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New
SCPA Structure
Since
2008 the Summer Course on Pharmaceutical Analysis (SCPA) will
change its structure and will cover a three-year program
on the most advanced analytical methodologies involved into the
launch of new drugs, starting from the discovery phase (hit identification,
structure-property relationships), through drug development (lead
optimisation, ADMET studies, biomarkers identification) ending
with formulation quality control and validation. New cycles will
follow in which the most recent analytical topics in the specific
phase will be introduced.
The
SCPA first year program is focused on ‘ADVANCED
ANALYTICAL METHODOLOGIES IN DRUG DISCOVERY’
(click here for the first year program).
In 2009, the second year of SCPA cycle will be
focused on ‘ADVANCED ANALYTICAL
METHODOLOGIES IN DRUG DEVELOPMENT’.
Specifically, second year main topics will be: 1) ADME/PK as part
of a rational approach to drug discovery and 2) Biomarkers in
drug discovery and development.
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ADME/PK as part of a rational approach to drug discovery
In 90’s, 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.
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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.
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