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Final program

Ph.D presentation



Course contents

ADME/PK as part of a rational approach to drug discovery
In 90s, up to 40% of new chemical entities (NCEs) failed to proceed in clinical development because of drug metabolism or pharmacokinetic (DMPK) issues. As a result, most major pharmaceutical companies incorporated drug metabolism and pharmacokinetic screens in the lead optimization phase, and this resulted in less than 10% of failure due to DMPK issues. In modern medicinal chemistry, lead optimization can be defined as the process of turning chemical lead into drug-like molecule that have passed a series of absorption, distribution, metabolism, excretion and toxicity (ADMET) screens, in addition to appropriate efficacy screens. This means that preclinical ADMET screening, besides to facilitate the early elimination of weak candidates that do not satisfy basic ADMET requirements, also drives the structural modifications in order to improve suitable DMPK properties. Hence DMPK experts are integral members of those discovery teams, finding the path of synthetic chemistry.
Due to the large number of compounds and samples in early drug discovery, high throughput and rapid turnaround of analysis and information are critical at this stage. New technologies and methodologies are imperative to make the DMPK screening process more effective, and a significant improvement in this direction is given by innovative analytical techniques and instrumentations, such as liquid chromatography tandem mass spectrometry.
The focus of this session will be to
present and discuss the bioanalytical ways that can be used to support the early ADME/DMPK studies for new chemical entities in a high throughput manner.


Biomarkers in drug discovery and development
Biomarkers are molecular analytes used as gauges for the presence and severity of disease and to determine whether a disease is being modified by therapy. Biomarkers are increasingly used in drug development to aid scientific and clinical decisions regarding the progress of candidate and marketed therapeutics, and to improve the understanding of diseases as well as therapeutic and off-target effects of drugs. Biomarkers used in drug discovery are either disease-related or efficacy-related biomarkers. The first are mechanistically linked to the disease, its progression, and susceptibility, while the latter aim to determine, if a drug hits the desired target, and if this binding leads to successful modulation of the pathway. The recent explosion in biomarker research is largely driven by the widespread belief that appropriate application of biomarkers to preclinical and clinical drug development will accelerate the process, increase efficiency (by providing early indications of efficacy or toxicity), and facilitate dose selection prior to expensive phase III clinical trials. Biomarkers thus seem likely to hasten the attrition of undesirable candidate compounds and to increase productivity in drug development, reducing the time and costs associated with bringing new therapies to patients.
Bio-analysis plays a pivotal role in the discovery and development of biomarker and in this regard, gas- and liquid-chromatography, mass spectrometry, and nuclear magnetic resonance spectroscopy have facilitated a great achievement in this area.
The first part of this topic will summarize the
concept of biomarkers; their application in drug development and in clinical platforms. This section will also focus on biotransformation studies in close relation to biomarker discovery and validation, and on major techniques utilized in this area. In the second part, practical examples will be addressed. The use of LC/MS, GC/MS, and NMR in these studies will be described, such as method development for protein and DNA oxidation products by LC-tandem MS and its application in mammalian cells and in humans. The potential and limitations of these techniques together with future perspectives will be discussed