7196 research outputs found
Sort by
Predicting and Confirming Bioequivalence of Alpelisib Oral Granules and Tablets for Patients With PIK3CA-Related Disorders.
No full textAlpelisib, an oral α-specific phosphoinositide 3-kinase (PI3K) inhibitor, has been shown to be safe and effective for some patients with gain-of-function mutation in the PIK3CA oncogene. Alpelisib has received US FDA accelerated approval as Vijoice® film-coated tablets to treat severe PIK3CA-Related Overgrowth Spectrum (PROS). PROS typically displays clinical manifestations in the first year of patient life. Therefore, oral granules were developed as an age-appropriate pediatric dosage form. Bioequivalence between alpelisib granules and tablet and the effect of food on granules pharmacokinetics were assessed in a single-center, randomized, three-treatment, six-sequence, three-period, crossover study among 60 healthy adults. Participants were randomly assigned to receive a single 50-mg alpelisib dose as: (i) tablet following a meal, (ii) granules following a meal, and (iii) granules while fasting. Statistical analysis of non-compartmental pharmacokinetic parameters demonstrated bioequivalence between the 50-mg alpelisib granules and tablet forms when administered with food: estimated geometric mean ratios (90% confidence interval) for granules-versus-tablet area under the curve (AUC) from time zero to infinity (AUCinf), to the last measurable concentration (AUClast) and maximum observed concentration (Cmax) were 0.984 (0.952, 1.02), 0.980 (0.946, 1.02), and 0.947 (0.891, 1.01), respectively. No clinically relevant food effect on 50-mg alpelisib granules pharmacokinetics was observed. These results were accurately predicted using physiologically based biopharmaceutical modeling. Alpelisib granules provide a bioequivalent alternative to tablets for patients prescribed a 50-mg dose and have difficulty swallowing tablets, an important consideration for convenience and compliance of this standard-of-care chronic therapy for patients with PROS. This study was registered in ClinicalTrials.gov on January 4, 2022 (NCT05195892)
Current Industry Practices on Closed System Transfer Devices (CSTD) for Drug Products
No full textUSP and NIOSH provide guidance on the use of Closed System Drug-Transfer Devices for
hazardous drug in the healthcare setting. However, CSTDs are used by clinical sites irrespective of drug
hazard status. In this paper, previous publications that describe evaluation and CSTD risk assessment
strategies are presented. In addition, a pharmaceutical industry survey was performed to describe the
current strategies for evaluation of CSTDs and how these devices are managed for clinical studies.
Finally, recommendations are proposed to mitigate risks associated with CSTDs. These
recommendations incorporate: testing considerations, risk assessments, and communication
Rational design and analytical characterization of self-assembling poly(N-isopropylacrylamide) and poly(2-alkyl-2-oxazoline) hyaluronic acid copolymers.
No full textIn this study, we applied a systematic approach to establish an iterative workflow and to drive the chemical design of thermosensitive, in situ forming injectables as a function of the intended target product profile. Self-assembly, mechanical properties, physical state, and thermal transition behavior were assessed via nuclear magnetic resonance, oscillatory rheology, turbidimetry and visual inspection techniques. Thus, poly(N-isopropylacrylamide) (PNIPAM) and poly(2-alkyl-2-oxazoline)s (PAOx)s with LCSTs below body temperature were studied before and after grafting them onto azido-substituted hyaluronic acid (HA) via strain-promoted azide-alkyne cycloaddition (SPAAC). Ultimately, we identified critical material attributes able to guide the pharmaceutical development of in situ gelling thermosensitive polymers
Chemical manipulation of RNA foci mobilizes G4C2 repeat RNA from nuclear storage foci for translation into dipeptide repeat polyproteins in C9Orf72 ALS neurons
No full textAn intronic G4C2 repeat expansion in the C9orf72 gene is the major known cause for Amyotrophic Lateral Sclerosis(ALS). The disease mechanism is still not fully understood,but a pathological gain of function of nuclear repeat RNA foci as well as translation into toxic dipeptide repeat (DPR) polyproteins have been proposed. We screened 100,000 small molecules in C9orf72 patient iPS derived neurons for modulation of RNA foci and identified analogs of known spliceosomal modulators
targeting SF3B1. These compounds trigger elimination of RNA foci post-transcriptionally, independent of C9orf72 pre-RNA splicing and gene context. This changes the interactome of RNA binding proteins bound to the G4C2 repeat RNA with a strongly enhanced binding of the splice and nuclear export factor SRSF1. As a result, the repeat RNA is licensed into RAN translation in the cytoplasm, thereby enhancing DPR cell toxicity. In turn, trapping SRSF1 in the cytoplasm by small molecule inhibition of SRPK resulted in build of nuclear RNA foci. These data suggest a protective rather than toxic role of
nuclear RNA foci and provide the first set of orthogonal pharmacological tools to study C9orf72 repeat RNA metabolism and ALS pathobiology
Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase
No full textLeukotriene C4 synthase (LTC4S) is a glutathione S-transferase that mediates the biosynthesis of cysteinyl leukotriene C4 (LTC4). Cysteinyl leukotrienes (CysLTs) are lipid mediators that drive type 2 inflammation, bronchoconstriction, and itch. LTC4S represents an attractive drug target for the treatment of allergic inflammatory diseases, but to date, no LTC4S inhibitor has been tested in patients. Herein, we disclose the discovery and preclinical profiling of the highly selective, oral LTC4S inhibitor GJG057 (compound 1), which exhibits 20-fold improved potency (IC50 = 44 nM) versus clinical candidate AZD9898 (IC50 = 900 nM) in a human whole blood LTC4 release assay. GJG057 showed efficacy in a murine asthma exacerbation model as well as in a murine mastoparan-induced skin challenge PK/PD model and was profiled in GLP toxicology studies with up to 16 weeks duration. Despite its promising properties, GJG057 was not progressed into clinical trials as an oral drug
Data- and knowledge-derived functional landscape of human solute carriers
No full textThe efforts to generate functional data on most of the human solute carrier (SLC) superfamily of membrane transporters coordinated within the RESOLUTE and REsolution consortia resulted in numerous rich and diverse data sets. To synthesize the different aspects of SLC function into a comprehensive SLC knowledge base, we consolidate generated data with selected information from the public domain, such as substrate annotation, subcellular localization, structure, tissue expression, disease association, availability of assays as well as knowledge from the literature. Employing ontologies turned out to be essential given the redundancy and ambiguity of SLC function. A web portal enables browsing and querying the SLC knowledge base and interactive dashboards allow generation of hypotheses, based on visual exploration of individual data sets and annotations. We further harmonize eight selected data sets and integrate them to a functional landscape of human SLCs. Based on all the available data and integration, we are able to assign a biochemical/biological function to each SLC, making it one of the largest systematic annotations of human gene function ever, potentially acting as blueprint for future endeavours and representing a watershed for transporter biology
Proceedings of the 15th European Immunogenicity Platform Open Symposium on Immunogenicity of Biopharmaceuticals
No full textThis year, the European Immunogenicity Platform celebrated the 15th edition of its Open Symposium on Immunogenicity of Biopharmaceuticals and its associated one-day workshop. The meeting attracted experts and newcomers across industry, regulatory agencies and academia, who actively participated in 3 days of discussion on risk assessment, monitoring and mitigation of unwanted immunogenicity of biologics. Besides oral presentations, poster sessions were held to maximize scientific exchange and networking opportunities. Here, we report the discussions that took place April 22-24 in Lisbon
Feasibility of Hot Melt Extrusion in Converting Water-Based Nanosuspensions into Solid Dosage Forms
No full textAim: In addition to numerous benefits provided by nanosuspensions (NSs) (e.g., enhanced saturation solubility, increased area for interaction with fluids), they suffer from major stability, handling and compliance issues. To overcome these challenges, we evaluated the feasibility of hot melt extrusion (HME) in transforming a cinnarizine-based NS, selected as a case study, into granules for oral intake. Methods: Thermoplastic polymers, in principle compatible with the thermal behavior of the selected drug and characterized by different interaction mechanisms with aqueous fluids, were used as carriers to absorb the NS and were processed by HME. Results: The extruded granules pointed out good physio-technological characteristics, a drug content > 85% with coefficient of variation (CV) < 5% and tunable in vitro performance coherent with the polymeric carriers they were composed of. Particle size as well as the solid state of cinnarizine was checked using several analytical techniques in combination (e.g., DSC, SEM, FT-IR, Raman). Depending on the composition of the granules, and specifically for formulations processed below 85 °C, the drug was found to remain crystalline and in the desired nanoscale. Conclusions: HME turned out to be a versatile process to transform, in a single-step, NSs into multi-particulate solid products for oral administration showing a variety of release profiles
PET-based tracking of CAR T cells and viral gene transfer using a cell surface reporter that binds to lanthanide complexes.
No full textThe clinical translation of cell- and gene-based therapies is limited by the lack of non-invasive, quantitative and specific whole-body imaging tools. Here we present a positron emission tomography reporter system based on a membrane-anchored anticalin protein that binds a fluorine-18-labelled lanthanide complex with picomolar affinity via a bio-orthogonal interaction. The reporter was introduced into therapeutic cells, including CAR T cells and adeno-associated virus-transduced cells. In vitro, reporter expression conferred >800-fold higher radioligand binding versus controls. In mice, the radioligand demonstrated rapid renal clearance, showed no off-target accumulation and enabled high-contrast detection of as few as 1,200 CAR T cells in the bone marrow. Longitudinal positron emission tomography imaging over 4 weeks revealed precise tracking of CAR T cell expansion and migration, with signal intensity correlating linearly with flow cytometry data. The system also enabled the quantitative imaging of in vivo gene transfer using an adeno-associated viral vector. This depth-independent whole-body imaging platform offers a powerful tool for monitoring therapeutic cell dynamics and gene delivery in preclinical and potentially clinical settings
Blood characteristics of adults with type 2 diabetes and response of their peripheral blood mononuclear cells to inhibitors of the NLRP3-inflammasome and caspase-1
No full textObesity and aging are associated with increased activity of the innate immune system. This chronic systemic inflammation contributes to the development of type 2 diabetes and long-term complications and is partly driven by the activation of the NLRP3 inflammasome. We conducted a comparative analysis of clinical parameters, non-esterified fatty acid (NEFA) profiles, immune cell subsets, and inflammatory responses of peripheral blood mononuclear cells obtained from both healthy individuals and those diagnosed with type 2 diabetes. Plasma NEFA profiling revealed a dysregulation in patients with type 2 diabetes, indicating potential modulation of immune cell responses by lipids, along with leukocytosis, elevated serum levels of inflammatory cytokines, the inflammasome-related protein ASC, IL-1RA, and IL-18BPa. Surprisingly, functional assessments demonstrated comparable NLRP3 inflammasome activity in peripheral blood mononuclear cells (PBMCs) from both groups, suggesting that systemic inflammation in type 2 diabetes is driven by elevated leucocyte numbers or resident tissue macrophages. Treatment of PBMCs with NLRP3 and caspase-1 inhibitors attenuated the release of pro-inflammatory cytokines ex vivo. Therefore, inhibition of inflammasome activation emerges as a promising therapeutic strategy for management of diabetes-related complications