Pharmacological Approach

To Drug Development
Prepared by: Dr. C. Suhas Reddy
D ep t. o f Ph a rm acy Pra ctice
 Introduction
Pharmacology is a scientific discipline that specialises in the mechanism of
action, uses and undesired effects of drugs.

Pharmacological studies should be conducted to support use of therapeutics in

humans.

In the early stages of drug development enough information may not be
available to rationally select study design for safety assessment. In such a
situation, a general approach to safety pharmacology studies can be applied.
Animal pharmacology testing provides the initial conformation that the
molecular targets is involved in a metabolic pathway or integrated physiological
process that is abnormal in the disease state.

Animal pharmacology studies allow the effects of the lead compound on the
disease process (Pharmacodynamics) to be correlated with the concentration of
compound need to achieve these effects (Pharmacokinetics).
If the results of the tests suggest potential beneficial activity, related compounds
are tested to see which version of the molecule produces the highest level of
pharmacological activity and demonstrates the most therapeutic promise, with the
smallest number of potentially harmful biological properties.
 Types

1 ◦
Research
pharmacology
studies
PHARMACOLOGICAL
STUDIES 2 ◦
Safety pharmacology
studies
Unlike primary and secondary pharmacology studies that explore the mode of
action of the candidate drug and its effects related or unrelated to the therapeutic
target, respectively, Safety Pharmacology identifies the “potential undesirable
pharmacodynamic effects of a substance on physiological functions in relation to
exposure in the therapeutic range and above”
which are not identified by standard non-clinical toxicological studies.
SP studies are, therefore, performed to ensure the safety of clinical participants
in first in human (FiH) trials through improved decision-making in the selection
of lead candidate drugs.
 1. Research pharmacological studies:
Research pharmacological studies are conducted at the starting of a drug
development program. They need to be performed to GLP standards.

 There are two types:

a) Primary research pharmacology studies
b) Secondary research pharmacology studies
 a) Primary research pharmacology
studies
Primary actions are related to proposed therapeutic use.

These studies focus on the mechanism of action of drug and can be conducted in vitro
and in vivo.

Studies conducted in vitro include radioligand binding studies and focus on drugs
action on specific receptor sites

Studies conducted in vivo investigate the pharmacological action of the drug in animal
models.
 b) Secondary research pharmacology
studies
Secondary actions focus on the overall pharmacological activity of the drug compound.

And also relates to the actions that occur which is not directly related to the proposed
therapeutic use.

This can be conducted in vitro and in vivo. In vitro studies investigate the binding of the
drug molecule with the non-target receptors.

In vivo studies investigate the general pharmacological actions in animal models.
 2. Safety pharmacology studies:
Safety pharmacology studies are studies that investigate potential undesirable
pharmacodynamic effects of a substance on physiological functions in relation to
exposure within the therapeutic range or above.

Safety pharmacology studies investigate potentially undesirable effects of the

drug compound.

They are conducted in animal models, that are single dose studies using
intended therapeutic dose.
In vitro studies should be designed to establish a concentration-effect
relationship. The range of concentrations used should be selected to increase the
likelihood of detecting an effect on the test system. The upper limit of this range
may be influenced by physicochemical properties of the test substance and other
assay specific factors.

In vivo safety pharmacology studies should be designed to define the dose-
response relationship of the adverse effect observed. When feasible, the time
course (e.g. onset and duration of response) of the adverse effect should be
investigated.
The essential safety pharmacology is to study the effects of the test drug on vital
functions. Vital organ systems such as cardiovascular, respiratory and central
nervous systems should be studied.
 Examples
CVS blood pressure, heart rate, and the electrocardiogram.
CNS motor activity, behavioural changes, coordination, sensory and
motor reflex responses and body temperature
RS tidal volume and haemoglobin oxygen saturation should be
studied.
 Supplemental Safety Pharmacology
Studies
required to investigate the possible adverse pharmacological effects that are not
assessed in the essential safety pharmacological studies and are a cause for
concern.
CVS ventricular contractility, vascular resistance and the effects of chemical mediators, their
agonists and antagonists on CVS
CNS learning and memory, electrophysiology studies , neurochemistry and ligand binding studies.
RS airway resistance, compliance, pulmonary arterial pressure, blood gases and blood pH.
Urinary urine volume, specific gravity, osmolality, pH, proteins, cytology and BUN, creatinine and
system plasma proteins estimation.
ANS binding to receptors relevant for the autonomic nervous system, and functional response to
agonist or antagonist responses in vivo or in vitro, and effects of direct stimulation of
autonomic nerves and their effects on cardiovascular responses
GIS gastric secretion, gastric pH measurement, gastric mucosal examination, bile secretion, gastric
emptying time in vivo and ileocaecal contraction in vitro.
Others Effects of the investigational drug on organ systems not investigated elsewhere should be
assessed when there is a cause for concern. For example dependency potential, skeletal
muscle, immune and endocrine functions may be investigated.
 Safety pharmacology studies are
usually not required when;
Product is to be used for local application, e.g. dermal or ocular
The pharmacology of the investigational drug is well known
Systemic absorption from the site of application is low
Safety pharmacology testing is also not necessary, in case of a new derivative
having similar pharmacokinetics and pharmacodynamics.
For biotechnology-derived products that achieve highly specific receptor
targeting.
 Timing Of Safety Pharmacology Studies In
Relation To Clinical Development
1. Prior To First Administration In Humans
The effects of an investigational drug on the vital functions listed in the essential
safety pharmacology should be studied prior to first administration in humans

2. During Clinical Development

Additional investigations may be warranted to clarify observed or suspected
adverse effects in animals and humans during clinical development
3. Before applying for marketing Approval
Follow-up and supplemental safety pharmacology studies should be assessed prior
to approval unless not required, in which case this should be justified. Available
information from toxicology studies addressing safety pharmacology endpoints or
information from clinical studies can replace such studies.
4. Application Of Good Laboratory Practices (GLP)
The animal studies be conducted in an accredited laboratory. Where the safety
pharmacology studies are part of toxicology studies, these studies should also be
conducted in an accredited laboratory.
 References
DRUG DISCOVERY AND CLINICAL RESEARCH - SK Guptha
https://www.fda.gov/ForPatients/Approvals/Drugs/ucm405382.htm
https://www.researchgate.net/profile/Dominic_Williams2/publication/23701632
5_Safety_pharmacology_-
_Current_and_emerging_concepts/links/59e07a4d45851537161225d5/Safety-
pharmacology-Current-and-emerging-concepts.pdf
https://prezi.com/g95fbzxyu6fi/various-approaches-to-drug-discovery/
New drug development –design methodology & analysis by J. RICK TURNER.
THAN ‘Q’