Transcript New drug development and approval process

New Drug Development
and
Approval Process
NEW DRUG DEVELOPMENT PROCESS
NEW CHEMICAL ENTITY
SOURCES:
• Organic Synthesis
• Molecular Modification
• Isolation from plants
• Genetic Engineering
PRECLINICAL STUDIES
Including
• Chemistry
• Physical Properties
• Biological
Pharmacology
ADME
Toxicology
• Preformulation
CLINICAL TRIALS
• Phase I
• Phase II
• Phase III
PRECLINICAL STUDIES (Continued)
• long term animal toxicity
• product formulation
• Manufacturing and controls
• Package and label design
NEW DRUG APPLICATION (NDA)
• Submission
• FDA Review
• Pre-approval Plant inspection
• FDA action
POST MARKETING TRIALS
• Phase IV Clinical Trials
clinical pharmacology/Toxicology
additional indications
• Adverse Reaction Reporting
• Product Defect Reposting
• Product Line Extension
4 Phases Of Clinical Studies In Man
PHASE 1 (Clinical Pharmacology)
• fewer than 100 healthy people
• design to determine that the drug is
safe and the side effects might be
• provide basic information about how
drug works in the body
(Pharmacokinetic activity)
PHASE II (Clinical Investigation)
• several 100 patients – disorders
• evaluate dosage needed
• detail how and why drug works in
the body and side effect it
causes
• the drug must be effective and
safe
PHASE III (Clinical Trials)
• larger group of patients (2,000 to
3,000)
• compare the drug with the existing
drugs
• provide statistics on adverse
reaction
PHASE IV (Post Marketing
Clinical Trials)
• postmarketing surveillance may
be required
• unexpected reactions are detected,
reported, and evaluated
• new indications for using the drug,
problems of people who take
the drug
• Some products, however, have
been approved and later removed
from the market for safety reasons,
including the following:
• Grepafloxacin HCL (Raxar)
• Brofenac sodium (Duract)
• Cisapride (Propulsid)
• Alosetron HCL (Lotrovec)
• Fenfluramine HCL (Pondimin)
• Dexfenfluramine HCL (Redux)
• Terfenadine (Seldane)
• Cerivastatin (Baycol)
• Mibefradil (Posicor)
• Astemizole (Hismanal)
• Troglitazone (Rezulin)
Preclinical
Research and
Development
Initial synthesis
and
characterization
Clinical
Research and Development
NDA Review
Post Marketing
Surveillance
Adverse
reaction
Phase 1
Phase 2
Surveys/sampling
testing
Phase 3
Animal testing
Short term
Long term
Average 61/2
years
Average 7 years
FDA 30-day safety review
Inspection
Average 1 1/2
years
NDA submitted
Average of approx. 15 years from initial synthesis to approval of NDA
NDA approval
Drug Discovery and Drug Design
- R and D activities on new Rx drugs for human
- OTC drugs, generic drugs, biotechnology
products, animal health care drugs,
diagnostic products, and medical devices
- development of new agents, such as
vaccines to protect against poliomyelitis,
measles, and influenza
- new pharmacologic categories of
drugs including oral hypoglycemic
drugs effective against certain types
of diabetes mellitus
- antineoplastic or anticancer drugs,
- immunosuppressive agents to assist the
body’s acceptance of organ
transplant
- contraceptives to prevent pregnancy
- tranquilizers and antidepressant
drugs to treat the emotionally
distressed
New and Important Innovative Therapeutic
Agents Approved by FDA
1.
2.
3.
4.
5.
6.
7.
Efavirenz - Sustiva - to treat AIDS
Didanosine - Videx EC - to treat AIDS
Tenofovir - Viread - to treat AIDS
Leuprolide acetate - Eligard – prostate cancer
Triptorelin pamoate - Trelstar - prostate cancer
Lovastatin - Mevacor - hyperlipidemic
Treprostinil sodium - Remodulin - pulmonary
arterial hypertensive
8. Moxifloxacin HCl - Avelox - infectious disease
9. Montelukast sodium - Singulair - chronic
asthma
10. Tegaserod maleate - Zelnorm - irritable bowel
syndrome in women
11. Sodium oxybate -Xyrem - cataplexy in patient
with narcolepsy
12. Galantamine HCl - Reminyl - dementia with
Alzheimer’s disease
13. Fondaparinux sodium - Arixtra - deep vein
thrombosis
14. Voriconazole - Vfend - infectious disease
SOURCES Of DRUGS
1. Pure organic compound
2. Natural or Synthetic
3. Organometallic
These remedial have their origin in
essentially 3 ways
1. Naturally occurring materials in both
plants and animals
Example: Ergot, opium, curare,
cinchona
2. Synthesis of organic compounds
whose structure are closely related to
those naturally occurring compounds
Example: morphine, atropine,
cortisone, cocaine
3. Pure synthesis in which no attempt
has been made to pattern after a
known naturally occurring
compounds exhibiting some
activity
Example: antihistamine,
barbiturates, diuretics, antiseptic, etc.
Sources of New Drugs
1. Reserpine - tranquilizers and hypotensive agent
- isolated from Rauwolfia serpentina
2. Periwinkle or Vinca rosea - use as treatment of
diabetes mellitus
3. Vinblastine and Vincristine - Vinca rosea cancer, including acute leukemia, Hodgkin’s
disease and lymphocytic lymphoma and
other malignancies
4. Paclitaxel (Taxol)- Pacific yew tree ovarian cancer
5. Dioscorea - Mexican yams - chemical
steroid structure - cortisone and estrogen
are semisynthetically produced
6. Endocrine glands of cattle, sheep, and
swine - hormonal substances like thyroid,
insulin, and pituitary hormone
replacement therapy in the human body
7. Urine of pregnant mares - rich source
of estrogen
8. Animals - serum, vaccines, toxins
9. Renal monkey tissue - poliomyelitis
vaccines
10. Fluid of chick embryo - mumps and
influenza vaccines
11.Duck embryo – rubella (German
measles)
12. Skin of Bovine calves inoculated
with vaccinia virus- smallpox
vaccines
13. Cell and Tissue cultures - new
vaccines for diseases AIDS and
cancer
14. Genetic engineering - manipulation
of the helix, the spiral DNA chain of
life.
2 basic technologies that drive the
genetic field
1. Recombinant DNA
2. Monoclonal antibody production
15. Gene splicing - can be transplanted
from higher species, such as human,
into lower bacterium
- to produce proteins
- human insulin, human growth
hormone, hepatitis B vaccine, epoetinalpha, and interferon are being
produced in this manner.
16. Monoclonal antibodies - the ability of
the cells with potential to produce a
desired antibody and stimulates an
unending stream of pure antibody
production.
Example: Pregnancy testing products
In these test, the monoclonal
antibody is highly sensitive to binding
on one site on the human chorionic
gonadotropin (HCG) molecule, a
specific marker to pregnancy
because in healthy women. HCG is
synthesized exclusively by the
placenta
In medicine: MA are being used to
stage and to localize malignant
cells of cancer, and it is anticipated
that they will be used in the future
to combat disease such as lupus
erythematosus, juvenile-onset
diabetes, and myasthenia gravis
17. Human Gene Therapy - used to
prevent, treat, cure, diagnose, or mitigate
human disease caused by genetic disorders
- Human body contains up to 100,000
genes
- adenine and thymine (A and T
respectively), cytosine and guanine (C
and G) respectively) constitute the
instructions on a gene.
-genetic diseases, gene expression may
be altered, gene sequences may be
mismatched, partly missing, repeated too
many times, causing cellular malfunction
and disease
- modification of the genetic material of
living cells may be modified outside the
body (ex vivo) for subsequent
administration or modified within the
body ( in vivo) by gene therapy products
given directly to the patient
- the first human gene therapy used
was to treat adenosine deaminase
(ADA) deficiency, a condition that
results in abnormal functioning of the
immune system.
- many companies exploring
application of Gene therapy to treat
sickle cell anemia, malignant melanoma,
renal cell cancer, heart disease, familial
hypercholesterolemia, cystic fibrosis,
lung and colorectal cancer, and AIDS
Goal Drug - In theory, a goal drug
1.Would produce the specifically desired
effect
2.Be administered by the most desired
route at minimal dosage and dosing
frequency
3.Have optimal onset and duration of
activity
4.Exhibit no side effects
5. Following its desired effect would be
eliminated from the body efficiently and
completely
6. No residual side effect
7. It would be easily produced at low cost
8. Be pharmaceutically elegant
9. Physically and chemically stable under
various conditions of use and storage.
Methods of Drug Discovery
• Although some drugs may be the
result of fortuitous discovery, most
of drugs are the result of carefully
designed research programs of
screening, molecular modification,
and mechanism-based drug design
1. Random or untargeted screening
involves the testing of large numbers of
synthetic organic compounds or
substances of natural origin for biologic
activity
• 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
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
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
3. Mechanism-based drug design
- is a molecular modification to design a
drug that interferes specifically with
the known or suspected biochemical
pathway or mechanism of a disease
process
PURPOSE:
The intention is the interaction of the drug
with specific cell receptors, enzymes
systems, or metabolic process of pathogens
or tumor cells, resulting in blocking,
disruption, or reversal of the disease
process
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
2. Ranitidine - Zantac - an inhibitor of
histamine at the histamine H2receptors, including receptors on the
gastric cells. Used to treat gastric
ulcers
3. Sertraline - Zoloft - which inhibits
the central nervous system’s
neuronal uptake of serotonin,
making the drug useful in the
treatment of depression.
Lead compound
-is a prototype chemical
compound which has a
fundamental desired
biologic or pharmacologic
activity.
Example of Lead Compound
1. Cephalosporin antibiotics - additional
H2 antagonists from the pioneer drug
Cimetidine
2. Large series of antianxiety drugs
derived from Benzodiazepine structure
and the innovator drug chlordiazepine
-Librium.
3. Most drugs exhibit activities
secondary to their primary
pharmacologic action.
Example: Finasteride -Proscar
was originally developed and
approved to treat benign prostatic
hyperplasia. Later, the same drug Propecia was approved at lower
recommended dosage to treat male
pattern baldness
Prodrugs
-is a term used to described a
compound that requires
metabolic biotransformation
following administration to yield
the desired pharmacologically
active compound.
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
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
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
FDA’s Definition of a New Drug
and
NEW DRUG - is any that is not recognized
as being safe and effective in the conditions
recommended for its use among experts
who are qualified by scientific training
experience.
A combination of two or more old drugs or a
change in the usual proportions of drugs in an
established combination product is considered
new if the change introduces a question of
safety or efficacy.
- A new dosage schedule or regimen, a new
rout of administration, new dosage form all
cause a drug or drug product’s status to new
and triggers reconsideration for safety and
efficacy
- A drug need not be a new chemical entity to
be considered new. A change in a previously
approved drug product’s formulation or method
of manufacture constitutes newness under
the law, since such changes can alter the
therapeutic efficacy and/or safety of a product.
NOMENCLATURE OR NAMING OF
DRUG
The task of designating appropriate
non-proprietary 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
in contrast to the proprietary or brand
names or trademark names given by
the specific manufacturers or
distributors of the drug.
The term generic name, has been
used extensively in referring to the
nonproprietary names of the drugs.
Brand name is registered as a
trademark with the United States
Patent Office
CATEGORY OR USE
In general, drugs exert their effects by
one of three means:
1. By exerting a physical action such
as the protective effects of
ointments and lotions upon
topical application
2. By reacting chemically outside
the body cells.
Example: antacids counteract
excess acidity in the stomach or
antibiotics to act against invading
pathogenic microorganism.
3. By modifying the metabolic
activity of the body’s cell.
Majority of the drugs belong
to the 3rd manner where
brain, liver, kidney, etc. are
affected
Proposals for Nonproprietary
Names
1. Be short and distinctive in
sound and spelling and not
be such that it is easily
confused with existing
names
2.Indicate the general pharmacologic
or therapeutic class into which the
substance falls or the general
chemical nature of the substance if
the latter is associated with the
specific pharmacologic activity
3. Embody the syllable or syllables
characteristic of a related group of
compounds
Pharmacology
pharmaco= drugs;
logos = study of; is the
science concerned with
drugs, their sources,
appearance, chemistry,
actions, and uses.
The term can be expanded to
include
1. Properties
2. Biological and physiologic
effects
3. Mechanism of actions
4. 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
Pharmacologic profile = In vitro
cultures of cells and enzymes systems
and in vivo animal models are used to
define a chemical’s 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,
the ease of administration by
various routes (oral, inhalation,
intravenous) and experience with
drug testing in these species
Animal models: dog or rat for hypertension; dog and guinea
pig - for respiratory effects; dogfor diuretic activity; rabbit - for
blood coagulation; mouse and
rats - for CNS studies
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 drug’s
residence
3.The rate, primary and secondary
sites, and mechanism of the
drug’s metabolism in the body
and the chemistry and
pharmacology of any metabolites
4. The proportion of administered
dose eliminated from the body
and its rate and route of
elimination
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 will also be
seen in humans
Example: headache
Purpose of Safety Evaluation and
Toxicity Studies
1.The substance’s potential for toxicity
with short-term (acute effects) or
long- term use (chronic effects)
2.The substance’s potential for
specific organ toxicity
3.The mode, site, and degree of
toxicity
4.Dose-response relationships for
low, high, and intermediate
doses over a specified time
5.Gender, reproductive, or
teratogenic toxicities
6. The substance’s carcinogenic
and genotoxic potential
Acute or Short-Term Toxicity
Studies
These studies are designed
to determine the toxic effects of a
test compound when administered
in a single dose and/or in multiple
dose doses over a short period,
usually a single day.
Animals are observed: eating and
drinking habits; weight changes; toxic
effects; psychomotor changes; feces
and urine are collected.
Animal death: recorded; study on
histology; pathology and statistically
evaluated on the basis of dose
response
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 ad
ministration of a single dose in
human clinical testing.
Chronic toxicity studies
The initial human dose is
usually one-tenth of the highest
nontoxic dose (in milligrams per
kilogram of subject’s weight) shown
during the animal studies. For drugs
intended to be given to humans for a
week or more, animal studies of 90
to 180 days must demonstrate
safety.
If the drug is to be used for a chronic
human illness, animal studies 1 year or
longer must be undertaken to support
human use.
Compare the strain, sex, age, dose
levels and ranges, routes of
administration, duration of treatment,
observed effects, mortality, body weight
changes, food and water consumption,
physical examination
(electrocardiography, ophthalmic,
examination), hematology, clinical
chemistry, organ weights, gross
pathology, neoplastic pathology,
histopathology, urinalysis, ADME
data
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
Data on the causes of animal
death, tumor incidence, type and
site, and necropsy findings are
collected and evaluated
Preneoplastic lesions and/or
tissue-specific proliferation
effects are important findings
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
In these studies, the maternal
parent, fetus, neonates, and
weaning offspring are evaluated for
anatomic abnormalities, growth, and
development. The animal used in
other toxicity studies in reproductive
studies, usually the rats.
In embryotoxicity studies
only, a second mammalian species
traditionally has been required. The
rabbit is the preferred choice for
practically and the extensive
background knowledge
accumulated on this species.
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.
Early Formulation Studies
- As a promising compound is
characterized for biological activity, it is
also evaluated with regard to chemical
and physical properties that have
bearing on its ultimate and successful
formulation into stable and effective
pharmaceutical product
- This is the area of responsibility
of pharmaceutical scientists and
formulation pharmacists trained
in pharmaceutics
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 drug’s solubility,
partition coefficient, dissolution rate,
physical form, and stability
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
Partition Coefficient
-A drug partition coefficient is a measure
of its distribution in a lipophilichydrophilic 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
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
Initial Product Formulation and
Clinical Trial Materials
- Prepared for Phase 1 and Phase 2
for clinical trials
- Phase 1 studies, for orally
administered drugs, capsules are
employed containing the active
ingredient alone, without
pharmaceutical excipients
-Phase 2, the final dosage form is selected and
developed for Phase 3 trials, this is the formulation
that is submitted to the FDA for marketing approval
Clinical Supplies or Clinical Trial
Materials
- Comprise all dosage formulations used in the
clinical evaluation of a new drug
- This includes the proposed new drug, placebos
(inert substances for controlled studies) and drug
products against which the new drug is to be
compared (compactor drugs or drug products)
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
In all clinical study programs, the package
label of the investigational drug must bear
the statement “Caution: new drug – limited
by federal ( or United States) law to
investigational use”
- Blister packaging is commonly used in
clinical studies, with intermediate labels
containing the clinical study or protocol number,
patient identification number, sponsor number,
directions for use, code number to distinguish
between investigational drug, placebo, and or
compactor product, and other relevant
information
INVESTIGATIONAL NEW DRUG
1.Full description of new drug
2.Where and how it is manufactured
2.All quality control information and
standards
4.Stability
5. Analytical method
6. Pharmacology
7. Toxicology
8. Efficacy in animals
9. Persons who will do the clinical
studies
Content of the IND
The content of an IND is prescribed in
the Code of Federal Regulations and is
submitted under a cover sheet (Form FDA1571):
• Name, address, and telephone number of
the sponsor of the drug
• Name and title of the person responsible
for monitoring the conduct and progress of
the investigation
• Names and titles of the persons
responsible for the review and evaluation
of information relevant to the safety of the
drug
• Name and address of any contract
research organization involved in the
study
• Identification of the phase or phases of
the clinical investigation to be conducted
•Introductory statement and general
investigational plan
•Description of the investigational plan
•Brief summary of previous human
experience with the drug (domestic or
foreign)
•Chemistry, manufacturing, control
information
•Pharmacology and toxicology information
• If the new drug is a combination of
previously investigated components, a
complete preclinical summary of these
components when administered singly and
any data or expectations relating to the
effect when combined
• Clinical protocol for each planned study
• Commitment that an Institutional Review
Board has approved the clinical study and
will continue to review and monitor the
investigation
• 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
Clinical Protocol
As a part of IND application, clinical
protocol must be submitted to ensure the
appropriate design and conduct of the
investigation
Clinical Protocol include:
• Statement of the purpose and
objectives of the study
• Outline of the investigational plan and
study design
• Estimate of the number of patients to be
involved
• Basis for subject selection, with inclusion
and exclusion criteria
• Description of the dosing plan, including
dose levels, route of administration, and
duration of patient exposure
• Description of the patient observations,
measurements, and tests to be used
• Clinical procedures, laboratory tests,
and monitoring to be used in
minimizing patient risk
• Names, addresses, and credentials of
the principal investigators and co
investigators
• Locations and descriptions of the
clinical research facilities to be used
FDA Review of an IND
Application
To protect the safety and
rights of the human subjects and
to help ensure that the study
allows the evaluation of the drug’s
safety and effectiveness.
FDA Drug Classification System
By Chemical Type
Type 1 – New Molecular entity, not
marketed in US
Type 2 – New ester, new salt, or other
derivative of an approved active moiety
Type 3 – New formulation of a drug
marketed in US
Type 4 – New combination of two or
more compounds
Type 5 – New manufacturer of a drug
marketed in US
Type 6 – New therapeutic indication
for an approved drug
By Therapeutic Classification
Type P – Priority review, a
therapeutic gain
Type S – Standard review, similar to
other approved drugs
Additional Classification
Type AA – For treatment of AIDS
or HIV-related disease
Type E – For life-threatening or
severely debilitating disease
Type F – Review deferred pending
data validation
Type G – Data validated,
removal of F rating
Type N – Nonprescription drug
Type V – Drug having orphan
drug status
Drug Dosage and Terminology
The safe and effective dose of a drug
depends on different FACTOR:
1.Characteristics of the drug substance
2.The dosage form and its route of
administration
3.Variety patient factors - age, body
weight, general health status, pathologic
conditions
4. Concomitant drug therapy
Usual adult dose - the amount of
drug that will produce the desired effect
in most adult patients.
Usual Dosage range - indicates
the quantitative range or amounts of the
drug that may be prescribed safely
within the framework of usual medical
practice.
Underdosage / Overdosage doses falling outside of the usual range
Usual Pediatric dose - dose
usually given to children
Schedule of dosage or Dosage
regimen - determined during the clinical
investigation and is based largely on a
drug’s inherent duration of action, its
pharmacokinetics, and characteristics of
the dosage form
MEC Minimum Effective
Concentration - An average blood serum
concentration represents the minimum
concentration that can be expected to
produce the drug’s desired effects in a
patient
MTC Minimum toxic
Concentration - The second level of
serum concentration of drugs expected to
produce dose-related toxic effects in the
average individual
MED Median Effective Dose of a
drug is the amount that will produce
the desired intensity of effect in 50%
of the individuals tested.
MTD Median Toxic Dose - is the
amount that will produce a defined toxic
effect in 50% of the individuals tested
The relationship between the
desired and undesired effects of a drug
is commonly expressed as the
Therapeutic index and is defined as
the ratio between a drug’s median toxic
dose and its median effective dose,
TD50/ED50.
Some factors of patients considered in
determining a drug’s dose in clinical
investigations and in medical practice include
the following:
• Age
• Body Weight
• Body Surface Area
• Sex
• Pathologic State
• Tolerance
Therapeutic and Toxic Blood Level Concentrations of Some Drugs
Substance
Drug Substances concentration, mg/L Drug
Therapeutic
Toxic
Lethal
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
Dextropropoxyphene
0.05-0.2
5-10
57
Diazepam
0.5-2.5
5-20
:50
Digoxin
0.0006-0.0013
0.002-0.009
--
Imipramine
0.05-0.16
0.7
2
Lidocaine
1.2-5.0
6
--
Lithium
4.2-8.3
13.9
13.9-34.7
Meperidine
0.6-0.65
5
30
Morphine
0.1
--
0.05-4
Phenytoin
5-22
50
100
Quinidine
3-6
10
30-50
Theophylline
20-100
--
--
Barbiturate
Short Acting
Intermediate
Long Acting
Therapeutic Indices For Various Drug Substances
Less Than 5
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
Routes Of Drug Administration
TERM
SITE
oral
mouth
peroral (per os, p.o.)
gastrointestinal tract via mouth
sublingual
parenteral
under the tongue
other than GIT (by injection)
intravenous
vein
intraarterial
artery
TERM
SITE
intracardiac
heart
intraspinal/intrathecal
spine
intraosseous
bone
intraarticular
joint
intrasynovial
joint-fluid area
intracutaneous/intradermal skin
subcutaneous
beneath the skin
intramuscular
muscle
Routes Of Drug Administration
TERM
SITE
epicutaneous (topical)
skin surface
transdermal
skin surface
conjunctival
conjunctiva
TERM
intraocular
intranasal
aural
intrarespiratory
rectal
vaginal
urethral
SITE
eye
nose
ear
lung
rectum
vagina
urethra
Drug Product Labeling (Package
Inserts)
1. Description of the product
2. Clinical Pharmacology
3. Indications and usage
4. Contraindications
5. Warnings
6.Precautions
7.Adverse reactions
8.Drug abuse and Dependence
9.Over dosage
10.Dosage and Administration
11. How supplied
Supplemental, Abbreviated, and
Other Applications
Supplemental New Drug Application
Abbreviated New Drug Application
Biologics License Application
Animal Drug Applications
Medical Devices