Safety pharmacology is a branch of pharmacology with its aim to predict the potential clinical risk profile of new chemical entities (NCEs).
It has the ability to predict the potential off-target drug effects on major organ systems which are associated with exposure in the therapeutic range and above.
As an essential part of the spectrum of drug discovery and development, safety pharmacology studies are generally conducted to determine the relative drug effect on main organs, including respiratory system, central nervous system, and cardiovascular system.Safety pharmacology is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials.
SP studies are described in the international conference on harmonization (ICH) S7A and S7B Guidelines.
2. Safety Pharmacology
• Safety pharmacology is a branch of pharmacology with its aim to
predict the potential clinical risk profile of new chemical entities
(NCEs).
• It has the ability to predict the potential off-target drug effects on
major organ systems which are associated with exposure in the
therapeutic range and above.
• As an essential part of the spectrum of drug discovery and
development, safety pharmacology studies are generally conducted
to determine the relative drug effect on main organs, including
respiratory system, central nervous system, and cardiovascular
system.
3.
4. • Safety pharmacology is an essential part of the drug development
process that aims to identify and predict adverse effects prior to
clinical trials.
• SP studies are described in the international conference on
harmonization (ICH) S7A and S7B Guidelines.
• S6 : Pre clinical safety evaluation of biotechnology derived
pharmaceuticals.
• S7A:Safety Pharmacology Studies for Human Pharmaceuticals .
• S7B:The Non-clinical Evaluation of the Potential for Delayed
Ventricular Repolarization(QT Interval Prolongation) By Human
Pharmaceuticals .
8. Pumping Apparatus Gas Exchange Unit
Function : Regulate gas
exchange between
Environment and airways.
Regulate gas exchange
between airways and blood.
Components : Respiratory
Muscles , CNS , Chemo /
Mechano Receptors.
Components : Airways, alveoli,
Vasculature , fibrous network.
Measurements :
Tidal Volume , Respiratory
Rate, minute volume,
Inspiratory rate, expiratory and
apneic times.
Measurements :
Airway resistance, lung
compliance, gas diffusion
capacity, PaO2/PaCO2
9. Respiratory system
• Drugs of various Pharmacological classes are known to have
deleterious effects on respiratory system. More recently , drugs
which had serious respiratory Implications include duragesic patch
and advair.
• Prozac increased the risk of pulmonary hypertension of the newborns
delivered by women who used prozac during the third trimester of
their pregnancy.
• As per ICH recommendations , the SP assessment of the potential
adverse reactions of new drugs requires evaluation of respiratory
function as part of the core battery involving the vital organ system.
• The guidelines indicate to carry out the two sets of studies, the core
battery tests and follow up studies.
10. • The core battery tests include the assessment of respiratory rate,
tidal volume and hemoglobin oxygen saturation.
• Follow up studies provide greater depth of understanding of the core
test observations include the assessment of airway resistance,
compliance, Pulmonary arterial pressure, blood gases and blood
patch.
• Animals used for the routine tests include rodents, dogs and primates
11. Non-Invasive Plethysmography
• Involves the assessment of pumping efficiency and gaseous exchange
using a variety of measuring apparatus to assess these parameters.
• Accurate ventilatory patterns are assessed to directly monitor lung
volume changes or airflows generated by thoracic movements in
conscious animals using plethysmograph chamber.
• Head out, dual chamber and whole body plethysmography
Techniques are non invasive methods that are currently used to
evaluate typical parameters of respiration including tidal volume,
Minute volume, Mid expiratory flow, and respiratory rate.
• The recent study reported that respiratory function can be accurately
evaluated using head out plethysmography
12. Invasive plethysmography
• Follow Up Respiratory SP studies using invasive plethysmography
methods are performed to further investigate any unwanted
potentially deleterious effects on respiratory functions observed
during core battery studies.
• It involves assessment of changes in the Mechanical properties of
lungs such as pulmonary resistance and compliance for the
identification of bronchoconstriction and obstruction.
• These methods involves orotracheal intubation, pulmonary
monoeuvres and surgical implantation of pleural pressure sensors for
chronic resistance recording or tracheotomised , intubated animals .
• It is accepted as the gold standard for accurate assessment of
resistance and compliance .
13. Newer Technology
• Telemetry can be used effectively in Respiratory safety assessment.
• The Kearney group has evaluated a novel surgical implanted
telemetry method incorporated with an impedance sensor for
chronic evaluation of respiratory parameters .
• This type of technology has also been validated in non-human
primates allowing the simultaneous evaluation of both CVS and
respiratory function.
• Another variant in this technology is the use of respiratory inductive
plethysmography (RIP) with telemetry which allows the continuous
monitoring of respiratory parameters in non-restrained large animals
for extended periods of time including awake and sleep states .
• Newer and emerging approaches for respiratory SP include
modifications in plethysmography, telemetry and potential
biomarkers for specific respiratory disorder.
14. HERG Assay
• hERG (the human Ether-à-go-go-Related Gene) is a gene (KCNH2)
that codes for a protein known as Kv11.1, the alpha subunit of
a potassium ion channel. This ion channel is best known for its
contribution to the electrical activity of the heart: the hERG channel
mediates the repolarizing IKr current in the cardiac action potential,
which helps coordinate the heart's beating.
• When this channel's ability to conduct electrical current across the
cell membrane is inhibited or compromised, either by application of
drugs or by rare mutations in some families, it can result in a
potentially fatal disorder called long QT syndrome.
• Conversely, genetic mutations that increase the current through
these channels can lead to the related inherited heart rhythm
disorder Short QT syndrome.
15. • A number of clinically successful drugs in the market have had the
tendency to inhibit hERG, lengthening the QT and potentially leading
to a fatal irregularity of the heartbeat (a ventricular tachyarrhythmia
called torsades de pointes).
• This has made hERG inhibition an important antitarget that must be
avoided during drug development.
• hERG has also been associated with modulating the functions of
some cells of the nervous system and with establishing and
maintaining cancer-like features in leukemic cells.
• hERG forms the major portion of one of the ion channel proteins (the
'rapid' delayed rectifier current (IKr)) that conducts potassium (K+)
ions out of the muscle cells of the heart (cardiac myocytes), and this
current is critical in correctly timing the return to the resting state
(repolarization) of the cell membrane during the cardiac action
potential.
16.
17. • A number of drugs have been withdrawn from late stage clinical trials
due to these cardiotoxic effects, therefore it is important to identify
inhibitors early in drug discovery.
18. Method
• Characterization of substance binding to the hERG channel is a critical
step in cardiac safety pharmacology.
• The Dynaflow system and DF-8 Pro II chips were validated as a GLP
hERG screening platform.
• The study covers a variety of inhibitory substances including
hydrophobic compounds.
• Substance IC50 values obtained with the Dynaflow system show
similar potency to those from conventional patch clamp and
recording stability allowed for full dose response curves to be
extracted from single cells.
• The performance of the Dynaflow system in this study demonstrates
its suitability for conducting safety studies.
19. • The results were obtained by eliciting hERG current responses with a
voltage pulse protocol.
• CHO cells were stably transfected with cDNA encoding for the
recombinant hERG potassium channel and kept under standard cell
culture conditions.
• Cell suspension was achieved with standard procedure documented
in the Cellectricon Cell Handling Document.
• All experiments were performed at room temperature.
• Validation of IC50 values with Dynaflow
