7196 research outputs found
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MicroCycle: An Integrated and Automated Platform to Accelerate Drug Discovery.
No full textWe herein describe the development and application of a modular technology platform which incorporates recent advances in plate-based microscale chemistry, automated purification, in situ quantification, and robotic liquid handling to enable rapid access to high-quality chemical matter already formatted for assays. In using microscale chemistry and thus consuming minimal chemical matter, the platform is not only efficient but also follows green chemistry principles. By reorienting existing high-throughput assay technology, the platform can generate a full package of relevant data on each set of compounds in every learning cycle. The multiparameter exploration of chemical and property space is hereby driven by active learning models. The enhanced compound optimization process is generating knowledge for drug discovery projects in a time frame never before possible
Sire: An interoperability engine for prototyping algorithms and exchanging information between molecular simulation programs.
No full textSire is a Python/C++ library that is used both to prototype new algorithms and as an interoperability engine for exchanging information between molecular simulation programs. It provides a collection of file parsers and information converters that together make it easier to combine and leverage the functionality of many other programs and libraries. This empowers researchers to use sire to write a single script that can, for example, load a molecule from a PDBx/mmCIF file via Gemmi, perform SMARTS searches via RDKit, parameterize molecules using BioSimSpace, run GPU-accelerated molecular dynamics via OpenMM, and then display the resulting dynamics trajectory in a NGLView Jupyter notebook 3D molecular viewer. This functionality is built on by BioSimSpace, which uses sire's molecular information engine to interconvert with programs such as GROMACS, NAMD, Amber, and AmberTools for automated molecular parameterization and the running of molecular dynamics, metadynamics, and alchemical free energy workflows. Sire comes complete with a powerful molecular information search engine, plus trajectory loading and editing, analysis, and energy evaluation engines. This, when combined with an in-built computer algebra system, gives substantial flexibility to researchers to load, search for, edit, and combine molecular information from multiple sources and use that to drive novel algorithms by combining functionality from other programs. Sire is open source (GPL3) and is available via conda and at a free Jupyter notebook server at https://try.openbiosim.org. Sire is supported by the not-for-profit OpenBioSim community interest company
Developing Low Molecular Weight PET and SPECT Imaging Agents
No full textImaging agents for positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) have shown their utility in many situations, answering clinical questions related to drug development and medical considerations. The discovery and development of imaging agents follow a well-understood process, with variations related to available starting points and to the envisaged imaging application. This article describes the general development path leading from the expression of an imaging need and project initiation to a clinically usable imaging agent. The definition of the project rationale, the design and optimization of early leads, and the assessment of the imaging potential of an imaging agent candidate are followed by preclinical development activities that differ from those required for therapeutic agents. They lead to radiolabeling with a positron emitter and first-in-human clinical studies that will rapidly evaluate the ability of a new imaging agent to address the questions it was designed to answer
Clinical trial recommendations using Semantics-Based inductive inference and knowledge graph embeddings.
No full textDesigning a new clinical trial entails many decisions, such as defining a cohort and setting the study objectives to name a few, and therefore can benefit from recommendations based on exhaustive mining of past clinical trial records. This study proposes an approach based on knowledge graph embeddings and semantics-driven inductive inference for generating such recommendations.The proposed recommendation methodology is based on neural embeddings trained on first-of-its-kind knowledge graph constructed from clinical trials data. The methodology includes design of a knowledge graph for clinical trial data, evaluation of various knowledge graph embedding techniques for it, application of a novel inductive inference method using these embeddings, and generation of recommendations for clinical trial design. The study uses freely available data from clinicaltrials.gov and related sources.The proposed approach for recommendations obtained relevance scores ranging from 70% to 83%. These scores were determined by evaluating the text similarity of recommended elements to actual elements used in clinical trials that are in progress. Furthermore, the most pertinent recommendations were consistently located towards the top of the list, indicating the effectiveness of our method.Our study suggests that inductive inference using node semantics is a viable approach for generating recommendations using graphs neural embeddings, and that there is a potential for improvement in training graph embeddings using node semantics
Re-thinking the Current Paradigm for Clinical Immunogenicity Assessment: an update from the discussion in the European Bioanalysis Forum
No full textImmunogenicity regulatory guidance and industry recommendations have evolved over the last two decades since unexpected immune reactions were first reported with erythropoietin. Since then, the guidelines and practices for immunogenicity have stemmed from a reaction to a high-risk molecule causing significant clinical impact. Similar thinking is often applied to all biotherapeutic drugs, even when a well-defined risk assessment suggests otherwise. In recent years, the current testing paradigm for immunogenicity has been challenged with more informative approaches being proposed. In a Focus Workshop held by the European Bioanalysis Forum in September 2023, the current immunogenicity testing paradigm was challenged based on the experience and learning of 20+ years of immunogenicity strategies. The workshop recommendations proposed a new paradigm, challenging the value of multiple tiers depending on the immunogenicity risk assessment based on context of use, and moving towards treating immunogenicity as a pharmacodynamic biomarker for the drug. Such rethinking focuses on the value added for the patient, moving to a new paradigm where implementation of appropriate and truly informative immunogenicity testing strategies, depending on the context-of-use, become the norm
How Athletic Swiss Patients Experience Their Return to Sports After Anterior Cruciate Ligament Reconstruction: Results from a Retrospective Self-Assessment.
No full textAnterior cruciate ligament (ACL) ruptures are frequent injuries, especially in athletes. Return to sports after reconstruction of the ligament is a frequently debated topic and of high relevance for these patients. It is mostly achieved at 9-12 months post-surgery. However, the risk of subsequent knee injuries is high and psychological factors play an important role in the process and success of returning to sports. Little is known about patients' perception of their journey returning to sports. This study aims to fill the gap.The study aimed to include patients treated surgically for an ACL injury over 5 years at a specialized sports-medicine clinic. Patients were surveyed on the impact of the injury on their lives, their return to sports experience, and medical history.In total, 100 (of 474) patients aged 35.9 years responded. Within 5 years, 19% experienced a reoperation and 23% a new knee injury. Overall, 83% of patients returned to their main sport, 72% reached their pre-injury level. However, 45% reported at least one distinct or severe consequence of their ACL injury. The ability to return to sports had more impact on the perception of the course of treatment than the experience of new injuries or surgery.The rate of successful return to sports was comparable to previous reports despite a higher average age in this cohort. A successful return to sports seems to be a major determinant for the perception of impact from the injury and may be more important than the avoidance of repeat trauma
A multifaceted approach to understanding protein-buffer interactions in biopharmaceuticals.
No full textThe excipient selection process plays a crucial role in biopharmaceutical formulation development to ensure the long-term stability of the drug product. Though there are numerous options approved by regulatory authorities, only a subset is commonly utilized. Previous research has proposed various stabilization mechanisms, including protein-excipient interactions. However, identifying these interactions remains challenging due to their weak and transient nature. In this study, we present a comprehensive approach to identify such interactions. Using the 1HT2 CPMG (Carr-Purcel-Meiboom-Gill) filter experiment we identified interactions of rituximab with certain buffers and amino acids, shedding light on its Fc fragment instability that manifested during the enzymatic cleavage of the antibody. Moreover, chemometric analyses of 2D NMR fingerprints revealed interactions of selected excipients with antibody fragments. Furthermore, molecular dynamics simulations revealed potential interacting hotspots without NMR spectra assignment. Our results highlight the importance of an orthogonal methods approach to uncovering these critical interactions, advancing our understanding of excipient stabilization mechanisms and rational formulation design in biopharmaceutics
The Current State of Biotransformation Science – Industry Survey of In Vitro and In Vivo Practices, Clinical Translation, and Future Trends
No full textEmbedded within the field of drug metabolism and pharmacokinetics (DMPK), biotransformation is a discipline that studies
the origins, disposition, and structural identity of metabolites to provide a comprehensive safety assessment, including the
assessment of exposure coverage in toxicological species. Spanning discovery and development, metabolite identification
(metID) scientists employ various strategies and tools to address stage-specific questions aimed at guiding the maturation
of early chemical matter into drug candidates. During this process, the identity of major (and minor) circulating human
metabolites is ascertained to comply with the regulatory requirements such as the Metabolites in Safety Testing (MIST)
guidance. Through the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), the
“Translatability of MetID In Vitro Systems Working Group” was created within the Translational and ADME Sciences
Leadership Group. The remit of this group was to objectively determine how accurate commonly employed in vitro systems
have been with respect to prediction of circulating human metabolites, both qualitatively and quantitatively. A survey
composed of 34 questions was conducted across 26 pharmaceutical companies to obtain a foundational understanding of
current metID practices, preclinically and clinically, as well as to provide perspective on how successful these practices
have been at predicting circulating human metabolites. The results of this survey are presented as an initial snapshot of
current industry-based metID practices, including our perspective on how a harmonized framework for the conduct of in
vitro metID studies could be established. Future perspectives from current practices to emerging advances with greater
translational capability are also provided
Prefilled-syringes PFS made of glass and polymer
No full textThis article provides a comprehensive review of prefilled syringes (PFS), including their components, manufacturing processes, advantages and disadvantages and regulatory considerations. The article aims to provide readers with a thorough understanding of PFS, their characteristics, and application in the pharmaceutical industry.
PFS have become increasingly popular due to their convenience, dosage accuracy, lower risk of use errors, and shelf-life stability. With the growth of the biopharmaceutical industry, there is a growing demand for pre-fillable syringes for the administration of vaccines, monoclonal antibodies, xRNAs and other new modalities in development
A first-in-human phase 1/2 dose-escalation study of MAK683 (EED inhibitor) in patients with advanced malignancies.
No full textMAK683, a first-in-class and highly selective allosteric inhibitor of the embryonic ectoderm development subunit of polycomb repressive complex 2, has shown sustained antitumor activity in tumor xenograft models. This first-in-human phase 1/2 study evaluated the safety, pharmacokinetics (PK), and clinical activity of single-agent MAK683 in advanced malignancies.MAK683 was administered fasted once daily or twice daily continuously in 28-day treatment cycles. Safety assessments included the nature of dose-limiting toxicities (DLTs) and the incidence and severity of adverse events (AEs) and serious AEs. The PK profile of MAK683 was assessed in sequential blood samples of cycles 1-6, and pharmacodynamic profiles were measured by H3K27me3 changes from baseline.Overall, 139 patients (clear cell carcinoma of the ovary [CCCO], 9 [6.5%]; castration-resistant prostate cancer [CRPC], 22 [15.8 %]; diffuse large B-cell lymphoma [DLBCL], 31 [22.3%]; epithelioid sarcoma [ES], 17 [12.2 %]; gastric cancer [GC], 37 [26.6 %]; nasopharyngeal carcinoma [NPC], 17 [12.2 %]; SWI/SNF-mutated sarcoma, 6 [4.3 %]) received MAK683. Median duration of exposure was 57 days (range: 4-1006). Fifteen patients experienced 22 DLTs including thrombocytopenia (4.9 %) and febrile neutropenia (3.3 %). MAK683-related AEs were reported in 98 patients (70.5 %); 43 patients had grade 3/4 drug-related AEs, including neutropenia, thrombocytopenia, and anemia. MAK683 was quickly absorbed, with peak plasma concentrations ranging from 0.975 to 4.08 h. Median progression-free survival was 1.9 months (90 % confidence interval [CI]: 1.8-2.3), and overall response rate was 5.8 % (90 % CI: 2.52-11.03 %). Clinical activity was observed in patients with advanced DLBCL and ES.Overall, MAK683 treatment was well tolerated, and clinical activity was observed in patients with advanced DLBCL and ES.NCT02900651