Subcutaneous Injection Site Pain of Formulation Matrices

Shi, Galen; Pisupati, Karthik; Parker, Jonathan G; Corvari, Vincent; Payne, Christopher D.; Xu, Wen; Collins, D. M.; Felippis, Michael R. De

doi:10.1007/s11095-021-03047-3

Cited by 19 publications

(31 citation statements)

References 33 publications

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“…SC vedolizumab contains citrate which has been pointed out to be causing pain, but studies that have addressed this issue underscore that citrate is merely one of several factors that may affect potential pain sensation at SC injection and that some of the studies attributing pain at the injection site to citrate are difficult to interpret since citrate was one of several factors modified 42–44 . Other factors that may be equally important in this context are other buffers commonly used such as phosphate and histidine, the buffer concentration, injected volume, solution temperature, pH, osmolality, needle gauge, injector device, injection speed, injection technique and low body weight 42–44 …”

Section: Discussionmentioning

confidence: 99%

“…36 Such transient reactions are thus not likely to be an effect of the drug per se but more likely representing nonpharmacological potentially immune-mediated adverse effects, 38,39 alternatively representing a nocebo effect. 40 [42][43][44] We also investigated various aspects of the patients' experience with the injector pen and the switch from IV to SC treatment. Overall patients found the injector pen to be user-friendly and they were very satisfied with switching to SC treatment, was reflected in all aspects explored.…”

Section: Ventress Et Al Suggested That the First Dose Of Sc Vedolizumabmentioning

confidence: 99%

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Real‐world data on switching from intravenous to subcutaneous vedolizumab treatment in patients with inflammatory bowel disease

Bergqvist

Holmgren

Klintman

et al. 2022

Aliment Pharmacol Ther

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Summary Background and Aims Vedolizumab is a gut‐selective treatment approved for Crohn’s disease (CD) and ulcerative colitis (UC). Recently, a subcutaneous formulation of vedolizumab was approved. The aims of this study were to evaluate efficacy, safety, pharmacokinetics, patient experience and costs following a switch from intravenous to subcutaneous vedolizumab treatment. Methods Patients were switched from intravenous to subcutaneous vedolizumab maintenance treatment and followed prospectively for 6 months and a subgroup for 12 months. The primary endpoint was change in faecal calprotectin levels. Furthermore, we evaluated clinical disease activity, remission rates, plasma CRP, drug persistence, adverse events, local injection reactions, serum drug concentrations, patient satisfaction, quality‐of‐life and treatment costs. Results Eighty‐nine patients were included (48 CD; 41 UC). Faecal calprotectin decreased significantly in CD but not in UC. Clinical indices, remission rates, plasma CRP levels and quality‐of‐life scores remained unchanged. Patients that had been on standard compared to optimised IV vedolizumab dosing displayed similar outcomes on standard SC dosing. Drug persistence at 6 and 12 months was 95.5% and 88.5%, respectively. Frequencies of adverse events were similar before and after the switch. No serious adverse events occurred. Transient severe local injection reactions were experienced by 1.2% of patients. Median vedolizumab trough levels were 2.3 times higher on subcutaneous compared to intravenous treatment. Patient satisfaction was generally high. Annualised treatment costs were reduced by 15% following the switch. Conclusions The switch from intravenous to subcutaneous vedolizumab could be done with preserved therapeutic effectiveness, safety, high patient satisfaction and low discontinuation rate, at a reduced cost.

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Section: Discussionmentioning

confidence: 99%

Section: Ventress Et Al Suggested That the First Dose Of Sc Vedolizumabmentioning

confidence: 99%

Real‐world data on switching from intravenous to subcutaneous vedolizumab treatment in patients with inflammatory bowel disease

Bergqvist

Holmgren

Klintman

et al. 2022

Aliment Pharmacol Ther

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“… 2 , 4 , 5 , 8 Thus, when developing a protein therapeutic formulation, to enhance solubility while preventing aggregation, as a first stage, solution pH is adjusted and solutions with minimal salt concentration and low ionic strength are typically used. 2 , 3 , 13 …”

Section: Introductionmentioning

confidence: 99%

Ionic Liquid-Based Strategy for Predicting Protein Aggregation Propensity and Thermodynamic Stability

Shmool

Martin

Matthews

et al. 2022

JACS Au

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Novel drug candidates are continuously being developed to combat the most life-threatening diseases; however, many promising protein therapeutics are dropped from the pipeline. During biological and industrial processes, protein therapeutics are exposed to various stresses such as fluctuations in temperature, solvent pH, and ionic strength. These can lead to enhanced protein aggregation propensity, one of the greatest challenges in drug development. Recently, ionic liquids (ILs), in particular, biocompatible choline chloride ([Cho]Cl)-based ILs, have been used to hinder stress-induced protein conformational changes. Herein, we develop an IL-based strategy to predict protein aggregation propensity and thermodynamic stability. We examine three key variables influencing protein misfolding: pH, ionic strength, and temperature. Using dynamic light scattering, zeta potential, and variable temperature circular dichroism measurements, we systematically evaluate the structural, thermal, and thermodynamic stability of fresh immunoglobin G4 (IgG4) antibody in water and 10, 30, and 50 wt % [Cho]Cl. Additionally, we conduct molecular dynamics simulations to examine IgG4 aggregation propensity in each system and the relative favorability of different [Cho]Cl-IgG4 packing interactions. We re-evaluate each system following 365 days of storage at 4 °C and demonstrate how to predict the thermodynamic properties and protein aggregation propensity over extended storage, even under stress conditions. We find that increasing [Cho]Cl concentration reduced IgG4 aggregation propensity both fresh and following 365 days of storage and demonstrate the potential of using our predictive IL-based strategy and formulations to radically increase protein stability and storage.

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“…Solubility can be highly pH/buffer-dependent and we chose to conduct these studies in a histidine buffer matrix, as such a buffer system is common for mAb-based drug products 29 and has been shown to induce minimal injection site pain. 36 Antibodies with Fv A require the highest %PEG to precipitate, which also show the lowest turbidity compared to the antibodies with the other variable regions. Similarly, the antibodies that require the lowest %PEG to precipitate also demonstrate the highest turbidity, such as the mAbs with Fv B.…”

Section: Discussionmentioning

confidence: 99%

Impact of IgG subclass on molecular properties of monoclonal antibodies

Tang

Cain

Anguiano

et al. 2021

mAbs

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Immunoglobulin G-based monoclonal antibodies (mAbs) have become a dominant class of biotherapeutics in recent decades. Approved antibodies are mainly of the subclasses IgG1, IgG2, and IgG4, as well as their derivatives. Over the decades, the selection of IgG subclass has frequently been based on the needs of Fc gamma receptor engagement and effector functions for the desired mechanism of action, while the effect on drug product developability has been less thoroughly characterized. One of the major reasons is the lack of systematic understanding of the impact of IgG subclass on the molecular properties. Several efforts have been made recently to compare molecular property differences among these IgG subclasses, but the conclusions from these studies are sometimes obscured by the interference from variable regions. To further establish mechanistic understandings, we conducted a systematic study by grafting three independent variable regions onto human IgG1, an IgG1 variant, IgG2, and an IgG4 variant constant domains and evaluating the impact of subclass and variable regions on their molecular properties. Structural and computational analysis revealed specific molecular features that potentially account for the differential behavior of the IgG subclasses observed experimentally. Our data indicate that IgG subclass plays a significant role on molecular properties, either through direct effects or via the interplay with the variable region, the IgG1 mAbs tend to have higher solubility than either IgG2 or IgG4 mAbs in a common pH 6 buffer matrix, and solution behavior relies heavily on the charge status of the antibody at the desirable pH.

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Subcutaneous Injection Site Pain of Formulation Matrices

Cited by 19 publications

References 33 publications

Real‐world data on switching from intravenous to subcutaneous vedolizumab treatment in patients with inflammatory bowel disease

Real‐world data on switching from intravenous to subcutaneous vedolizumab treatment in patients with inflammatory bowel disease

Ionic Liquid-Based Strategy for Predicting Protein Aggregation Propensity and Thermodynamic Stability

Impact of IgG subclass on molecular properties of monoclonal antibodies

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