The Experts below are selected from a list of 147 Experts worldwide ranked by ideXlab platform
Leslie Evans - One of the best experts on this subject based on the ideXlab platform.
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albumin as a versatile platform for Drug Half Life extension
Biochimica et Biophysica Acta, 2013Co-Authors: Darrell Sleep, Jason Cameron, Leslie EvansAbstract:Abstract Background Albumin is the most abundant plasma protein, is highly soluble, very stable and has an extraordinarily long circulatory Half-Life as a direct result of its size and interaction with the FcRn mediated recycling pathway. In contrast, many therapeutic molecules are smaller than the renal filtration threshold and are rapidly lost from the circulation thereby limiting their therapeutic potential. Albumin can be used in a variety of ways to increase the circulatory Half-Life of such molecules. Scope of review This article will review the mechanisms which underpin albumin's extraordinarily long circulatory Half-Life and how the understanding of these processes are currently being employed to extend the circulatory Half-Life of Drugs which can be engineered to bind to albumin, or are conjugated to, or genetically fused to, albumin. Major conclusions The recent and growing understanding of the pivotal role of FcRn in maintaining the extended circulatory Half-Life of albumin will necessitate a greater and more thorough investigation of suitable pre-clinical model systems for assessing the pharmacokinetic profiles of Drugs associated, conjugated or fused to albumin. General significance Association, conjugation or fusion of therapeutic Drugs to albumin is a well-accepted and established Half-Life extension technology. The manipulation of the albumin–FcRn interaction will facilitate the modulation of the circulatory Half-Life of albumin-enabled Drugs, leading to superior pharmacokinetics tailored to the disease state and increased patient compliance. This article is part of a Special Issue entitled Serum Albumin.
Nicholas J White - One of the best experts on this subject based on the ideXlab platform.
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the evolution of Drug resistant malaria the role of Drug elimination Half Life
Philosophical Transactions of the Royal Society B, 2002Co-Authors: Ian M Hastings, W M Watkins, Nicholas J WhiteAbstract:This paper seeks to define and quantify the influence of Drug elimination Half-Life on the evolution of antimalarial Drug resistance. There are assumed to be three general classes of susceptibility of the malaria parasite Plasmodium falciparum to a Drug: Res0, the original, susceptible wildtype; Res1, a group of intermediate levels of susceptibility that are more tolerant of the Drug but still cleared by treatment; and Res2, which is completely resistant to the Drug. Res1 and Res2 resistance both evolve much faster if the antimalarial Drug has a long Half-Life. We show that previous models have significantly underestimated the rate of evolution of Res2 resistance by omitting the effects of Drug Half-Life. The methodology has been extended to investigate (i) the effects of using Drugs in combination, particularly when the components have differing Half-lives, and (ii) the specific example of the development of resistance to the antimalarial pyrimethamine-sulphadoxine. An important detail of the model is the development of Drug resistance in two separate phases. In phase A, Res1 is spreading and replacing the original sensitive forms while Res2 remains at a low level. Phase B starts once parasites are selected that can escape Drug action (Res1 genotypes with borderline chemosensitivity, and Res2): these parasites are rapidly selected, a process that leads to widespread clinical failure. Drug treatment is clinically successful during phase A, and health workers may be unaware of the substantial changes in parasite population genetic structure that predicate the onset of phase B. Surveillance programs are essential, following the introduction of a new Drug, to monitor effectively changes in treatment efficacy and thus provide advance warning of Drug failure. The model is also applicable to the evolution of antibiotic resistance in bacteria: in particular, the need for these models to incorporate Drug pharmacokinetics to avoid potentially large errors in their predictions.
Darrell Sleep - One of the best experts on this subject based on the ideXlab platform.
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albumin as a versatile platform for Drug Half Life extension
Biochimica et Biophysica Acta, 2013Co-Authors: Darrell Sleep, Jason Cameron, Leslie EvansAbstract:Abstract Background Albumin is the most abundant plasma protein, is highly soluble, very stable and has an extraordinarily long circulatory Half-Life as a direct result of its size and interaction with the FcRn mediated recycling pathway. In contrast, many therapeutic molecules are smaller than the renal filtration threshold and are rapidly lost from the circulation thereby limiting their therapeutic potential. Albumin can be used in a variety of ways to increase the circulatory Half-Life of such molecules. Scope of review This article will review the mechanisms which underpin albumin's extraordinarily long circulatory Half-Life and how the understanding of these processes are currently being employed to extend the circulatory Half-Life of Drugs which can be engineered to bind to albumin, or are conjugated to, or genetically fused to, albumin. Major conclusions The recent and growing understanding of the pivotal role of FcRn in maintaining the extended circulatory Half-Life of albumin will necessitate a greater and more thorough investigation of suitable pre-clinical model systems for assessing the pharmacokinetic profiles of Drugs associated, conjugated or fused to albumin. General significance Association, conjugation or fusion of therapeutic Drugs to albumin is a well-accepted and established Half-Life extension technology. The manipulation of the albumin–FcRn interaction will facilitate the modulation of the circulatory Half-Life of albumin-enabled Drugs, leading to superior pharmacokinetics tailored to the disease state and increased patient compliance. This article is part of a Special Issue entitled Serum Albumin.
Tristan S. Maurer - One of the best experts on this subject based on the ideXlab platform.
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Relevance of Half-Life in Drug Design
Journal of medicinal chemistry, 2017Co-Authors: Dennis A. Smith, Kevin Beaumont, Tristan S. MaurerAbstract:Drug Half-Life has important implications for dosing regimen and peak-to-trough ratio at the steady state. A Half-Life of 12–48 h is generally ideal for once daily dosing of oral Drugs. If the Half-Life is too short, it may require more frequent dosing in order to maintain desired exposures and avoid unnecessarily high peak concentrations. This may pose challenges to achieving optimal efficacy, safety, and patient compliance. If the Half-Life is too long, the time over which accumulation and subsequent elimination occur may be prolonged. This may pose problems with managing adverse effects and the design of efficient clinical trials. Half-Life is a key parameter for optimization in research and development. Structural modification to affect clearance, and to a lesser extent volume of distribution, is the preferred means of modulating Half-Life. An effective approach to Half-Life optimization requires an understanding of the many pitfalls associated with its estimation and interpretation.
Yuhang Zhang - One of the best experts on this subject based on the ideXlab platform.
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the use of gene ontology term and kegg pathway enrichment for analysis of Drug Half Life
PLOS ONE, 2016Co-Authors: Yuhang Zhang, Chen Chu, Shaopeng Wang, Lei Chen, Xiangyin Kong, Tao Huang, Yudong CaiAbstract:A Drug’s biological Half-Life is defined as the time required for the human body to metabolize or eliminate 50% of the initial Drug dosage. Correctly measuring the Half-Life of a given Drug is helpful for the safe and accurate usage of the Drug. In this study, we investigated which gene ontology (GO) terms and biological pathways were highly related to the determination of Drug Half-Life. The investigated Drugs, with known Half-lives, were analyzed based on their enrichment scores for associated GO terms and KEGG pathways. These scores indicate which GO terms or KEGG pathways the Drug targets. The feature selection method, minimum redundancy maximum relevance, was used to analyze these GO terms and KEGG pathways and to identify important GO terms and pathways, such as sodium-independent organic anion transmembrane transporter activity (GO:0015347), monoamine transmembrane transporter activity (GO:0008504), negative regulation of synaptic transmission (GO:0050805), neuroactive ligand-receptor interaction (hsa04080), serotonergic synapse (hsa04726), and linoleic acid metabolism (hsa00591), among others. This analysis confirmed our results and may show evidence for a new method in studying Drug Half-lives and building effective computational methods for the prediction of Drug Half-lives.
