Safety, Tolerability, and Pharmacokinetics of High-Volume Subcutaneous Crenezumab, With and Without Recombinant Human Hyaluronidase in Healthy Volunteers.

Compared with intravenous formulations, subcutaneous (s.c.) formulations of therapeutic monoclonal antibodies may provide increased patient access and more convenient administration options, although historically high-volume s.c. administration (> 10-15 mL) has been challenging. We report results from two phase I studies in healthy participants (GP29523 and GP40201) that evaluated s.c. crenezumab, an anti-Aß monoclonal antibody in development for individuals at risk for autosomal-dominant Alzheimer's disease. GP29523 assessed safety, tolerability, and pharmacokinetics (PK) in 68 participants (aged 50-80 years) who received single ascending doses (600-7,200 mg) of crenezumab or placebo (4-40 mL). GP40201 assessed safety, tolerability, and PK in 72 participants (aged 18-80 years) who received different combinations of dose (1,700-6,800 mg), infusion volume (10-40 mL), and flow rate (2-4 mL/minute), with/without recombinant human hyaluronidase (rHuPH20). There were no serious or dose-limiting adverse events in either study. There were no meaningful differences in pain scores among reference placebo (4 mL), test placebo (4-40 mL), or crenezumab (600-7,200 mg) in GP29523, or across treatments with varying infusion volume, flow rate, dose, or rHuPH20 co-administration or concentration in GP40201. Transient erythema was the most common infusion site reaction in both studies. In GP40201 at volumes of ≥ 20 mL, rHuPH20 co-administration appeared to reduce infusion site swelling incidence, but, in some cases, was associated with larger areas of infusion site erythema. Crenezumab exhibited approximately dose-proportional PK, and s.c. bioavailability was 66% and independent of dose or rHuPH20 co-administration. High-dose, high-concentration, high-volume s.c. crenezumab formulated with/without rHuPH20 was well-tolerated in healthy participants, with an acceptable safety profile.

Treatment of subcutaneous nodules after infusion of apomorphine; a biopsy-controlled study comparing 4 frequently used therapies.

This study aimed to provide clinical evidence for existing treatments of subcutaneous nodules after subcutaneous infusion of apomorphine, using a biopsy-controlled prospective crossover design of four treatments. We demonstrated that dilution of apomorphine significantly improved patient satisfaction, while subcutaneous hydrocortisone reduced nodule size, however with no differences in the histopathology.

Safety and Tolerability of Subcutaneous IgPro20 at High Infusion Parameters in Patients with Primary Immunodeficiency: Findings from the Pump-Assisted Administration Cohorts of the HILO Study.

PURPOSE: To evaluate the safety and tolerability of subcutaneous IgPro20 (Hizentra®, CSL Behring, King of Prussia, PA, USA) administered at high infusion parameters (> 25 mL and > 25 mL/h per injection site) in patients with primary immunodeficiency. METHODS: The Hizentra® Label Optimization (HILO) study was an open-label, parallel-arm, non-randomized study (NCT03033745) of IgPro20 using a forced upward titration design for infusion parameters. Patients experienced with pump-assisted IgPro20 infusions received weekly IgPro20 infusions at a stable dose in the Pump-Assisted Volume Cohort (N = 15; 25-50 mL per injection site) and in the Pump-Assisted Flow Rate Cohort (N = 18; 25-100 mL/h per injection site). Responder rates (percentage of patients who successfully completed ≥ 75% of planned infusions), safety outcomes, and serum immunoglobulin G (IgG) trough levels were evaluated. RESULTS: Responder rates were 86.7% (13/15, 25 mL) and 73.3% (11/15, 40 and 50 mL) in the Volume Cohort, and 77.8% (14/18, 25 and 50 mL/h), 66.7% (12/18, 75 mL/h), and 61.1% (11/18, 100 mL/h) in the Flow Rate Cohort. Infusion compliance was ≥ 90% in all patients in the Volume Cohort and in 83.3% of patients in the Flow Rate Cohort. The number of injection sites (Volume Cohort) and the infusion duration (Flow Rate Cohort) decreased with increasing infusion parameters. The rate of treatment-emergent adverse events per infusion was low (0.138 [Volume Cohort] and 0.216 [Flow Rate Cohort]). Serum IgG levels remained stable during the study. CONCLUSION: Pump-assisted IgPro20 infusions are feasible at 50 mL and 100 mL/h per injection site in treatment-experienced patients, which may result in fewer injection sites and shorter infusion times. TRIAL REGISTRATION: NCT03033745 ; registered January 27, 2017.

Pain Management in Pectus Excavatum Surgery: A Comparison of Subcutaneous Catheters Versus Epidurals in a Pediatric Population.

BACKGROUND: Pectus excavatum is a common chest wall anomaly. Achieving optimal pain control is a priority for adolescents undergoing surgical correction of this condition. Options for pain control include the use of subcutaneous catheters (On-Q® pumps) and epidurals. The objective of this study is to demonstrate the feasibility of using subcutaneous catheters for pain control and to compare them with the use of epidurals during surgical correction of pectus excavatum. MATERIALS AND METHODS: We identified patients who underwent pectus excavatum repair at our institution between January 2010 and August 2016. Patients were divided into two cohorts (epidural or On-Q pump). Patient charts were reviewed for length of stay, pain scores, pain medications, and complications. RESULTS: A total of 124 patients were included. Forty percent of patients used an epidural (n = 50), and 60% had the On-Q pump (n = 74). The average patient age was 15.6 years. The average Haller index was 4.3. The On-Q pump population had a significant decrease in postoperative length of stay (mean [M] = 4.86, standard deviation [SD] = 0.85) compared with the epidural population (M = 5.60, SD = 0.97); P ≤ .001. There was a significant difference observed in pain scores for patients on the epidural (M = 2.91, SD = 1.13) and On-Q pump (M = 3.81, SD = 1.19; P ≤ .001). There was n = 1 wound infection in each group. CONCLUSION: The use of bilateral subcutaneous infusion catheters is a safe and effective method for pain control in patients undergoing surgical correction of pectus excavatum. Even though the degree of pain control is not necessarily superior to epidurals, in this study, the catheters were associated with a shorter postoperative length of stay in this patient population and did not increase the incidence of complications.

Feasibility of subcutaneous gentamicin and pressurized irrigation as adjuvant strategies to reduce surgical site infection in colorectal surgery: results of a pilot study.

Surgical site infections (SSIs) remain a common and costly morbidity after colorectal surgery. This rate remains high even in the setting of strict adherence to Surgical Care Improvement Project Protocols. The aim of our pilot study was to determine the feasibility and safety of subcutaneous gentamicin injection or pressurized irrigation as adjuncts to reduce SSI. A total of 132 patients who underwent colorectal surgery at the VA North Texas Health Care System were prospectively assigned to a pressurized irrigation group (n = 44), a preincision gentamicin injection group (n = 48), or control (n = 40). The primary objective was to assess safety and feasibility of these strategies. Patient demographics were matched among groups. Univariate and multivariate analyses were performed to identify possible predictions of SSI in this cohort. The rate of SSI in the control group was 25 per cent, 13.5 per cent in the pressurized irrigation group, and 12.5 per cent in the gentamicin group (P = 0.26). Combined, the intervention groups had a 13 per cent SSI versus 25 per cent control (P = 0.09). Operative time was not increased by the interventions and no intraoperative complications specifically related to the interventions were noted. Postoperative complications were not different between groups. Both albumin and body mass index were associated with SSI. Body mass index was and independent predictor of SSI (P = 0.006). In conclusion, this pilot study demonstrates the feasibility of the interventions described. There was no detrimental effect of either intervention. There was trend toward a reduction in SSI in the intervention group, which warrants further investigation.

Selective TNF-α inhibitor-induced injection site reactions.

INTRODUCTION: During the last decade, many new biological immune modulators entered the market as new therapeutic principles. TNF-α is a pro-inflammatory cytokine known to a have a key role in the pathogenic mechanisms of various immune-mediated or inflammatory diseases. TNF-α blockers have demonstrated efficacy in large, randomized controlled clinical trials either as monotherapy or in combination with other anti-inflammatory or disease-modifying anti-rheumatic drugs. AREAS COVERED: Although generally well tolerated and safe, potential adverse events may be associated with TNF-α inhibitor treatment. The authors will briefly review the potential adverse drug reactions and the immunological mechanisms of injection site reactions (ISRs) in patients treated with etanercept and adalimumab. EXPERT OPINION: Patients treated with TNF-α inhibitors can develop ISR around the sites of injections. 'Type IV delayed type reaction' or 'recall ISRs'. Eosinophilic cellulitis or 'Wells syndrome', 'type III' and 'type I' reactions are reported. Long-term studies are necessary to determine the durability of response and the real risk of ISRs with golimumab and certolizumab pegol. Further studies are also necessary to evaluate the immunogenicity of these drugs.

Incidence and causes for syringe driver site reactions in palliative care: A prospective hospice-based study.

BACKGROUND: Syringe drivers are routinely used in palliative care for the subcutaneous infusion of drugs for pain and symptom control. Local site reactions occurring at the site of infusion can lead to patient discomfort and the potential for sub-optimal symptom control. AIM: The aim of this study was to investigate whether there was a correlation between drugs administered subcutaneously via a syringe driver and the incidence of syringe driver site reactions, further linking this to time to syringe driver site reaction. DESIGN: Prospective quantitative data collection of syringe driver use for 170 hospice inpatients. SETTING/PARTICIPANTS: Specialist palliative care inpatient facility in the UK. Syringe driver recording forms were retrieved from case notes of consecutive patients who received medication via a syringe driver. RESULTS: An association between the presence of cyclizine and levomepromazine and the incidence of syringe driver site reactions was identified. A marked difference in incidence of syringe driver site reaction was observed between the two study centres (26.5% vs. 7.7%). Although baseline patient characteristics were comparable, a difference in practice between the centres was identified, i.e. use of parenteral cannulae. An association between the time a syringe driver was in situ and the occurrence of a syringe driver site reaction was also demonstrated. CONCLUSIONS: Recommendations can be made for the frequency of syringe driver site changes based on which drugs are in use. Incidental findings from the study have been used to change practice at the hospice study site, with regard to choice of parenteral cannulae.

Uso de bomba de infusão subcutânea de insulina e suas indicações: [revisão] / Insulin pump therapy in patients with type 1 diabetes: [review]

Tanto a bomba de infusão de insulina quanto a terapêutica de múltiplas doses de insulina (MDI) são meios efetivos de implementar o manejo intensivo do diabetes melito tipo 1 (DM1), com o objetivo de chegar a níveis glicêmicos quase normais e obter-se um estilo de vida mais flexível. A terapia com bomba de infusão de insulina é tão segura quanto a MDI e tem vantagens sobre ela, sobretudo em pacientes com hipoglicemias freqüentes, com um fenômeno do alvorecer importante, com gastroparesia, na gravidez, em crianças e em pacientes com DM1 e com um estilo de vida errático. A terapia com bomba de infusão de insulina possibilita maior probabilidade de se alcançar melhor controle glicêmico com menos hipoglicemia, hipoglicemias assintomáticas e melhor qualidade de vida. Além disso, os riscos e os efeitos adversos da terapêutica insulínica em pacientes com DM1 em insulinização intensiva são menores nos pacientes usando esta terapia, quando comparados a pacientes em MDI. Para tal, o ajuste cuidadoso das doses basais e de bólus e o seguimento adequado do paciente são vitais.

Both Continuous Subcutaneous Insulin Infusion (CSII) and Multiple Daily Injections (MDI) are effective ways of implementing intensive management of DM1 to attain near normal glycemic levels and a more flexible lifestyle. CSII is as safe as MDI and has some advantages over it mostly in diabetic patients with frequent hypoglycemias with important dawn phenomenum, gastroparesia, during pregnancy, in children and in patients with an erratic way of living. CSII allows a better chance to reach better glycemic control with less hypoglycemia, asymptomatic hypoglycemias and a better quality of life. Besides, risks are lower and adverse events are less frequent in DM1 patients under CSII as compared to MDI. To obtain results like this, a careful adjustment of basal and boluses insulin doses and an adequate patient follow-up are essential.