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Drug Discovery Today. Technologies

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https://www.readbyqxmd.com/read/27978993/leverage-nonclinical-development-of-bispecifics-by-translational-science
#1
REVIEW
Andreas Baumann, Stephanie Fischmann, Guenter Blaich, Matthias Friedrich
Bispecific antibody constructs (Bispecifics, bsAbs) may have greater functionality compared to established monoclonal antibodies because they bind to 2 different targets or, potentially, to 2 epitopes on the same target (dual targeting). This may result in enhanced binding avidity with preferential binding to cells that express both targets or binding to targets on different cells. However, development of these next-generation biologics, including new formats, creates unique challenges due to their increased complexity...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978992/translational-immunotoxicology-of-immunomodulatory-monoclonal-antibodies
#2
REVIEW
Frank R Brennan, Andrea Kiessling
While immunomodulatory monoclonal antibodies (mAbs) have a wide therapeutic potential, exaggerated immunopharmacology may drive both acute and delayed immunotoxicity. The existing tools for immunotoxicity assessment do not accurately predict the full range of immunotoxicities observed in humans. New and optimized models, assays, endpoints and biomarkers in animals and humans are required to safeguard patients and allow them access to these often transformational therapies.
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978991/translational-pharmacokinetics-and-pharmacodynamics-of-monoclonal-antibodies
#3
REVIEW
Amrita V Kamath
Monoclonal antibodies (mAbs) are an important therapeutic class with complex pharmacology and interdependent pharmacokinetic (PK) and pharmacodynamics (PD) properties. Understanding the PK and PD of mAbs and their biological and mechanistic underpinnings are crucial in enabling their design and selection, designing appropriate efficacy and toxicity studies, translating PK/PD parameters to humans, and optimizing dose and regimen to maximize success in the clinic. Significant progress has been made in this field however many critical questions still remain...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978990/perspectives-in-regulatory-science-translational-and-clinical-pharmacology
#4
REVIEW
Joseph A Grillo, Shiew Mei Huang
This paper focuses on the role of clinical and translational pharmacology in the drug development and the regulatory process. Contemporary regulatory issues faced by FDA's Office of Clinical Pharmacology (OCP) in fulfilling its mission to advance the science of drug response and translate patient diversity into optimal drug therapy are discussed. Specifically current focus of the following key aspects of the drug development and regulatory science processes are discussed: the OCP vision and mission, two key OCP initiatives (i...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978989/quantitative-systems-pharmacology-a-promising-approach-for-translational-pharmacology
#5
REVIEW
K Gadkar, D Kirouac, N Parrott, S Ramanujan
Biopharmaceutical companies have increasingly been exploring Quantitative Systems Pharmacology (QSP) as a potential avenue to address current challenges in drug development. In this paper, we discuss the application of QSP modeling approaches to address challenges in the translational of preclinical findings to the clinic, a high risk area of drug development. Three cases have been highlighted with QSP models utilized to inform different questions in translational pharmacology. In the first, a mechanism based asthma model is used to evaluate efficacy and inform biomarker strategy for a novel bispecific antibody...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978988/translational-pharmacokinetic-pharmacodynamic-analysis-in-cancer-pharmacology-a-tool-to-maximize-the-value-of-antitumor-efficacy-from-tumor-bearing-mice
#6
REVIEW
Harvey Wong, Stephen E Gould
Translational pharmacokinetic/pharmacodynamic (PK/PD) analysis is becoming an increasingly important tool for the identification and selection of new anticancer agents. There are two important elements of effectively using PK/PD analysis to translate preclinical antitumor efficacy from tumor bearing mice (xenografts and allografts) to cancer patients. These two sometimes overlapping elements are termed translation 'WITHIN' and 'ACROSS' species. Translating 'WITHIN' species refers to the quantitative characterization of drug action and disease behavior within tumor bearing mice using PK/PD modeling in order to use this information to make predictions of drug response in humans...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978987/translational-pk-pd-of-anti-infective-therapeutics
#7
REVIEW
Chetan Rathi, Richard E Lee, Bernd Meibohm
Translational PK/PD modeling has emerged as a critical technique for quantitative analysis of the relationship between dose, exposure and response of antibiotics. By combining model components for pharmacokinetics, bacterial growth kinetics and concentration-dependent drug effects, these models are able to quantitatively capture and simulate the complex interplay between antibiotic, bacterium and host organism. Fine-tuning of these basic model structures allows to further account for complicating factors such as resistance development, combination therapy, or host responses...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978986/pharmacological-considerations-for-predicting-pk-pd-at-the-site-of-action-for-therapeutic-proteins
#8
REVIEW
Weirong Wang, Honghui Zhou
For therapeutic proteins whose sites of action are distal to the systemic circulation, both drug and target concentrations at the tissue sites are not necessarily proportional to those in systemic circulation, highlighting the importance of understanding pharmacokinetic/pharmacodynamic (PK/PD) relationship at the sites of action. This review summarizes the pharmacological considerations for predicting local PK/PD and the importance of measuring PK and PD at site of action. Three case examples are presented to show how mechanistic and physiologically based PK/PD (PBPK/PD) models which incorporated the PK and PD at the tissue site can be used to facilitate understanding the exposure-response relationship for therapeutic proteins...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978985/translational-biomarkers-from-discovery-and-development-to-clinical-practice
#9
REVIEW
Meena Subramanyam, Jaya Goyal
The refinement of disease taxonomy utilizing molecular phenotypes has led to significant improvements in the precision of disease diagnosis and customization of treatment options. This has also spurred efforts to identify novel biomarkers to understand the impact of therapeutically altering the underlying molecular network on disease course, and to support decision-making in drug discovery and development. However, gaps in knowledge regarding disease heterogeneity, combined with the inadequacies of surrogate disease model systems, make it challenging to demonstrate the unequivocal association of molecular and physiological biomarkers to disease pathology...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978984/translational-pk-pd-modeling-to-increase-probability-of-success-in-drug-discovery-and-early-development
#10
REVIEW
Thierry Lavé, Antonello Caruso, Neil Parrott, Antje Walz
In this review we present ways in which translational PK/PD modeling can address opportunities to enhance probability of success in drug discovery and early development. This is achieved by impacting efficacy and safety-driven attrition rates, through increased focus on the quantitative understanding and modeling of translational PK/PD. Application of the proposed principles early in the discovery and development phases is anticipated to bolster confidence of successfully evaluating proof of mechanism in humans and ultimately improve Phase II success...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978983/endonuclease-mediated-genome-editing-in-drug-discovery-and-development-promises-and-challenges
#11
REVIEW
Vidya Prabhu, Han Xu
Site specific genome editing has been gradually employed in drug discovery and development process over the past few decades. Recent development of CRISPR technology has significantly accelerated the incorporation of genome editing in the bench side to bedside process. In this review, we summarize examples of applications of genome editing in the drug discovery and development process. We also discuss current hurdles and solutions of genome editing.
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978982/pharmacogenomics-in-the-age-of-personalized-medicine
#12
REVIEW
Leslie J Dickmann, Joseph A Ware
The aim of personalized medicine is to offer the right treatment to the right person at the right dose, thus maximizing efficacy and minimizing toxicity for each individual patient. Pharmacogenomic approaches attempt to refine the aim of personalized medicine by utilizing an individual's germline and somatic DNA signatures to guide treatment. In this review, we highlight the current use of pharmacogenomic based biomarker information in drug labeling. We also present several case studies on the implementation of pharmacogenomic strategies in drug discovery and development...
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27978981/introduction-to-the-theme-technology-translational-pharmacology
#13
EDITORIAL
Saileta Prabhu
No abstract text is available yet for this article.
September 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27986226/glutathione-conjugation-dose-dependently-increases-brain-specific-liposomal-drug-delivery-in-vitro-and-in-vivo
#14
David Maussang, Jaap Rip, Joan van Kregten, Angelique van den Heuvel, Susanne van der Pol, Burt van der Boom, Arie Reijerkerk, Linda Chen, Marco de Boer, Pieter Gaillard, Helga de Vries
The blood-brain barrier (BBB) represents a major obstacle for the delivery and development of drugs curing brain pathologies. However, this biological barrier presents numerous endogenous specialized transport systems that can be exploited by engineered nanoparticles to enable drug delivery to the brain. In particular, conjugation of glutathione (GSH) onto PEGylated liposomes (G-Technology(®)) showed to safely enhance delivery of encapsulated drugs to the brain. Yet, understanding of the mechanism of action remains limited and full mechanistic understanding will aid in the further optimization of the technology...
June 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27986225/liposome-technologies-and-drug-delivery-to-the-cns
#15
REVIEW
Jaap Rip
Brain and nervous system disorders represent a large unmet medical need. Central nervous system drug development is hampered by the restricted transport of drugs across the blood-brain barrier. Different strategies to deliver drugs to the brain have been developed. We discuss the current status of development of liposomal drug delivery to the brain. There is a growing interest in targeted delivery of liposomes to the brain and much progress has been made towards successful development of novel treatments for patients with devastating brain diseases...
June 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27986224/altered-blood-brain-barrier-transport-in-neuro-inflammatory-disorders
#16
REVIEW
Geert J Schenk, Helga E de Vries
During neurodegenerative and neuroinflammatory disorders of the central nervous system (CNS), such as Alzheimer's disease (AD) and multiple sclerosis (MS), the protective function of the blood-brain barrier (BBB) may be severely impaired. The general neuro-inflammatory response, ranging from activation of glial cells to immune cell infiltration that is frequently associated with such brain diseases may underlie the loss of the integrity and function of the BBB. Consequentially, the delivery and disposition of drugs to the brain will be altered and may influence the treatment efficiency of such diseases...
June 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27986223/exploiting-transferrin-receptor-for-delivering-drugs-across-the-blood-brain-barrier
#17
REVIEW
Judy Paterson, Carl I Webster
Delivery of large molecule drugs across the blood brain barrier is increasingly being seen as an achievable goal. Several technologies have been described where following peripheral administration the molecules can be detected in the brain. Foremost amongst these technologies are antibodies against the transferrin receptor. Following a burst of publications in the very early twenty first century, excitement seemed to wane as contrary data started to emerge. Over the last few years antibodies against transferrin receptor have again started to raise hopes of successful drug delivery to the central nervous system, as protein engineering techniques have allowed a more detailed understanding of the antibody properties necessary for successful transport across the blood brain barrier...
June 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27986222/ultrasound-mediated-drug-delivery-to-the-brain-principles-progress-and-prospects
#18
REVIEW
Anshuman Dasgupta, Mengjiao Liu, Tarun Ojha, Gert Storm, Fabian Kiessling, Twan Lammers
The blood-brain barrier (BBB) limits drug delivery to the central nervous system. When combined with microbubbles, ultrasound can transiently permeate blood vessels in the brain. This approach, which can be referred to as sonoporation or sonopermeabilization, holds significant promise for shuttling large therapeutic molecules, such as antibodies, growth factors and nanomedicine formulations, across the BBB. We here describe the basic principles of BBB permeation using ultrasound and microbubbles, and we summarize several (pre-) clinical studies showing the potential of BBB opening for improving the treatment of cancer and neurodegenerative disorders...
June 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27986221/modulating-the-paracellular-pathway-at-the-blood-brain-barrier-current-and-future-approaches-for-drug-delivery-to-the-cns
#19
REVIEW
Eoin O'Keeffe, Matthew Campbell
The blood-brain barrier (BBB) is the tightly regulated point of entry by which any neuro-targeting therapy must pass through. BBB modulation is a means to loosen the size exclusion properties of the barrier by temporarily interfering with the formation of intercellular tight junction (TJ) or adheren junction (AJ) complexes, allowing for diffusion of small molecule therapeutics from blood to brain. Several technologies, such as RNAi, peptidomimetics, high frequency ultrasound and nanoparticles, have been developed and refined over the years, paving the way for barrier modulation to become an effective part of conventional central nervous system therapies...
June 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27986220/measuring-blood-brain-barrier-penetration-using-the-neurocart-a-cns-test-battery
#20
REVIEW
Geert Jan Groeneveld, Justin Luke Hay, Johannes Marinus Van Gerven
To systematically study the pharmacodynamics of a CNS drug early in the development process, we developed and validated a battery of drug-sensitive CNS tests, which we call NeuroCart. Using this test battery, data-intensive phase 1 studies in healthy subjects can be performed to demonstrate the specific, time- and dose-dependent, neurophysiological and/or neuropsychological effects of a compound, thereby confirming whether the test compound reaches its intended target in the CNS - or does not reach its intended target...
June 2016: Drug Discovery Today. Technologies
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