Drug Discovery and Drug Product Development

In vivo test

inducing a clinical condition and treated with the test drug

In vitro test

drugs activity is tested on isolated tissues, cells or enzymes

Plant kingdom

morphine, cocaine, quinine, periwinkle (vincristine and vinblastine), reserpine, paclitaxe

Microbiological world

penicillin, cephalosphorin, tetracyclines, aminoglycosides, lovastatin

Animal sources

proteins (somatostatin, glucagon) polysaccharides (heparin) bile acids, estrogens (urine of pregnant mare)

Biological source

vaccines (living or killed microorganisms)

Ways of Discovering a Lead Compound

1. Combinatorial synthesis

2. Use of NMR

3. Medical folklore

Existing Drugs

A popular term for a generic drug with an identical formulation and stated indications as a drug previously approved by the FDA

Isolate and purify the lead compound
Design a manufacturing process
Identify the structure-activity relationship – in vitro

New Drug Development Process

Pharmacology

the science of the properties of the drugs and its effects in the body

Pharmacodynamics

the study of the interaction of drugs with cells

Pharmacokinetics

the handling of a drug within the body, it includes the ADME processes

Toxicity Testing

in vitro and in vivo testing , determination of LD 50

Pharmaceutics

the general area of study concerned with the formulation, manufacturing, stability and effectiveness of a pharmaceutical dosage form

20-80

Phase 1 number of patients

100-300

Phase 2 number of patients

1000-3000

Phase 3 number of patients

Healthy volunteer

Phase 1 patients target

suffer from the target illness

Phase 2 patients target

with the target illness

Phase 3 patients target

Safety

Phase 1 purpose

Safety and effectiveness

Phase 2 purpose

Safety, effectiveness and dosage

Phase 3 purpose

67%

Phase 1 percent

45%

Phase 2 percent

5-10%

Phase 3 percent

Phase 4

post-marketing studies and manufacturing scale-up activities take place

Phase 3

These studies are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug.

Phase 2

This phase of testing also helps determine the common short-term side effects and risks associated with the drug.

Phase 1

These studies are designed to determine the metabolic and pharmacological actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness.

Thalidomide

For morning sickness in pregnant women

Phocomelia

Thalidomide S/E

Leprosy treatment

Current Use of Thalidomide

Receptors

macromolecules involved in chemical signaling between and within cells; they may be located on the cell surface membrane or within the cytoplasm

Enzyme

protein catalysts produced by living cells by acting as a surface or focus for the reaction, bringing the substrate together and holding them in the best position for the reaction.

Lock and Key Theory

completely complementary relationship between the drug molecule and a specific area on the surface of the receptor molecule

Induced Fit Theory

complementary relationship between the drug molecule and its active site

Occupational Theory of Response

the intensity of pharmacologic activity of a structurally specific drug is directly proportional to the number of receptors occupied by the drug

Affinity

measure of how strongly a drug binds to a receptor.

Efficacy/Intrinsic Activity

maximum biological effect resulting from a drug binding to its target

Agonist

affinity for the receptor and has intrinsic effect

Antagonist

lack the intrinsic activity but with affinity for the receptor

Competitive

competes with the endogenous molecule from binding at the receptor; reversible

Non-competitive

do not compete with the endogenous molecule; reversible or irreversible

Down-Regulation

caused by continuous prolonged exposure of receptors to drugs that disrupt the homeostatic equilibrium and result in altered levels of the receptors.

Desensitization

Result of down-regulation. The target cells become desensitized and the effect of subsequent exposure to the same concentration of the drug is reduced