7196 research outputs found
Sort by
Central versus peripheral drug exposure ratio, a key differentiator for siponimod over fingolimod ?
No full textSiponimod, a potent and selective sphingosine-1-phosphate (S1P1,5) agonist, is the only therapeutic agent that has shown efficacy on disability progression, decline in cognitive processing speed, total brain volume loss, gray matter atrophy, and signs of demyelination in patients with secondary progressive multiple sclerosis (SPMS). Although the pathophysiology of progression in SPMS and primary progressive MS (PPMS) is thought to be similar, fingolimod, the prototype S1P1,3,45 agonist, failed to show efficacy on disability progression in PPMS. Differentiating the mechanisms of siponimod’s effects on progression from those of fingolimod is believed to be key to better understand the key characteristics that could make siponimod uniquely efficacious in progressive MS (PMS).
Here, we compared the dose-dependent central vs peripheral drug exposure of siponimod and fingolimod in healthy mice and mice with experimental autoimmune encephalomyelitis (EAE). Siponimod treatment achieved dose-dependent efficacy and dose-proportional increases in steady state drug blood levels, with a similar central nervous system (CNS)/blood drug-exposure ratio (CNS/BloodDER) in both healthy and EAE mice. In contrast, fingolimod treatment achieved dose-proportional increases in fingolimod/fingolimod-P drug blood levels with a CNS/BloodDER that was markedly increased in EAE vs healthy mice. These results, taken together with recent preclinical observations implying a bell-shaped dose-effect relationship for S1P receptor-dependent central effects, suggest that at human-equivalent therapeutic doses an increase in CNS/BloodDER with loss of central efficacy for fingolimod/fingolimod-P but not for siponimod. Therefore, CNS/bloodDER is a potential new differentiator for siponimod over fingolimod, that warrants further investigation and clinical validation
Characterization and Reverse Engineering of Pharmaceuticals: Role of Thermoanalytical Techniques
No full textDuring pharmaceutical and biopharmaceutical drug product development, the most important step is characterization and reverse engineering. Out of so many tools and techniques, thermoanalytical methods are the most useful techniques. Different thermoanalytical techniques are used to identify, quantify and to understand the interaction between different polymorphic forms of drug substances and excipients. These techniques are used to monitor the physical form (amorphous or crystalline) of the API in drug product throughout its manufacturing process and also help in omitting or modifying the step or process responsible for alternation of the polymorphic form. Thermoanalytical techniques are not only useful for characterisation of small molecules bust also extensively applied in analysis of biological samples and Nano-formulations. In current scenario of pharmaceutical development specifically for generic drug development the most useful step is reverse engineering. When reverse engineering of drug product is concerned, thermoanalytical techniques are the best tools to be used to prove the similarity of physico-chemical properties or same state of matter or arrangement of matter between test and reference products. However, in earlier days these techniques were not used as frequently as the other techniques like spectroscopy and chromatography. Various reasons for less use of thermoanalytical techniques were unavailability of software or compatible hardware and sample analysis as well as calculation was complete manual and tedious process which consumes lots of time. Now a day, due to advancement of technology, automation, use of robotics, and better understanding, the thermal analysis not only become a powerful tool but also increase the throughput. The present review focuses on some of the most commonly used Thermoanalytical techniques e.g. Differential Scanning Calorimeter(DSC), Thermogravimatric Analysis(TGA), Solution Calorimeter(SC), Thermo Mechanical Analysis(TMA) and Isothermal Titration Calorimeter (ITC) for characterization and reverse engineering of different dosage forms like solid oral dosage forms, injectable formulation, inhalation formulation, ophthalmic formulation and biosimilar formulation products such as peptides and proteins using specific case studies
Streamlining Food Effect Assessment — Are Repeated Food Effect Studies Needed? An IQ Analysis
No full textCurrent regulatory guidelines on drug-food interactions recommend an early assessment of food effect to inform clinical dosing instructions, as well as a pivotal food effect study on the to-be-marketed formulation if different from that used in earlier trials. Study waivers are currently only granted for BCS class 1 drugs. Thus, repeated food effect studies are prevalent in clinical development, with the initial evaluation conducted as early as the first-in-human studies. Information on repeated food effect studies is not common in the public domain. The goal of the work presented in this manuscript from the Food Effect PBPK IQ Working Group was to compile a dataset on these studies across pharmaceutical companies and provide recommendations on their conduct. Based on 54 studies collected, we report that most of the repeat food effect studies do not result in meaningful differences in the assessment of the food effect. Seldom changes observed were more than twofold. There was no clear relationship between the change in food effect and the formulation change, indicating that in most cases,
once a compound is formulated appropriately within a specific formulation technology, the food effect is primarily driven by inherent compound properties. Representative examples of PBPK models demonstrate that following appropriate validation of the model with the initial food effect study, the models can be applied to future formulations. We recommend that repeat food effect studies should be approached on a case-by-case basis taking into account the totality of the evidence including the use of PBPK modeling
The application of organ-on-chip models for the prediction of human pharmacokinetic profiles during drug development.
No full textOrgan-on-chip (OoC) technology has led to in vitro models with many new possibilities compared to conventional in vitro and in vivo models. In this review, the potential of OoC models to improve the prediction of human oral bioavailability and intrinsic clearance is discussed, with a focus on the functionality of the models and the application in current drug development practice. Multi-OoC models demonstrating the application for pharmacokinetic (PK) studies are summarized and existing challenges are identified. Physiological parameters for a minimal viable platform of a multi-OoC model to study PK are provided, together with PK specific read-outs and recommendations for relevant reference compounds to validate the model. Finally, the translation to in vivo PK profiles is discussed, which will be required to routinely apply OoC models during drug development
Meeting Report on the 2nd Chinese American Society for Mass Spectrometry (CASMS) Conference
No full textThe 2nd CASMS conference was held virtually through Gather.Town platform from October 17 to 21, 2022, with a total of 363 registrants including an outstanding and diverse group of scientists at the forefront of their research fields from both academia and industry worldwide, especially in the US and China. The conference offered a 5-day agenda with an exciting scientific program consisting of two plenary lectures, 14 parallel symposia and 4 special sessions, in which a total of 97 invited speakers presented technological innovations and their applications in proteomics & biological mass spectrometry, and metabo-lipidomics & pharmaceutical mass spectrometry. In addition, 18 invited speakers/panelists presented at 3 research focused and 2 career development workshops. Moreover, 144 posters, 54 lightning talks, 5 sponsored workshops, and 14 exhibitions were presented, from which 20 posters and 8 lightning talks received presentation awards. Furthermore, the conference featured 1 MCP lectureship and 5 young investigator awardees for the first time to highlight outstanding mid-career and early-career rising stars in mass spectrometry from our society. The conference provided a unique scientific platform for young scientists (i.e., graduate students, postdocs and junior faculty/investigators) to present their research, meet with prominent scientists, and learn about career development and job opportunities (http://casms.org)
Scientific and Regulatory Policy Committee Technical Review: Biology and Pathology of Ganglia in Animal Species Used for Nonclinical Safety Testing.
No full textDorsal root ganglia (DRG), trigeminal ganglia (TG), other sensory ganglia, and autonomic ganglia may be injured by some test article classes, including anti-neoplastic chemotherapeutics, adeno-associated virus-based gene therapies, antisense oligonucleotides, nerve growth factor inhibitors, and aminoglycoside antibiotics. This article reviews ganglion anatomy, cytology, and pathology (emphasizing sensory ganglia) among common nonclinical species used in assessing product safety for such test articles (TAs). Principal histopathologic findings associated with sensory ganglion injury include neuron degeneration, necrosis, and/or loss; increased satellite glial cell and/or Schwann cell numbers; and leukocyte infiltration and/or inflammation. Secondary nerve fiber degeneration and/or glial reactions may occur in nerves, dorsal spinal nerve roots, spinal cord (dorsal and occasionally lateral funiculi), and sometimes the brainstem. Ganglion findings related to TA administration may result from TA exposure and/or trauma related to direct TA delivery into the central nervous system or ganglia. In some cases, TA-related effects may need to be differentiated from a spectrum of artifactual and/or spontaneous background changes
Which boronic acids are used most frequently for synthesis of bioactive molecules?
No full textBoronic acids are essential building blocks used for the synthesis of bioactive molecules, the generation of chemical libraries and the exploration of structure-activity relationships. As a result, more than ten thousand boronic acids are commercially available. Medicinal chemists are therefore facing a challenge; which of them should they select to maximize information obtained by the synthesis of new target molecules. The present article aims to help them to make the right choices. The boronic acids used frequently in the synthesis of bioactive molecules were identified by mining several large molecular and reaction databases and their properties were analyzed. Based on the results a diverse set of boronic acids covering well the bioactive chemical space was selected and is suggested as a basis for library design for the efficient exploration of structure-activity relationships. A Boronic Acid Navigator web tool which helps chemists to make their own selection is also made available at https://bit.ly/boronics
A Phase 1b/2 Study of Alpelisib in Combination with Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.
No full textAlpelisib in combination with cetuximab showed synergistic anti-tumour activity in head and neck squamous cell carcinoma (HNSCC) models.The recommended phase 2 dose (RP2D) was determined in a phase 1b dose-escalation study. Phase 2 evaluated anti-tumour activity with a randomised part in cetuximab-naïve patients and a non-randomised part in cetuximab-resistant patients. Alpelisib was administered in 28 d cycles as whole tablets, suspension from crushed tablets or suspension from dispersible tablets in patients with platinum-resistant, recurrent/metastatic HNSCC.The RP2D determined for alpelisib was 300 mg/d. Alpelisib-cetuximab achieved an overall response rate of 25% and 9.9% and disease control rate of 75% and 43.7% in phase 1b and phase 2 studies, respectively. Median progression-free survival (PFS) per central review was 86 d for combination treatment and 87 d for cetuximab monotherapy (unadjusted HR 1.12; 95% CI 0.69-1.82; P > 0.05). When adjusted for baseline covariates [sum of longest diameters from central data, haemoglobin and white blood cell (WBC), the results favoured combination treatment (adjusted HR 0.54; 95% CI 0.30-0.97; P = 0.039). PFS per investigator assessment resulted in an unadjusted HR of 0.76 (95% CI 0.49-1.19; P > 0.05) favouring combination treatment. The median PFS in cetuximab-resistant patients was 3.9 months.The addition of alpelisib to cetuximab did not demonstrate a PFS benefit in cetuximab-naïve patients with advanced HNSCC. The alpelisib-cetuximab combination showed moderate activity in cetuximab-resistant patients, with a consistent safety profile.ClinicalTrials.gov NCT01602315; EudraCT 2011-006017-34