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Friday, November 16, 2012
Basic Concepts of Pharmacology in Drug Development
Review of Basic Concepts of Pharmacology in Drug Development - S&TD conference session 2012 by R. A. (Bob) Lyon, Section Head R&D Proctor and Gamble - reviewed by Brian Howells email@example.com
The objective of the talk was to
outline the process of drug development, the principles underlying this process
and some of the associated terminology and techniques.
are exogenous substances that bring about a change in biological function
through a chemical interaction with the endogenous mechanisms within the body.
The overall flow of
drug development is as follows
Identification of a target
mechanism in the body which brings about a desired alteration in biological
function (e.g. 5HT1A (serotonin) receptor activation, alleviating anxiety)
Screening of numerous compounds in vitro to try to identify compounds
having the desired effect and narrow down to a single “lead compound” which has
the best and “cleanest" effect (low toxicity and fewest other, possibly
Various animal studies, examining
the specific and general pharmacology of the lead substance, and its safety (toxicity,
mutagenicity, effect on reproduction, etc.)
Phase I (preclinical) studies on
humans, typically healthy, investigating safety (adverse effects), tolerance
(dosage) and pharmacokinetics (absorption, distribution, metabolism, excretion)
Phase II clinical studies on
small numbers of target subjects to investigate efficacy (proof of concept -
effect on target, e.g. anti-anxiety) safety, and dose-effect relationships in
Phase III large-scale clinical
studies on the target population
Submission to the regulatory
(possibly with contingencies)
This process typically takes of
the order of 10 years, and costs of the order of $500 million.
Principles of drug
Drugs largely work by interacting
with signalling between cells. In the talk, this was illustrated by signalling
at the synapse between neurons.
There are various possible
targets for this interaction, which include:
direct effect at the cell level to stimulate or block the release of a chemical
substance such as a hormone, neurotransmitter or enzyme (e.g. releasing
or blocking of the receptors for such chemical substances, provoking the
receptor to produce a response by mimicking the natural substance (agonist); or
blocking or altering the receptor so that the natural substance cannot produce
a response (antagonist)
or blocking of a transporter substance, to enable a substance, or nerve
impulse, etc., to reach its target, or stop it from so doing.
or inhibition of an enzyme, by altering the molecule to make it more or less
active, or by mimicking a natural substrate and blocking active sites
or repression at gene level, to activate or inhibit expression of an enzyme
There are numerous possibilities,
and the molecular mechanisms are exceedingly complex.
Expressing drug dose/response
Agonists can be full agonists,
giving a 100% response, or partial agonists, giving less than a 100% response. The
effect of an agonist is typically expressed as ED50 or EC50
- the dose or concentration giving a 50% effect. The maximum effect is Emax.
For measuring dose [D] vs. effect, log[D] vs. (E/Emax) is generally
used, which gives a sigmoidal curve.
The dose-response is an
expression of the affinity of the agonist for the receptor or receptor
Potency expresses dose/effect -
i.e. is related to EC50; in general, high potency is preferred since
a lower dose is likely to generate fewer side effects.
Antagonists do not have intrinsic
activity but shift the effect of an agonist. Antagonism can be competitive,
when binding to a receptor is reversible and the antagonist competes with the
agonist, or non-competitive, when the antagonist binds irreversibly or alters
the receptor. Competitive antagonism increases EC50, and it may be
possible to achieve a maximal effect with more agonist. Non-competitive
antagonism on the other hand lowers Emax, because fewer receptors
The remarks on competitive and
non-competitive antagonism also broadly apply to competitive and
non-competitive inhibition of enzymes, except that in this case competition is
between an inhibitor which can reversibly bind to an active site on the enzyme,
and a natural substrate.
Effectiveness of course needs to
be weighed against safety. One index of this is the therapeutic index, which is
ED50 for a
therapeutic effect/ED50 for a lethal effect
Radioligand binding was
introduced as a method for studying receptor interactions, by radiolabelling
drugs (ligands) to study affinity for receptors by comparison with the same or
different unlabelled ligands. Reviewed by Brian
Brian Howells has a bachelor’s degree in agricultural
science and has been a freelance translator from Japanese to English for around
25 years specializing in technical (principally chemical) and patent-related
translation. For the last 20 years he has been living on the beach in São Paulo