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Pharmacy 3
PRECLINICAL STUDIES
Including:
Chemistry
Physical Properties
Biological
Pharmacology
ADME
Toxicology
Preformulation
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INVESTIGATIONAL NEW
DRUG APPLICATION (IND)
Submission
FDA Review
CLINICAL TRIALS
Phase I
Phase II
Phase III
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NEW DRUG
APPLICATION (NDA)
Submission
FDA Review
Pre-approval Plant inspection
FDA action
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Lead
Finding
IND
Track
Development
P
H
A I
Phase
S
E
I
Phase
II
Phase
III
Registration
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PHASE 1
Duration: 1 to 3 years
Sample size: less than 100 patients
Test on: Healthy volunteers
If passed this Phase, chances of the product
reaching to the market will be 30%
Begins to analysis and develop the drugs
safety profile
How the drug is absorbed, distributed,
metabolized and excreted
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CONCLUSION: Phase I
Studies
How well does Phase I measure?
!
!
!
Selection of doses
Safety monitoring strategy
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Lead
Finding
IND
Track
Development
Phase
I
P
H
A
Phase
II S
E
2
Phase
III
Registration
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PHASE II (Clinical
Investigation)
Duration: 2 years
Establishes the
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PHASE II (Clinical
Controlled clinical trials (randomized, blinded,
Investigation)
etc.)
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Lead
Finding
IND
Track
Development
Phase
I
Phase
II
P
H
A
Phase
III S
E
3
Registration
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NDA
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NDA Filing
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NDA Review/Approval
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Clinical Data
Analysis
Full
Development
Studies in 100-300
Patients (Phase II)
Studies in Healthy
Volunteers Phase I
Large Amounts of
Candidate Medicine
Synthesized
Extensive
Safety
Studies
ExploratoryDevelopment
Project Team
and Plans
Candidate
Formulations
Developed
Early
Safety
Studies
Synthesis
of Compounds
Screening
Discovery
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~100
~100 Discovery
Discovery Approaches
Approaches
1-2
Products
Clinical Pharmacology
& Safety
Discovery
Exploratory Development
Phase I
Phase II
Phase III
15
10
Idea
Full Development
Drug
11 - 15 Years
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Preclinical
Clinical
Research and
Research and Development
Surveillance Development
Initial synthesis
and
characterization
NDA Review
Post Marketing
Adverse
reaction
Phase 1
Phase 2
Surveys/sampling
testing
Phase 3
Animal testing
Short term
Long term
Average 61/2
years
Average 7 years
Inspection
Average 1 1/2
years
NDA submitted
NDA approval
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Pharmacologists
Cellular
Molecular
Bacteriologists
Virologists
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Organic
Physical
Analytical
Combinatorial
Synthesis
Pharmacists
Formulations
Clinical Supply
Product Stability
Analytical
Pharmacologists
Cellular
Molecular
Bacteriologists
Virologists
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Clinical Specialists
Medical Monitors
Clinical Scientists
Medical Writers
Biostatisticians
Data Management
Specialists
Pharmacists
Formulations
Clinical Supply
Product Stability
Analytical
Pharmacologists
Cellular
Molecular
Bacteriologists
Virologists
Organic
Physical
Analytical
Combinatorial
Synthesis
Clinical Specialists
Medical Monitors
Clinical Scientists
Medical Writers
Biostatisticians
Data Management
Specialists
Pharmacologists
Cellular
Molecular
Bacteriologists
Virologists
Pharmacists
Formulations
Clinical Supply
Product Stability
Analytical
Specialists
Toxicologists
Drug Metabolism
Project Managers
Human Relations
Regulatory
Legal
Safety Surveillance
Communications
Discovery
Screening
Specific Tests to
Aid in Selection
(e.g. Bioassay or
in vitro
Functionality)
Candidate
Nomination for
Development
General
Pharmacology
Profiles and Special
Models
Phase IV
Monitoring
GENERAL
PHARMACOLOGY
IND
Mechanistic Followup Studies and Other
Therapeutic
Indications
Investigate
Side-Effect
Issues
NDA
Clinical
Trials
Supercompression of Drug
Discovery
Cell & Molecular
Sciences
Biotechnology
R
Robotics
Genetics
Combinatorial
Chemistry
Computer &
Inform. Technology
Informatics &
Databases
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SOURCES Of DRUGS
1. Pure organic compound
2. Natural or Synthetic
3. Organometallic
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Purposes:
to detect an unknown activity of the test
compound or substance
to identify the most promising compounds
to be studied by more sophisticated
nonrandom or targeted screens
to determine a specific activity
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2. Molecular modification
is chemical alteration of a known
and previously characterized organic
compound (frequently a lead
compound) for the purpose of
enhancing its useful as a drug
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PURPOSES:
1. Enhance its specificity for a particular body target
site
2. Increasing its potency
3. Improving its rate and extent of absorption
4. Modifying the advantage its time-course in the body
5. Reducing its toxicity
6. Changing its physical and chemical properties
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EXAMPLES:
Dichloroisoproterenol 1st
compd. with beta
adrenoreceptor action; had
partial agonist
(sympathomimetic) activity
Pronetalol - beta
adrenoreceptor blocking
agent relatively free
sympathomimetic; limited
side effect, including lightheadedness, incoordination,
nausea & vomiting
Propranolol - beta
adrenoreceptor, free
sympathomimetic, lacking
side effects
Burimamide - ist
histamine H2 receptor
blocking agent, poor oral
availability
Metiamide - histamine H2
receptor blocking agent;
good oral activity,
produced reversible
agranulocytosis in some
people
Cimetidine - histamine H2
receptor blocking agent;
good oral activity, No
agranulocytosis in man
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PURPOSE:
The intention is the interaction of the drug
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Example of Mechanism-based
Drug Design
1. Enalaprilat -Vasotec - inhibits the
angiotensin-coverting enzymes that catalyzes
the conversion of AI to the vasoconstrictor
substance AII. Inhibition of the enzymes results
decreased plasma AII, leading to decrease
vasopressor effects and lower blood pressure
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LEAD COMPOUND
is a prototype chemical
compound which has a
fundamental desired biologic
or pharmacologic activity.
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PRODRUGS
is a term used to described a
compound that requires metabolic
biotransformation following administration
to yield the desired pharmacologically
active compound.
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Example of Prodrug
Enapril maleate Vasotec
which, after oral administration,
bioactivated by hydrolysis to enaprilat, an
ACE inhibitor used in the treatment of
hypertension
Prodrug may be design preferentially for
solubility, absorption, biostability and
prolonged release
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Solubility
Enabling the use of specifically desired
dosage forms and routes of administration
Absorption
A drug may be made more water or lipid
soluble, as desired, to facilitate absorption
via the intended route of administration
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Biostability
An active drug is prematurely destroyed
by biochemical or enzymatic process, the
design of a prodrug may protect the drug
during its transport in the body
Prolonged Release
Depending on a prodrugs rate of
metabolic conversion to active drug, it may
provide prolonged release and extended
therapeutic activity
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NOMENCLATURE OR NAMING OF
DRUG
The task of designating appropriate nonproprietary names for newly found
chemical agents rests primarily with the
USAN Council.
The official name for a drug is referred to
as the drug nonproprietary or public
name
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CATEGORY OR USE
In general, drugs exert their effects by one
of three means:
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3.
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Pharmacology
pharmaco = drugs
logos = study of
is the science concerned with drugs,
their sources, appearance, chemistry,
actions, and uses.
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biochemical
physiologic effects
mechanism of action
ADME
Pharmacodynamics
the study of the biochemical and physiologic
effects of drugs and their mechanism of action
Pharmacokinetics = ADME
Clinical Pharmacology
applies pharmacologic principles to the study
of the effects and actions of drugs in humans
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Pharmacologic profile
= In vitro cultures of cells and enzymes
systems and in vivo animal models are
used to define a chemicals pharmacologic
profile
= Most animal testing is done on small
animals, usually rodents (mouse, rats) for a
number of reasons including cost,
availability, the small amount of drug
required for a study,
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Drug Metabolism
1. The extent and rate of drug absorption
from various routes of administration,
including the one intended for human use
2. The rate of distribution of the drug through
the body and the site or sites and duration of
the drugs residence
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Toxicology
Deals with the adverse or undesired
effects of drugs
Not all side effects of new drugs to be
tested in animals will be detected but
the greater the likelihood the effect
also be seen in humans
ill
Example: headache
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Subacute or Subchronic
Studies
Animal toxicity studies of a minimum of 2
weeks of daily drug administration at three
or more dosage levels to two animal
species are required to support the initial
administration of a single dose in human
clinical testing.
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physical examination
(electrocardiography, ophthalmic,
examination), hematology, clinical
chemistry, organ weights, gross
pathology, neoplastic pathology,
histopathology, urinalysis, ADME data
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Carcinogenicity Studies
Usually component of chronic testing and is
undertaken when compound has shown
sufficient promise as a drug to enter human
clinical trials.
Carcinogenicity studies are long term (18-24
months), with surviving animals killed and
studied at defined weeks during the test
period
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Reproduction Studies
Reproduction studies are undertaken to
reveal any effect of an active ingredient on
mammalian reproduction
Included in these studies are fertility and
mating behavior; early embryonic, prenatal,
and postnatal development,
multigenerational effects, teratology
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Genotoxicity or Mutagenicity
Studies
Performed to determine whether
the test compound can affect gene
mutation or cause chromosome or DNA
damage. Strains Salmonella
typhimurium are routinely used in
assays to detect mutations.
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Preformulation Studies
Each drug substance has intrinsic
chemical and physical characteristic that
must be considered before the
development of a pharmaceutical
formulation
Among these are the drugs solubility,
partition coefficient, dissolution rate,
physical form, and stability
2016 UST: NTT Chapter 2
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Drug Solubility
A drug substance administered by any
route must posses some aqueous
solubility for systemic absorption and
therapeutic response
Poorly soluble compounds (example less
than 10mg per ml aqueous solubility) may
exhibit incomplete, erratic, and or slow
absorption and thus produce a minimal
response at desired dosage
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Partition Coefficient
A drug partition coefficient is a measure of its
distribution in a lipophilic-hydrophilic phase
system and indicates its ability to penetrate
biologic multiphase system
Dissolution Rate
Is the speed at which a drug substance
dissolves in a medium
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Physical Form
The crystal or amorphous forms and or the
particle size of a powdered drug can affect
the dissolution rate, thus the rate and extent
of absorption, for a number of drugs
Stability
The chemical and physical stability of a drug
substance alone, and when combined with
formulation components, is a critical to
preparing a successful pharmaceutical
product
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Blinded Studies
Are controlled studies in which at least
one of the parties (example, patient,
physician) does not know which
product is being administered
Some studies are open label, in which
case all parties may know what
products are administered
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5. Analytical method
6. Pharmacology
7. Toxicology
8. Efficacy in animals
9. Persons who will do the clinical studies
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Investigator brochure
Commitment not to begin clinical
investigations until the IND is in
effect, the signature of the
sponsor
or authorized representative, and the
date of the signed application
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Clinical Protocol
As a part of IND application, clinical
protocol must be submitted to ensure the
appropriate design and conduct of the
investigation, include:
Statement of the purpose and objectives of
the study
Outline of the investigational plan and study
design
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By Therapeutic Classification
Type P Priority review, a therapeutic gain
Type S Standard review, similar to other
approved drugs
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Additional Classification
Type AA For treatment of AIDS or HIVrelated disease
Type E For life-threatening or
severely debilitating disease
Type F Review deferred pending
data validation
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Additional Classification
Type G Data validated, removal of F rating
Type N Nonprescription drug
Type V Drug having orphan drug status
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Underdosage / Overdosage
doses falling outside of the usual range
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Acetaminophen
10-20
400
1500
Amitriptyline
0.5-.20
0.4
10-20
1
1-5
~10
7
10-30
40-60
10
30
80-100
0.05-0.2
5-10
57
Barbiturate
Short Acting
Intermediate
Long Acting
Dextropropoxyphene
Diazepam
0.5-2.5
Digoxin
0.0006-0.0013
Imipramine
0.05-0.16
Lidocaine
5-20
0.002-0.009
1.2-5.0
:50
--
0.7
--
Lithium
4.2-8.3
13.9
13.9-34.7
Meperidine
0.6-0.65
30
Morphine
0.05-4
0.1
--
Phenytoin
100
5-22
50
3-6
10
Quinidine
201650
UST: NTT
Chapter 2
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30-
Between 5 and 10
Greater Than 10
Amitriptyline
Barbiturates
Acetaminophen
Chlordiazepoxide
Diazepam
Bromide
Diphenhydramine
Digoxin
Chloral hydrate
Ethchlorvynol
Imipramine
Glutethimide
Lidocaine
Meperidine
Meprobamate
Methadone
Paraldehyde
Nortriptyline
Procainamide
Primidone
Pentazocine
Quinidine
Thioridazine
Propoxyphene
SITE
oral
mouth
intravenous
vein
intraarterial
artery
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TERM
SITE
intracardiac
heart
intraspinal/intrathecal
spine
intraosseous
bone
intraarticular
joint
intrasynovial
joint-fluid area
intracutaneous/intradermal skin
subcutaneous
beneath the skin
intramuscular
muscle
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SITE
epicutaneous (topical)
skin surface
transdermal
skin surface
conjunctival
conjunctiva
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TERM
intraocular
intranasal
aural
intrarespiratory
rectal
vaginal
urethral
SITE
eye
nose
ear
lung
rectum
vagina
urethra
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6.Precautions
7.Adverse reactions
8.Drug abuse and Dependence
9.Over dosage
10.Dosage and Administration
11. How supplied
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