Drug Development Process Flashcards by Cez Banzuela

When the nucleus of the drug from natural source as well as its
chemical structure is altered.
 Examples
Emetine Bismuth Iodide

Synthethic

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When the nucleus of drug obtained from natural source is
retained but the chemical structure is altered.
Examples Apomorphine, Diacetyl morphine, Ethinyl
Estradiol, Homatropine, Ampicillin and Methyl testosterone.

Semi synthetic

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Most of the drugs used nowadays such as antianxiety drugs,
anti convulsants are?

Synthethic

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GENETIC ENGINEERING

-Recombinant DNA & monoclonal antibody
-GENE THERAPY

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Is a medical intervention based on the modification of the
genetic material of living cells

GENE THERAPY

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technology involves cleavage of DNA by
enzyme restriction endonucleases. The desired gene is
coupled to rapidly replicating DNA (viral, bacterial or
plasmid). The new genetic combination is inserted into the
bacterial cultures which allow production of vast amount of
genetic material.

Recombinant DNA & monoclonal antibody

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CHARACTERISTICS OF A GOAL DRUG

 Specifically desired effect,
 Administered by the most desired route (generally orally)
at minimal dosage and dosing frequency
 Optimal onset and duration of activity
 Exhibit no side effects
 Eliminated in the body efficiently and completely
 Low cost
 Pharmaceutically elegant
 Physically & chemically stable

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Are chemical compounds that show desired biological or
pharmacological activity and may initiate the
development of a new clinically relevant compound.

LEAD COMPOUND

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are typically used as starting points in
drug design to give new drug entities.

lead compounds

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can be used to improve the
compound’s pharmacodynamic and pharmacokinetic
properties.

Drug design strategies

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Treatment IND are sought for to target small number of
patients with rare conditions/diseases (orphan diseases)
where there are no satisfactory alternative treatments

ORPHAN DRUG

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Rare disease/condition affecting fewer than 200,000
people:
*chronic lymphocytes *leukemia
*Gaucher’s disease *cystic fibrosis AIDS

ORPHAN DISEASE

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Before a prodrug can provide its intended effects in your body,
it needs to be?

broken down

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a chemical that is transformed before it has
pharmacological effects.

PRODRUG

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it may prevent a prodrug from becoming
active.

certain interactions

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drug is inactive before metabolism and drug becomes active after metabolism

Prodrug

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drugs takes effect directly

Active drug

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two major types of prodrugs

Type I
Type II

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prodrugs turn into their active forms inside of cells.

Type I

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prodrugs turn into their active forms outside of cells, such
as in blood or other fluids.

Type II

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is defined by FDA as an active
ingredient that has never before been marketed in any form.

New Molecular Entity (NME)

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A change in a previously approved drug product’s formulation
or method of manufacture constitutes newness under the
law such as changes can alter the therapeutic efficacy
and/or safety of a product.

NEW DRUG

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A proposed new use for an established drug, a new dosage
schedule or regimen, a new route of administration, or a
new dosage form makes a drug or a drug product’s status
new and triggers reconsideration for safety and effficacy

NEW DRUG

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indicates the number and relationship pf the atoms in the molecule Example: Amoxicillin- C16H19N3O3S.3H2O

Empirical formula

name of the compound’s every part of molecular structure Example: Amoxicillin- (2S,5R,6R)-6-[[(2R)-2-amino-2-(4- hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1- azabicyclo[3.2.0]heptane-2-carboxylic acid

chemical name

non-propriety name of the drug, serves to identify the substance to which is applies by means of a designation that maybe used by the professionals, refers to the active ingredient of the drug.  Example: Amoxicillin

Generic name

trademarked name/ marketed name assigned by the producing company Example: HimoxTM AmoxilTM TrimoxTM

Brand name

must undergo preclinical testing for biologic activity to assess their potential as useful therapeutic agents.  Pharmacology  Drug Metabolism  Toxicology

Prospective drug substances

To evaluate whether a drug is safe and effective, information must be gained on how it is absorbed, distributed throughout the body, stored, metabolized, and excreted and how it affects the action of the body’s cells, tissues, and organs.

BIOLOGICAL CHARACTERIZATION

The science concerned with drugs, their sources, appearance, chemistry, actions and uses. It includes the biochemical and physiologic effects, mechanism of action, absorption, distribution, biotransformation, and excretion.

Pharmacology

is the science that analyzes how the human body interacts with a drug.

Pharmacokinetics

examines how the drug is absorbed, distributed, metabolized, and excreted by the body.

Pharmacokinetics

is the science that studies the biochemical and physiologic effects of a drug and its organ-- specific mechanism of action, including effects on the cellular level.

pharmacodynamics

what the body does to the drug

pharmakokinetics

what the drug does to the body

pharmacodynamics

drug administration drug absorption drug distribution drug metabolism drug elimination

Pharmacokinetics

receptor enzyme ion channel transporter regulatory proteins binds to molecular target- affinity mechanism of drug action response to drug -efficacy

pharmacodynamics

to obtain basic information on the drugs effects that maybe safe and effective use in humans.

Animal studies

Hypertensive studies-

Dogs & rats

Respiratory effects studies

dogs and guinea pigs

Diuretic activities

Dogs

blood coagulation

rabbits

central nervous system studies

mice and rats

involves those chemical process within living organism to maintain life.

Drug Metabolism

Series of animal studies of a proposed drugs ADME are undertaken to determine the following:

-Extent and rate of drug absorption from various route of administration -Rate of distribution of the drug through the body and the site and duration of drug’s residence -Rate, primary and secondary sites, mechanism of the drug’s metabolism in the body -Proportion of administered dose eliminated from the body

Participate in drug metabolism (liver, kidneys, lung & git)

Specific & non-specific enzymes

exposed to rapid drug metabolism

Drugs following oral adm. that enter the hepatic circulation after absorption from gut

transit through the liver & exposure to the hepatic enzyme system

1st pass effect

performed through the collection & analysis of urine, blood & feces samples, & careful exam. Of animal tissues & organs upon autopsy

ADME studies

Deals with the adverse or undesired effects of drugs

TOXICOLOGY

- toxic effect of a test compound when administered in single dose and/or multiple doses over short period, usually a single day.

Acute or short-term toxicity studies

Animal toxicity studies (minimum of two weeks of daily drug administration at 3 or more dosage levels to two animal species) are required to support the initial administration of a single dose in human clinical testing

Subacute or subchronic studies

animal studies of 90 to 180 days

Chronic toxicity studies

For chronic human illness, long-term animal studies of

1 year or longer

For limited no. of rat and mouse strains Long term studies (18-24 months) with surviving animals killed & studied at defined weeks during the test period

Carcinogenicity studies

reveals any effect of an active ingredient on mammalian reproduction

Reproduction Studies

Determines whether test compd affects gene mutation or cause chromosome or DNA damage

Genotoxicity or Mutagenicity Studies

Used in assays to detect mutations:

Strains of Salmonella typhimurium

Each drug substance has intrinsic chemical and physical characteristics that must be considered before the development of a pharmaceutical formulation

 DRUG SOLUBILITY  PARTITION COEFFICIENT  DISSOLUTION RATE  PHYSICAL FORM  STABILITY

administered by any route must possess some aqueous solubility for systemic absorption and therapeutic response

DRUG SOLUBILITY

is a measure of its distribution in a lipophilic- hydrophilic phase system and indicates its ability to penetrate biologic multiphase system

PARTITION COEFFICIENT

It is the speed at which a drug substance dissolves in a medium

DISSOLUTION RATE

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

Physical forms

testing at various temperature, conditions of relative humidity (RH), durations, and environments of light, air and packaging is essential in assessing drug

Stability

To protect the rights and safety of the subjects and to ensure that the investigational plan is sound and is designed to achieve the stated objectives

Investigational New drug (IND)

part of the IND application  submitted to ensure the appropriate design and conduct of investigation  Includes: *purpose & objectives *investigational plan *number of patients *subject selection *dosing plan *clin. procedures, lab. tests *patient observations, measurements & tests, etc.

The clinical protoco;

FDA classifies the drug by:

*chemical type *therapeutic potential

Animal pharmacology & toxicology data are obtained - determines the safety & efficacy of the drug - submission of investigational new drug (IND) application for human testing to the FDA

Pre clinical

- initial introduction (Clinical testing) - subjects: Healthy volunteers (20-100) - determines drug tolerance & toxicity (assessing safety)

Phase 1

Controlled clinical studies to several hundred patients with the disease/condition are treated - Safety measured - determines the therapeutic index (ratio of toxic dose to effective dose)  final drug formulation developed bioequivalent (same rate & extent of drug absorption to the brand drug product) to the dosage form

Phase II

several hundred to several thousand patients with the disease/condition treated for which the drug was developed (controlled and uncontrolled trials) - Large scale, multicenter studies performed - to determine safety & and efficacy -Side effects are monitored

Phase III

Phases of Clinical Investigation

Phase 3a Phase 3b Submission of a new drug application (NDA) Phase IV Phase V (POST MARKETING SURVEILLANCE)

- completed studies sufficient for the NDA

Phase 3a

Additional studies are used to gather: *supplemental information to support certain labeling requests * information on patients’ quality of life issues *product advantages over already marketed competing drugs *evidence in support of possible additional drug indications *other clues for prospective postmarketing studies

Phase 3b

An NDA is submitted to the FDA for review & approval when clinical trials are completed

Submission of a new drug application (NDA)

- Continual clinical investigation - Manufacturing scale-up activities - Drug formulation modified slightly - To gather supplemental information (labeling, product advantages, additional indications, prospective postmarketing studies)

Phase IV

 Product development continues after the FDA’s market approval of drug product.  Drug product may be improved due to equipment, regulatory, supply or market demands

Phase V (POST MARKETING SURVEILLANCE)

Phases of Clinical Testing:

PRECLINICAL M PHASE I-Drug approved for testing in humans PHASE II PHASE 3 FDA Review PHASE 4- drug approved

STAGES OF DRUG DEVELOPMENT PROCESS

Discovery stage Development stage

Discovery stage

identify target identify compounds establish activity select clinical candidates

Development stage

Test for safety Human Clinical Trial Phase I Human Clinical Trial Phase II Human Clinical Trial Phase III Human clinical trial phase IV

Factors in determining drug’s dose

 Age  Body weight  Sex  Body surface are  tolerance  General health status  Pathologic condition(s)  Concomitant drug therapy  Dosage form, time & route of administration

amount of drug that produces the desired effect in the majority of adult patient

usual adult dose & starting dose for the patient

determined from: * clinical investigation * inherent duration of action * pharmacokinetics * characteristics of the dosage form.

Dosage regimen/schedule of dosage

drug’s Average blood serum concentration - Determines minimum concentration expected to produce the drug’s desired effects in a patient

Minimum effective concentration (MEC)

Second level of serum concentration of drug - Above the average blood serum concentration level producing toxic effects - Negates desirable effects of the drug compromising safety of the patient

Minimum toxic concentration (MTC)

Produces the desired intensity of effect in 50% of the individuals tested

ED50/Median Effective Dose

Produces a defined toxic effect in 50% of the individuals tested

Median toxic dose

Relationship between drug’s desired & undesired effects - Ratio of drug’s median toxic dose & median effective dose, TD50/EF50

Therapeutic index

regularly schedule subsequent administration to keep the most desirable concentration of drug in the blood

Maintenance dosage

required to attain desired concentration of the drug in the blood of tissues

Initial priming or loading dose

protects the patient from contracting the illness

Prophylactic dose

administered to the patient after exposure or contraction of the illness.

Therapeutic dose

- Effect of drug modified by prior/concurrent administration of another drug - Chemical or physical interaction between the drugs/alteration of the absorption, distribution, metabolism/excretion patterns of one of the drugs - Include “social” agents (tobacco & alcohol) affecting pharmacokinetics of a number of drugs & alter drug’s usual dose

Drug-drug interaction