7196 research outputs found
Sort by
Principled Drug-Drug Interaction Terms for Bayesian Logistic Regression Models of Drug Safety in Oncology Phase I Combination Trials
No full textIn Oncology, trials evaluating drug combinations are becoming more common. While combination therapies bring the potential for greater efficacy, they also create unique challenges for ensuring drug safety. In Phase-I dose escalation trials of drug combinations, model-based approaches enable efficient use of information gathered, but the models need to account for trial complexities: appropriate modeling of interactions becomes increasingly important with growing numbers of drugs being tested simultaneously in a given trial. In principle, we can use data from multiple arms testing varying combinations (like a backbone treatment combined with different candidate combination partners) to jointly estimate toxicity of the drug combinations. However, such efforts have highlighted limitations when modelling drug-drug interactions in the Bayesian Logistic Regression Model (BLRM) framework used to ensure patient safety. Previous models either do not account for non-monotonicity due to antagonistic toxicity, or exhibit the fundamental flaw of exponentially overpowering the contributions of the individual drugs in the dose-response. This specifically leads to issues when drug combinations exhibit antagonistic toxicity, in which case the toxicity probability gets vanishingly small as doses get very large.
We put forward additional constraints inspired by Paracelsus' intuition of "the dose makes the poison" which avoid this flaw and present an improved interaction model which is compatible with these constraints. We create instructive data scenarios that showcase the improved behavior of this more constrained drug-drug interaction model in terms of preventing further dosing at overly toxic dose combinations and more sensible dose-finding under antagonistic drug toxicity. This model is now available in the open-source OncoBayes2 R package that implements the BLRM framework for an arbitrary number of drugs and trial arms
Advanced analytical approaches for AAV empty/full Capsid characterAdvanced Analytical Approaches For AAV Empty/Full Capsid Characterization And Quantificationization and quantification
No full textno abstrac
Clonal hematopoiesis detection in patients with cancer using cell-free DNA sequencing.
No full textIn the context of cancer, clonal hematopoiesis of indeterminate potential (CHIP) is associated with the development of therapy-related myeloid neoplasms and shorter overall survival. Cell-free DNA (cfDNA) sequencing is becoming widely adopted for genomic screening of patients with cancer but has not been used extensively to determine CHIP status because of a requirement for matched blood and tumor sequencing. We present an accurate classification approach to determine the CH status from cfDNA sequencing alone, applying our model to 4324 oncology clinical cfDNA samples. Using this method, we determined that 30.3% of patients in this cohort have evidence of CH, and the incidence of CH varies by tumor type. Matched RNA sequencing data show evidence of increased inflammation, especially neutrophil activation, within the tumors and tumor microenvironments of patients with CH. In addition, patients with CH had evidence of neutrophil activation systemically, pointing to a potential mechanism of action for the worse outcomes associated with CH status. Neutrophil activation may be one of many mechanisms, however, because patients with estrogen receptor-positive breast cancer harboring TET2 frameshift mutations had worse outcomes but similar neutrophil frequencies to patients without CH. Together, these data show the feasibility of detecting CH through cfDNA sequencing alone and an application of this method, demonstrating increased inflammation in patients with CH both systemically and in the tumor microenvironment
The incidence of spontaneous arrhythmias in telemetered beagle dogs, Göttingen Minipigs and Cynomolgus non-human primates: A HESI consortium retrospective analysis.
No full textCharacterization of the incidence of spontaneous arrhythmias to identify possible drug-related effects is often an important part of the analysis in safety pharmacology studies using telemetry.A retrospective analysis in non-clinical species with and without telemetry transmitters was conducted. Electrocardiograms (24 h) from male and female beagle dogs (n = 131), Göttingen minipigs (n = 108) and cynomolgus non-human primates (NHP; n = 78) were analyzed.Ventricular tachycardia (VT) was observed in 3% of the dogs but was absent in minipigs and NHPs. Ventricular fibrillation (VF) was not observed in the 3 species. Ventricular premature beats (VPBs) were more frequent during daytime and atrioventricular blocks (AVBs) were more frequent at night in all species. A limited number of animals exhibited a high arrhythmia frequency and there was no correlation between animals with higher frequency of an arrhythmia type and the frequency of other arrythmias in the same animals. Clinical chemistry or hematology parameters were not different with or without telemetry devices. NHP with a transmural left ventricular pressure (LVP) catheter exhibited a greater incidence of VPBs and PJCs compared to telemetry animals without LVP.All species were similar with regards to the frequency of ventricular ectopic beats (26-46%) while the dog seemed to have more frequent junctional complexes and AVB compared to NHP and minipigs. Arrhythmia screening may be considered during pre-study evaluations, to exclude animals with abnormally high arrhythmia incidence
Wdr5 is essential for fetal erythropoiesis and hematopoiesis.
No full textWDR5 is a highly conserved protein that performs multiple scaffolding functions in the context of chromatin. However, efforts to understand the function of WDR5 in normal tissues physiologically are quite limited so far. In our study, we explored the function of Wdr5 in erythropoiesis and hematopoiesis by using a hematopoietic-specific Wdr5 knockout mouse model. We found that loss of Wdr5 mediated by Vav-iCre leads to embryonic lethality with defective erythropoiesis. In addition, Wdr5-deficiency completely impairs the hematopoietic stem and progenitor cells function and might alter the immunophenotype of these stem cells and progenitors by decreasing c-Kit expression. Collectively, we identified the pivotal role of Wdr5 in fetal hematopoiesis and erythropoiesis as the de novo findings
A high-throughput 3D cantilever array to model airway smooth muscle hypercontractility in asthma.
No full textAsthma is often characterized by tissue-level mechanical phenotypes that include remodeling of the airway and an increase in airway tightening, driven by the underlying smooth muscle. Existing therapies only provide symptom relief and do not improve the baseline narrowing of the airway or halt progression of the disease. To investigate such targeted therapeutics, there is a need for models that can recapitulate the 3D environment present in this tissue, provide phenotypic readouts of contractility, and be easily integrated into existing assay plate designs and laboratory automation used in drug discovery campaigns. To address this, we have developed DEFLCT, a high-throughput plate insert that can be paired with standard labware to easily generate high quantities of microscale tissues in vitro for screening applications. Using this platform, we exposed primary human airway smooth muscle cell-derived microtissues to a panel of six inflammatory cytokines present in the asthmatic niche, identifying TGF-β1 and IL-13 as inducers of a hypercontractile phenotype. RNAseq analysis further demonstrated enrichment of contractile and remodeling-relevant pathways in TGF-β1 and IL-13 treated tissues as well as pathways generally associated with asthma. Screening of 78 kinase inhibitors on TGF-β1 treated tissues suggests that inhibition of protein kinase C and mTOR/Akt signaling can prevent this hypercontractile phenotype from emerging, while direct inhibition of myosin light chain kinase does not. Taken together, these data establish a disease-relevant 3D tissue model for the asthmatic airway, which combines niche specific inflammatory cues and complex mechanical readouts that can be utilized in drug discovery efforts
Enhanced multi-component model to consider the lubricant effect on compressibility and compactibility.
No full textModeling of structural and mechanical tablet properties consisting of multiple components, based on a minimum of experimental data is of high interest, in order to minimize time- and cost-intensive experimental trials in the development of new tablet formulations. The majority of commonly available models use the compressibility and compactibility of constituent components and establish mixing rules between those components, in order to predict the tablet properties of formulations containing multiple components. However, their applicability is limited to single materials, which form intact tablets (e.g. lactose, cellulose) and therefore, they cannot be applied for lubricants. Lubricants are required in the majority of industrial tablet formulations and usually influence the mechanical strength of tablets. This study combines the multi-component compaction model of Reynolds et al. (2017) with a recently published lubrication model (Puckhaber et al. 2020) to describe the impact of multiple components on a formulation consisting of two diluents and a lubricant. By that, this model combination displays a meaningful extension of existing compaction models and allows the systematic prediction of properties of lubricated multi-component tablets
The European Federation for Medicinal Chemistry and Chemical Biology (EFMC) Best Practice Initiative: Hit generation
No full textHit generation is a crucial step in drug discovery that will determine the speed and chance of success of identifying drug candidates. Many strategies are now available to identify chemical starting points, or hits, and each biological target warrants a tailored approach. In this set of best practices, we detail the essential approaches for target centric hit generation and the opportunities and challenges they come with. We then provide guidance on how to validate hits to ensure medicinal chemistry is only performed on compounds and scaffolds that engage the target of interest and have the desired mode of action. Finally, we discuss the design of integrated hit generation strategies that combine several approaches to maximize the chance of identifying high quality starting points to ensure a successful drug discovery campaign
Structure and RAF family kinase isoform selectivity of type II RAF inhibitors tovorafenib and naporafenib.
No full textUpon activation by RAS, RAF family kinases initiate signaling through the MAP kinase cascade to control cell growth, proliferation, and differentiation. Among RAF isoforms (ARAF, BRAF, and CRAF), oncogenic mutations are by far most frequent in BRAF. The BRAFV600E mutation drives more than half of all malignant melanoma and is also found in many other cancers. Selective inhibitors of BRAFV600E (vemurafenib, dabrafenib, encorafenib) are used clinically for these indications, but they are not effective inhibitors in the context of oncogenic RAS, which drives dimerization and activation of RAF, nor for malignancies driven by aberrantly dimerized truncation/fusion variants of BRAF. By contrast, a number of "type II" RAF inhibitors have been developed as potent inhibitors of RAF dimers. Here, we compare potency of type II inhibitors tovorafenib (TAK-580) and naporafenib (LHX254) in biochemical assays against the three RAF isoforms and describe crystal structures of both compounds in complex with BRAF. We find that tovorafenib and naporafenib are most potent against CRAF but markedly less potent against ARAF. Crystal structures of both compounds with BRAFV600E or WT BRAF reveal the details of their molecular interactions, including the expected type II-binding mode, with full occupancy of both subunits of the BRAF dimer. Our findings have important clinical ramifications. Type II RAF inhibitors are generally regarded as pan-RAF inhibitors, but our studies of these two agents, together with recent work with type II inhibitors belvarafenib and naporafenib, indicate that relative sparing of ARAF may be a property of multiple drugs of this class
Closed System Transfer Devices (CSTDs): understanding potential over- and under- dosing of liquid vial drug products and how to generally mitigate.
No full textClosed system transfer devices (CSTDs) are a major challenge for drug manufacturers to assess and assure drug compatibility and acceptable dosing accuracy for a range of clinical administration strategies. In this article, we systematically investigate parameters affecting the loss of product during transfer by CSTDs from vials to infusion bags. We show that liquid volume loss increases with vial size, vial neck diameter, and solution viscosity - while dependent on stopper design. We further compared CSTDs' performance with a traditional syringe transfer and learned that loss is larger for CSTDs than for syringe transfer. Based on experimental data, a statistical model was developed to predict drug loss upon transfer by CSTDs. The model predicted that, for single dose vials with USP conforming overfill, a complete extraction and transfer of the full dose can be assured for a broad range of CSTDs, product viscosities, and vial types (2R, 6R, 10R, 20R) if a flush (of syringe, syringe adaptor, bag spike) is performed. The model also predicted that complete transfer cannot be achieved for fill volumes ≤ 2.0 mL. For multi-dose vials and pooling of several vials, respectively, the effective dose transfer (i.e., ≥ 95%) for all CSTDs tested was predicted to be achieved if a minimum of 5.0 mL is transferred