Bioanalysis
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Review
Current position of high-resolution MS for drug quantification in clinical & forensic toxicology.
This paper reviews high-resolution MS approaches published from January 2011 until March 2014 for the quantification of drugs (of abuse) and/or their metabolites in biosamples using LC-MS with time-of-flight or Orbitrap™ mass analyzers. Corresponding approaches are discussed including sample preparation and mass spectral settings. The advantages and limitations of high-resolution MS for drug quantification, as well as the demand for a certain resolution or a specific mass accuracy are also explored.
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For the last few decades intense scientific research has been placed on the relationship between trace substances found in exhaled breath such as volatile organic compounds (VOC) and a wide range of local or systemic diseases. Although currently there is no general consensus, results imply that VOC have a different profile depending on the organ or disease that generates them. ⋯ The present review describes the current advances in identifying and quantifying VOC used as biomarkers for a number of systemic diseases. A special focus will be placed on volatiles that characterize unpleasant breath 'fingerprints' such as fetor hepaticus; uremic fetor; fetor ex ore or trimethylaminuria.
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With the advent of novel technologies, considerable advances have been made in the evaluation of the relationship between PK and PD. Ligand-binding assays have been the primary assay format supporting PK and immunogenicity assessments. ⋯ This review illustrates key challenges with regard to understanding the relationship between anti-drug antibody and PK/PD, including confounding factors associated with the development and validation of ligand-binding assays, mechanisms by which anti-drug antibody impacts PK/PD, factors to consider during data analyses and interpretation, and a perspective on integrating immunogenicity data into the well-established quantitative modeling approach. Through recognizing these challenges, we propose some opportunities for improvements in the development and validation of fit-for-purpose bioanalytical methods.
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The revolution in disease diagnosis and treatment promised on the completion of the human genome project over a decade ago has materialized in the form of unified drug and biomarker discovery and development pipelines. This strategic shift has been principally catalyzed through success stories in the field of oncology, ushering in the era of personalized medicine. ⋯ Perhaps more importantly, however, the late adoption of biomarker strategies has also rescued drug candidates from complete late-stage failure. This review examines the historical lessons of key challenges in translating biomarker assay information into strategic and clinically actionable decisions and assesses the impact of personalized genome sequencing in the future of companion diagnostic development and commercialization.
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Pharmacokinetic-pharmacodynamic (PK-PD) modeling is an integral part of the preclinical and clinical development of protein drugs. Bioanalytical data from appropriately selected and well-characterized PK and PD biomarker assays can be incorporated into mechanistic PK-PD models and allow a quantitative relationship between protein drug exposure, target modulation, and biochemical, physiological and pathophysiological effects to be established. ⋯ The PK-PD data can provide an important link between magnitude of target modulation and clinical efficacy and safety outcomes, and guide the selection of doses and dosing schedules for clinical trials. In this article, approaches to the selection and development of fit-for-purpose, PK and PD assays for protein drugs are reviewed, and the applications of the assay results in PK-PD models are discussed.