once, on bare skin in the thigh. The tested treatment (the needle-free auto-injector ZENEO®) was administered three times: on bare skin in the thigh, on bare skin in the ventrogluteal area, and through clothing in the thigh. Repeated plasma samples were collected to obtain 36-h pharmacokinetic (PK) profiles. Primary PK parameters were area under the plasma concentration-time curve, from time zero to the last measurable time point (AUC0-t) and from time zero to infinity (AUC0-∞), and the maximum observed plasma concentration (Cmax). RESULTS: Forty adults were enrolled and included in the PK analysis set. In all comparisons, the 90% confidence interval (CI) of the least-squares geometric mean ratios for AUC0-t and AUC0-∞ were within the bioequivalence range of 80-125%, with low intra-individual coefficients of variation (< 20.5% for all parameters in all comparisons). Bioequivalence was also met for Cmax in all comparisons except when comparing the tested treatment through clothing versus the reference treatment, where the 90% CI lower limit was slightly outside the bioequivalence range (78.8%). With all tested treatments Cmax was slightly lower, but early mean plasma concentrations (first 10 min post-dosing) were higher when compared to the reference treatment. In general, all treatments were well tolerated, with maximum sedation 0.5-1 h post-injection. DISCUSSION/CONCLUSION: This study establishes that IM midazolam injection on bare skin in the thigh with the ZENEO® is bioequivalent to IM midazolam injection with a syringe and needle. An acceptable relative bioavailability, compatible with emergency practice, was also shown in multiple settings. Higher mean concentrations within the first 10 min with the ZENEO® device, and quicker two-step injection suggest a faster onset of action, and thereby an earlier seizure termination, thus preventing the occurrence of prolonged seizure and neurological complications. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier: NCT05026567. Registration first posted August 30, 2021, first patient enrolled May 9, 2022.

Seizures require urgent treatment when they last longer than 5 min. Indeed, when prolonged, seizures can lead to damage to the brain, coma, and ultimately death. Midazolam injected in the muscle (i.e., intramuscular (IM) injection) has become the first-line treatment of choice for long-lasting seizures and is usually administered with a syringe and 30-mm needle. The ZENEO^® needle-free auto-injector is an innovative, pre-filled, single-dose, disposable, ready-to-use, two-step device that could become an alternative method for midazolam IM administration. This study therefore compared midazolam IM injections with the ZENEO^® auto-injector versus IM injections with a conventional syringe and needle. The ZENEO^® auto-injector was tested in different conditions (on bare skin, through clothing, in the thigh, and in the hip) in healthy volunteers. The study showed, with a pharmacokinetic analysis (how much and how fast a drug is taken in the bloodstream), that midazolam absorption was similar in all tested conditions, indicating that the ZENEO^® auto-injector is a suitable method for midazolam administration. In addition, the study showed that in the first 10 min of the injection, the amount of midazolam in the blood seemed to be higher when injections were performed with the ZENEO^® auto-injector, suggesting that seizure treatment may start working sooner if injected with the device. This is particularly important and relevant in emergency situations and prehospital settings in order to prevent long-lasting seizures and irreversible damage to the brain (which can occur when a crisis lasts for 30 min) and ultimately improve the patient's outcome.

Impact of drone-specific dispatch instructions on the safety and efficacy of drone-delivered emergency medical treatments: A randomized simulation pilot study.

Introduction: Medical drones have potential for improving the response times to out-of-hospital emergencies. However, widespread adoption is hindered by unanswered questions surrounding medical dispatch and bystander safety. This study evaluated the impact of novel drone-specific dispatch instructions (DSDI) on bystanders' ability to interact effectively with a medical drone and provide prompt, safe, and high-quality treatment in a simulated emergency scenario. We hypothesized DSDI would improve bystanders' performance and facilitate safer bystander-drone interactions. Methods: Twenty-four volunteers were randomized to receive either DSDI and standard Medical Priority Dispatch (MPD) instructions or MPD alone in a simulated out-of-hospital cardiac arrest (OHCA) or pediatric anaphylaxis.,3 Participants in the DSDI group received detailed instructions on locating and interacting with the drone and its enclosed medical kit. The simulations were video recorded. Participants completed a semi-structured interview and survey. Results: The addition of DSDI did not lead to statistically significant changes to the overall time to provide care in either the anaphylaxis or OHCA simulations. However, DSDI did have an impact on bystander safety. In the MPD only group, 50% (6/12) of participants ignored the audio and visual safety cues from the drone instead of waiting for it to be declared safe compared to no DSDI participants ignoring these safety cues. Conclusions: All participants successfully provided patient care. However, this study indicates that DSDI may be useful to ensure bystander safety and should be incorporated in the continued development of emergency medical drones.

[EPIPEN INSTRUCTIONS FOR ANAPHYLAXIS PATIENTS DURING DISPENSING: FACTORS RELATED TO THE QUALITY OF PHARMACISTS' INSTRUCTIONS].

BACKGROUND AND AIM: We previously reported that pharmacists working in pharmacies don't have enough knowledge and enough experience teaching anaphylaxis (An) and EpiPen use. We administered a questionnaire survey to pharmacists with experience handling EpiPen prescriptions. We investigated the relationship between the questionnaire results and the factors in the pharmacists' background regarding the explanation and guidance to patients. RESULTS: The percentage of pharmacists working in pharmacies who provided guidance using visual information and demonstrations was insufficient. Moreover, this figure decreased after the second guidance session. Objective confirmation of patient understanding was also insufficient. The results indicated that self-examination and participation in drug information sessions were important background factors for pharmacists who provided detailed guidance to patients. DISCUSSION: For appropriate long-term management of their condition, An patients must master the EpiPen technique. Pharmacists' guidance plays a critical role in this regard. A support system should be established for proper instruction of pharmacy patients by improving pharmacists' self-education and other educational opportunities.

Evaluation of the origin and educational quality of youtube videos on adrenaline auto-injectors.

Summary: Background. Guidelines highlight the pivotal role of adrenaline auto-injector (AAI) training. However, the standards of visual training platforms has not been determined. Our aim was to evaluate the reliability and quality of the AAI related videos on YouTube. Methods. After a search on YouTube about AAI, all videos were categorized into groups based on their origin and the aim of the content. The quality, reliability, understandibility, and actionability of the videos were evaluated using the Global Quality Scale (GQS), Patient Education Materials Assessment Tool Audovisiual (PEMAT-A/V), Quality Criteria for Consumer Health Information (DISCERN), and a modified DISCERN. In each video, the application steps of AAI were evaluated according to a scale of correct usage. Results. 107 YouTube videos in English were included. No significant difference in terms of views, likes, duration and uploading time was observed between the health and non-health groups whereas the GQS (p=0.001), DISCERN (total: p=0.02, and overall: p=0.094), modified DISCERN (p=0.001) scores were higher in the health group. It was found that scores tended to be higher in educational videos. AAI use was mentioned in 85% videos. The median number of mentioned steps was 6. Conclusions. YouTube is an effective platform for visual learning for the use of AAIs. Although the visibility of the videos is equal independent of the origin, the ones recorded by medical professionals seem to provide the most qualified and reliable information.

Global disparities in availability of epinephrine auto-injectors.

Background: Anaphylaxis is the most severe clinical presentation of acute systemic allergic reactions and can cause death. Given the prevalence of anaphylaxis within healthcare systems, it is a high priority public health issue. However, management of anaphylaxis - both acute and preventative - varies by region. Methods: The World Allergy Organization (WAO) Anaphylaxis Committee and the WAO Junior Members Steering Group undertook a global online survey to evaluate local practice in the diagnosis and management of anaphylaxis across regions. Results: Responses were received from WAO members in 66 countries. While intramuscular epinephrine (adrenaline) is first-line treatment for anaphylaxis, some countries continue to recommend alternative routes in contrast to guidelines. Epinephrine auto-injector (EAI) devices, prescribed to individuals at ongoing risk of anaphylaxis in the community setting, are only available in 60% of countries surveyed, mainly in high-income countries. Many countries in South America, Africa/Middle-East and Asian-Pacific regions do not have EAI available, or depend on individual importation. In countries where EAIs are commercially available, national policies regarding the availability of EAIs in public settings are limited to few countries (16%). There is no consensus regarding the time patients should be observed following emergency treatment of anaphylaxis. Conclusion: This survey provides a global snapshot view of the current management of anaphylaxis, and highlights key unmet needs including the global availability of epinephrine for self-injection as a key component of anaphylaxis management.

Blinding Is Seeing: A Single-Centre Study Into the Viability of Auto-Injectors for Blinded-Drug Administration in Randomised Controlled Trials.

Objective The aim of the study was to assess the viability of auto-injector systems (A-INJ) for preserving investigator blinding in randomized controlled trials (RCT). Background Blinding refers to the concealment of group allocation from one or more individuals involved in a clinical research study. In the dosing of subcutaneous (SC) and intramuscular (IM) investigational medicinal products (IMP), specific challenges arise in maintaining investigator blinding. These challenges primarily involve the active injectate's viscosity and visual appearance (colour/translucency) in comparison to the placebo. Existing methods to control these issues are not perfect. Common approaches include using unblinded investigators or applying films or additives to make the active and placebo injectates appear similar. Method A single-centre experimental and descriptive study was carried out to compare the use of an A-INJ (Owen Mumford, Autoject 2) with the use of a conventional syringe (CS) in delivering a 1 ml dose of both placebo and reference IMP. The percentage delivery of the injectate was compared between the A-INJ IMP and placebo groups. Additionally, eight trained research physicians serving as investigators recorded their assessments of safety and effectiveness after performing serial injections with the A-INJ into a human-tissue analogue. Results Overall, a mean of 95.38% of 1ml placebo injectate was released from the A-INJ, compared to 96.00% from the CS. A total of 94.715% of 1 ml IMP injectate was released from the A-INJ, as opposed to 94.74% from the CS. Independent t-test analyses showed no statistical significance between the experimental arms. The mean administration time was 8.5 seconds. Investigators were unable to differentiate between the two solutions when using the A-INJ. There were no recorded concerns about investigators becoming unblinded, which stands in contrast to concerns associated with using the CS. Conclusion In assessing the viability of A-INJ use in RCTs, we noted a marked improvement when blinding was used. A-INJ systems effectively administer both placebo and active injectates, thereby maintaining the benefit of blinding without the need to alter the placebo through the addition of colourants or viscosity additives. While audio cues from the A-INJ and the time required to administer the injectate pose challenges, solutions are suggested. Although our findings are preliminary, they add to the existing literature on the advantages of A-INJs for administering injectable compounds and offer new perspectives on their utility in RCTs.

Stability of Monoclonal Antibodies as Solid Formulation for Auto-Injectors: A Pilot Study.

Drug adherence is a significant medical issue, often responsible for sub-optimal outcomes during the treatment of chronic diseases such as rheumatoid or psoriatic arthritis. Monoclonal antibodies (which are exclusively given parenterally) have been proven to be an effective treatment in these cases. The use of auto-injectors is an effective strategy to improve drug adherence in parenteral treatments since these pen-like devices offer less discomfort and increased user-friendliness over conventional syringe-based delivery. This study aims to investigate the feasibility of including a monoclonal antibody as a solid formulation inside an auto-injector pen. Specifically, the objective was to evaluate the drug stability after a concentration (to reduce the amount of solvent and space needed) and freeze-drying procedure. A preliminary screening of excipients to improve stability was also performed. The nano-DSC results showed that mannitol improved the stability of the concentrated, freeze-dried antibody in comparison to its counterpart without it. However, a small instability of the CH2 domain was still found for mannitol samples, which will warrant further investigation. The present results serve as a stepping stone towards advancing future drug delivery systems that will ultimately improve the patient experience and associated drug adherence.

The Reliability of Auto-Injectors in Clinical Use: A Systematic Review.

Auto-injectors are medical devices designed for the self-administration of injections by patients and for easy administration by healthcare professionals in emergency situations. Although they vary in design and application, auto-injectors are typically built around a spring-loaded syringe. Despite their widespread use in a variety of clinical settings, there have been limited attempts to assess their reliability. This systematic review investigates the reliability of auto-injectors, identifies common causes of failure, and summarizes the overall rate of malfunction. A systematic review of research published on the PubMed and Cochrane Library databases was performed in July 2022. The relevant studies were assessed for their methodological quality and risk of bias prior to extracting key study outcomes on auto-injector reliability. Finally, a summary rate covering all eligible studies was calculated.  The search identified a total of 110 articles, of which ten were found to be suitable for inclusion. The risk of bias was low, and the methodological quality was high across the ten studies. Out of a total of 2,964 injections administered from an auto-injector, there were 12 device malfunctions, giving a summary rate of 0.40% (±0.23) auto-injector failures. The causes of malfunction varied in nature, with the majority of cases (58.3%) not being specified or not identified. This review has demonstrated that auto-injectors are reliable devices. Although further research on the nature of malfunctions is needed, the low rate of malfunctions supports training programs for healthcare professionals and patients on the optimum use and maintenance of auto-injectors. It provides a rationale for their continued development.

A Case of Usefulness of Auto-Injectable Adrenaline as a Prophylactic Countermeasure Against Bee Sting for Forestry Workers.

Since 2015, the Ministry of Agriculture, Forestry and Fisheries in Japan has put in place regulations for forestry workers with bee or wasp allergies. These regulations allow workers to carry auto-injectable adrenaline when they engage in forestry work. A 48-year-old male worker identified as having a bee allergy was provided with an auto-injectable adrenaline prescription. The worker had experienced bee stings several times but never had an anaphylactic reaction. However, after suffering two bee stings to the head and face region, he developed an anaphylactic condition. He used the auto-injectable adrenaline on himself and was transported to an acute critical care center. The worker received additional injection of adrenaline at the health center for residual symptoms. The worker survived with no adverses outcome. The present study described the usefulness of prescribed auto-injectable adrenaline as a prophylactic countermeasure against bee stings for forestry workers with documented allergies. This framework may be useful for protecting forestry workers around the world.

Case report-wheat-dependent exercise-induced anaphylaxis in a patient with chronic spontaneous urticaria: A diagnostic challenge.

Wheat-dependent exercise-induced anaphylaxis is a rare but severe form of anaphylaxis that occurs after consuming wheat products and engaging in physical activity. A case study of a 30-year-old woman suffering from chronic urticaria for the last 5 years highlights the difficulty in diagnosing this condition, as specific triggers were not identified. A diagnostic study called MADx revealed a positive analysis for omega-5-gliadin, leading to a diagnosis of wheat-dependent exercise-induced anaphylaxis. Delayed diagnosis is a common issue, and it can be challenging to distinguish wheat-dependent exercise-induced anaphylaxis from other conditions with similar symptoms. The treatment involves avoiding wheat products and always carrying an epinephrine auto-injector. When evaluating patients with similar symptoms, healthcare providers should include wheat-dependent exercise-induced anaphylaxis in their differential diagnosis. Patients should be educated about the symptoms, triggers, and management to seek immediate medical attention in an emergency.

Optimal dose of adrenaline auto-injector for children and young people at risk of anaphylaxis: A phase IV randomized controlled crossover study.

BACKGROUND: Guidelines recommend intramuscular injection of 500 µg adrenaline (epinephrine) for anaphylaxis in teenagers and adults; however, most autoinjectors deliver a maximum 300 µg dose. We evaluated plasma adrenaline levels and cardiovascular parameters (including cardiac output) following self-injection with 300 µg or 500 µg adrenaline in teenagers at risk of anaphylaxis. METHODS: Subjects were recruited to a randomized, single-blind two period crossover trial. Participants received all 3 injections (Emerade® 500 µg, Emerade® 300 µg, Epipen® 0.3 mg) on 2 separate visits (allocated in a randomized block design), at least 28 days apart. Intramuscular injection was confirmed by ultrasound, and heart rate/stroke volume assessed using continuous monitoring. The trial was registered at Clinicaltrials.gov (NCT03366298). RESULTS: Twelve participants (58% male, median 15.4 years) participated; all completed the study. 500 µg injection resulted in a higher and more prolonged peak concentration (p = 0.01) and greater Area-Under-Curve for plasma adrenaline (p < 0.05) compared to 300 µg, with no difference in adverse events. Adrenaline caused a significant increase in heart rate irrespective of dose and device. Unexpectedly, 300 µg adrenaline resulted in a significant increase in stroke volume when delivered with Emerade®, but a negative inotropic effect with Epipen® (p < 0.05). CONCLUSIONS: These data support a 500 µg dose of adrenaline to treat anaphylaxis in individuals >40 kg in the community. The contrasting effects on stroke volume between Epipen® and Emerade®, despite similar peak plasma adrenaline levels, are unexpected. There is an urgent need to better understand differences in pharmacodynamics following adrenaline administration by autoinjector. In the meantime, we recommend adrenaline injection by needle/syringe in the healthcare setting in individuals with anaphylaxis refractory to initial treatment.

Pharmacokinetics and tolerability of prefilled syringe and auto-injector presentations of MSB11456: results of a randomized, single-dose study in healthy adults.

BACKGROUND: Tocilizumab is a monoclonal immunoglobulin G interleukin-6 receptor antagonist. MSB11456 is a proposed tocilizumab biosimilar. OBJECTIVE: To determine the pharmacokinetic equivalence of a single subcutaneous injection of MSB11456, when delivered via autoinjector (AI) and prefilled syringe (PFS), in healthy adult subjects. RESEARCH DESIGN AND METHODS: In this randomized, open-label, single fixed-dose, crossover study, 91 subjects received subcutaneous administration of tocilizumab 162 mg via AI and PFS presentations. The primary endpoint pharmacokinetic parameters were analyzed using analysis of variance. Safety data were summarized descriptively. RESULTS: There were no differences in pharmacokinetic parameters between presentations, and safety parameters were comparable. The 90% confidence intervals for the geometric least squares mean ratios of all primary pharmacokinetic parameters were contained within the predefined 80.00% to 125.00% bioequivalence limits, indicating pharmacokinetic equivalence between the AI and PFS. CONCLUSIONS: MSB11456 administration via AI was bioequivalent to administration via PFS. MSB11456 can be administered by AI or PFS, increasing the available range of self-injection devices. TRIAL REGISTRATION: The trial is registered at EudraCT, number 2020-003419-86.

Tocilizumab is a biologic drug that is used to treat autoimmune diseases, including rheumatoid arthritis. MSB11456 has been shown to be equivalent to the US-licensed and EU-approved tocilizumab when administered by subcutaneous injection. There are different devices available to administer subcutaneous injections, and depending on the device, the patient's experience can be enhanced, convenience and compliance increased, and cost-effectiveness ensured for patients taking this medicine. This randomized, single fixed-dose, crossover study tested the pharmacokinetic similarity of MSB11456 when given subcutaneously via an auto-injector device versus a pre-filled syringe device in 100 healthy subjects. A total of 91 healthy volunteers received MSB11456 via both auto-injector and pre-filled syringe using a crossover design. Blood was collected before the first dose and at regular intervals during the study to determine the pharmacokinetics of tocilizumab and ensure safety. This study found that the pharmacokinetics of tocilizumab following administration using the autoinjector and the prefilled syringe were equivalent, and the safety profiles were similar. These findings indicate that the auto-injector can be considered another option that can be used to subcutaneously inject MSB11456.

Bioavailability and cardiovascular effects of adrenaline administered by Anapen 500 µg auto-injector in healthy volunteers.

AIMS: Anaphylaxis guidelines recommend intramuscular adrenaline, commonly 300 µg administered using an auto-injector device. However, overweight/obese patients may require a higher adrenaline dose for adequate cardiovascular (CV) response. This study evaluated the pharmacokinetics (PK) and pharmacodynamic (PD) CV profiles after a single 500 µg adrenaline injection via Anapen auto-injector in healthy normal weight males and otherwise healthy, overweight or obese females. METHODS: In this exploratory open-label, single-centre study, 54 healthy volunteers aged 18-50 years received a single 500 µg adrenaline injection (Anapen auto-injector) in the thigh (antero-lateral middle third [18 males] or antero-inferior third [36 females]). Assessments included depot depth (ultrasonography), plasma adrenaline levels (liquid chromatography-tandem mass spectrometry) and heart rate (HR; ECG Holter monitor). RESULTS: Ultrasonography showed that 82.4% of normal weight males received intramuscular injections; all overweight and obese females received subcutaneous injections. Anapen injection produced rapid increases in circulating adrenaline levels and significant increases in systolic blood pressure (SBP) and HR. Second peak plasma adrenaline concentrations (Cmax2 ) were reduced, and time to Cmax2 increased in overweight and obese females compared with males with normal body mass index; area under the curve (0-240 min) (AUC(0-240) ) was increased in overweight and obese females. Obese females had reduced maximal SBP values compared with normal weight males or overweight females; overweight and obese females had markedly different HR time courses compared with normal weight males. CONCLUSION: A 500 µg adrenaline injection via Anapen produced rapid PK/PD changes in normal weight, overweight and obese subjects, irrespective of intramuscular or subcutaneous injection, and was well tolerated.

Etanercept is Effective and Halts Radiographic Progression in Rheumatoid Arthritis and Psoriatic Arthritis: Final Results from a German Non-interventional Study (PRERA).

INTRODUCTION: Etanercept (ETN) has been shown to slow radiographic progression of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in clinical trials. This real-world, non-interventional study assessed radiographic progression in patients with RA or PsA treated with ETN for ≤ 36 months in outpatient care in Germany (NCT01623752). METHODS: Patients with RA or PsA attended ≤ 10 visits across two study phases (phase 1: seven visits, baseline to month 18; phase 2: three visits until month 36). Radiographs were taken at baseline (Rx1), months 12-18 (Rx2), and/or months 30-36 (Rx3). Historic radiographs (Rx0) taken 12-48 months pre-baseline were also evaluated (if available). The primary endpoint was the change in modified total Sharp score (mTSS). The erosion score (ES) and joint space narrowing score (JSN) were also evaluated. RESULTS: Overall, 1821 patients were enrolled (RA: n = 1378; PsA: n = 440). In patients with Rx1 and Rx2 (RA: n = 511; PsA: n = 167), the mean mTSS remained stable for both disease groups, and the annualized median change in mTSS was 0. In patients with Rx0, Rx1, and Rx2 (RA: n = 180; PsA: n = 47), annualized radiographic progression in mTSS, ES, and JSN was larger in the pre-ETN treatment phase than during ETN treatment in both disease groups. The percentage of patients with radiographic non-progression was higher during ETN treatment versus pre-ETN. Improvement in clinical disease activity and patient-reported outcomes was also observed. CONCLUSIONS: This was the first real-world, non-interventional study to report systematically collected radiographic data in a large cohort of patients with RA or PsA under treatment with a biologic. In patients with available radiographic data, mean radiographic progression was lower and the proportion of patients without progression was greater during ETN treatment than in the pre-ETN period.

Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are diseases in which inflammation can lead to damage in the joints. X-ray images can show whether the disease gets worse; this is called radiographic progression. Etanercept is a drug that acts on the body's immune system and can reduce inflammation in the joints. In clinical studies, radiographic progression was slower in people with RA or PsA who received etanercept compared with people who received another drug called methotrexate. In this study, we wanted to know how radiographic progression changes in people in Germany who receive etanercept as part of their routine treatment. A total of 1378 people with RA and 440 people with PsA received etanercept for up to 36 months. We observed little to no radiographic progression for most people during the study. Radiographic progression was worse before people started taking etanercept. More people had no radiographic progression while taking etanercept compared with before they started treatment. The proportion of people who responded to treatment with etanercept as measured by the number of painful joints increased throughout the study. Overall, people felt that their health improved after they started taking etanercept.This was the first large study in which we investigated how radiographic progression changes when people with RA or PsA start taking etanercept as part of their routine treatment. We observed a slowing or halting of radiographic progression in most people and an improvement in their overall health.