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Drug Regulatory Affairs
Published in Gary M. Matoren, The Clinical Research Process in the Pharmaceutical Industry, 2020
Each of these goals obligates the R&D organization and DRA to a different, although cumulative, set of IND requirements. If the initial intent of the IND is to allow studies through goal 3, above, the animal toxicology requirements are substantially greater than for goal 2. Similarly, if the stability requirements of the investigation drug formulation are different, then the formulation itself may have to differ. Although the overall intent of the R&D program is to develop a therapeutically useful and approvable product, the IND has limited goals initially; as these early goals are met, the scope and purpose of the IND change. The DRA group must keep track of the progress of the investigations through attendance and participation at R&D project meetings and R&D discussions. As the clinical investigation program becomes more comprehensive, changes in and additions to various parts of the IND are required. These changes must be anticipated well in advance and filed at an appropriate time so that, for example, the clinical program does not exceed the bounds of the available animal toxicology studies.
Recent Advances in Repositioning Non-Antibiotics against Tuberculosis and other Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Although drug repositioning strategies offer significant benefits, they are not devoid of drawbacks. Repositioning approaches rely on the fact that clinically approved drugs carry immense privilege as they have undergone rigorous testing in human subjects. Reliance on previously validated data could avoid high costs incurred during drug development processes and narrow the chances of attrition in advanced clinical studies. Additionally, drugs that are off-patent and inexpensive may offer even more benefits for diseases endemic in resource-poor settings. Apart from intellectual property issues, one drawback of repositioning strategies is inherent effects of repositioned drugs which may become undesirable side effects in diseases of interest. Hence, structural remodelling is seen as a viable strategy to improve pharmacokinetics and pharmacodynamics post-repositioning. Such approaches have proven successful in enhancing activities of repositioned drugs; in some cases, new chemical entities were identified with antitubercular activities more potent than parent non-antibiotics or standard antitubercular drugs. Also, inherent effects of repositioned drugs could be abrogated to improve selectivity, particularly in the example of phenothiazines. Drug formulation is another medicinal chemistry approach that goes hand in hand with drug repositioning. As with examples provided herein, drug formulation offers advantages such as targeted drug delivery and minimized dose-related toxicities or drug metabolism.
Designing Smart Nanotherapeutics
Published in Suresh C. Pillai, Yvonne Lang, Toxicity of Nanomaterials, 2019
A. Joseph Nathanael, Tae Hwan Oh, Vignesh Kumaravel
Conventional cancer therapies (chemo and radiation therapies) have inherent limitations and side effects. The success rate of the chemotherapy highly depends on the careful selection of patient to receive the treatment because of the heterogeneity and complexity of the tumours. Progress with one patient cannot be always assured in another. Pharmacodynamics and pharmacokinetics of a drug will be affected by individual genetic variations (Wheeler et al. 2013). These limitations urged scientists to develop an alternative therapy that is less harmful as well as effective to treat the cancer cells. Use of nanotherapeutics, nanotechnology-based drug formulation, is one of the best choices for controlled and targeted drug delivery in the affected area. One of the unique characteristics of nanoparticles is enhanced permeability and retention (EPR) in which the nanoparticles could penetrate into tumour tissues, but due to the ineffective lymphatic system of the cancerous tumour, they cannot exit the cancer cells (Maeda et al. 2000, Talekar et al. 2011). Clinical studies proved that nanotherapeutics could reduce the adverse effects of chemotherapeutic agents, improve the bioavailability of drugs, and enhance drug tolerance thereby improving the overall survival rate of cancer patients (Uskokovic 2009). Substantial scientific success has been attained in this field but there are significant challenges to translate the technology into clinical practice and commercialization.
TRYBE®: an Fc-free antibody format with three monovalent targeting arms engineered for long in vivo half-life
Published in mAbs, 2023
Emma Davé, Oliver Durrant, Neha Dhami, Joanne Compson, Janice Broadbridge, Sophie Archer, Asher Maroof, Kevin Whale, Karelle Menochet, Pierre Bonnaillie, Emily Barry, Gavin Wild, Claude Peerboom, Pallavi Bhatta, Mark Ellis, Matthew Hinchliffe, David P. Humphreys, Sam P. Heywood
TrYbes® have been successfully manufactured and purified at a clinically relevant scale (2000 L). Due to the architecture consisting of a Fab scaffold, these molecules are simple to express, resulting in crude product yields of >3 g/L from clonal stable CHO cell lines in fed-batch cultures. The disulfide linkage of scFvs is an essential feature of TrYbes®, limiting the concentration and time-dependent multimerization of the antibody as discussed previously.17,35 This is an important consideration for manufacturing and long-term stability of the drug formulation where a highly concentrated product is clinically desirable. Disulfide stabilization of scFvs in immunotoxin fusions has also been reported to impart additional properties such as reduced aggregation, thereby increasing titers when renatured from inclusion bodies expressed in Escherichia coli.20 Despite soluble titers of immunotoxins comprising ds-Fvs or ds-scFvs being significantly lower than the reported TrYbe® titers, sufficient quantities of the immunotoxins with favorable biophysical and functional profiles have been manufactured at GLP scale for clinical trials in cancer therapy.20,38,84–86
Emerging data on rifampicin pharmacokinetics and approaches to optimal dosing in children with tuberculosis
Published in Expert Review of Clinical Pharmacology, 2022
Kendra K. Radtke, Elin M. Svensson, Louvina E. van der Laan, Anneke C. Hesseling, Radojka M. Savic, Anthony J. Garcia-Prats
New FDCs with more optimal drug ratios are one option for improved formulation development. A model-based approach to FDC dose selection for children with TB has been proposed previously [49]. New FDCs would have the benefit of improving target exposure attainment in children requiring routine drug-susceptible TB treatment and retain the ease of use of an FDC formulation. However, a single new FDC would not be able to support high dose rifampicin use in specific cases . Single-drug rifampicin formulations or multiple FDCs with drug ratios derived for specific indications (e.g. TB meningitis) may be needed to support multipurpose rifampicin use. Stand-alone formulations are highly flexible and could be used to support incremental dose increases when indicated. Additionally, their use could be maintained in the event that future dose alterations are recommended following emerging data. The disadvantage of a single-drug formulation is the added complexity for accurate prescription by health workers and for administration by caregivers. Multiple FDCs with specific indications for use would be the most advantageous, but are not likely a realistic option given the substantial costs involved in formulation development and distribution.
Filgrastim loading in PLGA and SLN nanoparticulate system: a bioinformatics approach
Published in Drug Development and Industrial Pharmacy, 2020
Ritu Karwasra, Saman Fatihi, Khalid Raza, Surender Singh, Kushagra Khanna, Shivkant Sharma, Nitin Sharma, Saurabh Varma
A compilation of numerous iterative steps involving all the forces that act simultaneously upon each atom in simulated conditions and in synchronize with the Newton’s Laws of motion are particularly termed as Atomic Molecular Dynamic (MD) simulation run. During the simulation run, the position and the respective velocity of each atom are updated at every step [9]. A set of physical constants and equations that are used to describe such forces are termed as force field. Recently, the approach of MD is used in fewer studies investigating drug formulation characteristics so as to avoid time and resource wastage. We are able to predict the required information from these studies and this was then extrapolated in in vivo settings. To this end, knowing selected calculated descriptors of drug and their corresponding binding energies with the help of cheminformatics/bioinformatics tools would be enough to deduce the information. Using this information, the drugs will then be translated into comprehensive numbers and developed by formulators in drug delivery laboratories [10]. With this attempt, we hypothesized to predict the behavior of filgrastim loading in SLN and PLGA systems. The developed approach would be an efficient tool for formulators and researchers that will eventually save most of the experimentation time and effort in designing a novel carrier system. Therefore, the objective of our study is to depict the interaction of filgrastim in particular carrier system (SLN & PLGA) and by preemptively selecting efficient carrier system for further laboratory experimentation.