Drug Discovery and DevelopmentHow are drugs discovered and developed?

Overview

Outline here the fundamental concepts and processes of drug discovery

Drug discoveryPre clinical studyInvestigational New DrugClinical researchNew Drug Approval ProcessMarketing

Drug Discovery and Development

Drug discovery

Pre clinical study

Clinical research

Marketing IND

NDA

Drug Discovery ProcessLead Discovery

Pre-

clinical

Clinical

Review

/ Approval

Post

Marketing Number of years:

2-3 2-3 5-8 1-2

Number of subjects: Ph I Ph II Ph III Ph IV

<50 <500 <5-5000 100s- 1000s

Cost $1

Billion

Process for Successful Molecule

Phase 15-10,000 Molecule

Phase 2250 Molecule

Phase 35 Molecule

NDA

1 Molecule

Identify disease

Isolate proteininvolved in disease (2-5 years)

Find a drug effectiveagainst disease protein(2-5 years)

Preclinical testing(1-3 years)

Formulation

Human clinical trials

(2-10 years)

Scale-up

FDA approval(2-3 years)

File

IN

D

File

NDA

Drug Discovery Process

The Steps Involved In Drug Discovery

Choose a Disease

Target Identification

Target Validation

Lead Identification

Lead Optimization

Preclinical studies

Clinical Studies

Marketing

Choosing a Disease

What factors? Medical Economic Geographical

Number of deaths Causes of death in developed countries Number of deaths

HIV-AIDS 2,678,000 Ischaemic heart disease 3,512,000

Lower respiratory infections 2,643,000 Cerebrovascular disease 3,346,000

Ischaemic heart disease 2,484,000 Chronic obstructive pulmonary disease 1,829,000

Diarrhea 1,793,000 Lower respiratory infections 1,180,000

Cerebrovascular disease 1,381,000 Lung cancer 938,000

Malaria 1,103,000 Stomach cancer 657,000

Tuberculosis 1,021,000 Hypertensive heart disease 635,000

Chronic obstructive pulmonary disease 748,000 Tuberculosis 571,000

Target Identification

Most of the drugs act on the cellular receptor or biological molecules in the body, which are associated with disease, is known as Targets.

Various methods are used to identify target.

Interactions and role of target in disease are studied.

TARGET IDENTIFICATION

PROTEINSHormon

es

Recepto

rsEnzymes

Ion Channel

s

DNA RNA AND RIBOSOMES

Drug targets fall into one of three main classes

Most current drugs are aimed at protein targets. However, current existing therapies only hit about 400 different drug targets out of an estimated pool ten times this size.

Potential Drug Targets

Potential Drug Targets

Agonist Agonist Agonist AgonistNa

Na

Activation of conductance

G- Protein Activation

Generation of Second Messenger

Activation of cell signaling

Phosphorylation of Tyrosines on key signaling Molecules

Activation of cell Signaling

Transport to the Nucleus

Activation of transcription and translation

Target Validation

To identify the most useful target

Compare target in association with specific disease

Design and execute relevant studies to identify the target

Lead IdentificationLead molecule - A molecule that is believed to have potential to treat

disease.

Scientists compare standard

drug in the specific disease

with new molecule to

determine the successful action.

Leads are developed as collections ,

libraries, individual

molecules etc.

Evaluation is done to confirm it’s effect on the

target.

Lead Identification -Process

1.Computer-aided Drug

Design (CADD) And Structure-

based Drug Design (SBDD)

2..Virtual (In-silico)

Screening Leads to HITS

3.Synthesis And

Combinatorial Chemistry

4.IN SILICO Predictive

Toxicity

5.Assay Development—HTS Leads

to LEAD Compound

Lead Identification

Tools for Drug Discovery

x-ray crystallography

NMR

Computer-aided drug design (CADD) and structure-based drug design (SBDD)

1.Computer-aided Drug Design (CADD) And Structure-based Drug Design (SBDD)

IN SILICO SCREENING

SCREENING THROUGH CADD/SBDD

HITS

COMBINATORIAL CHEMISTRY

HIGH THROUGHPUT SCREENING

LEADS

2.Virtual (in-silico) screening

Virtual (in-silico) screening sifts through large numbers of compounds based on a user-defined set of selection criteria.

Physical property such as

molecular weight or charge

Chemical property such as

number of hetero-atoms,

number of hydrogen-bond

acceptors or donors

Three dimensional

description of a binding pocket

of the target protein,

including chemical

functionality and solvation

parameters

Docking of ligands to a target site

3.Hits to Synthesis and Combinatorial Chemistry

1 • Hits to Synthesis and Combinatorial Chemistry

2

• New Compounds are supplied by chemist• New compounds are converted to large amount of precursor

3

• By rule of thumb, one chemist synthesizes, purifies, and characterizes about 100 novel compounds per year

• Which give 10,000 compound to develop one drug

Mutagenicity

Carcinogenicity Reproductive Toxicity

4.IN SILICO Predictive Toxicity

Computational programs ultimately fulfill the requirement for determining liabilities at the early stages of discovery

5.Assay Development—HTSDevelopment of AssayScreening of compounds

Primary screens will identify HitsConfirmation screens and counter screens will identify leads out of the pool of hits

High-throughput screening (HTS) aims to quickly review the goings-on of a large number of compounds.

Lead Optimization

• Quantitative structure activity relationship (QSAR)Lead

Optimization

• Structure Activity Relationship

Lead Optimization

• Animal PK/PD

Lead Optimization

• Toxicity

Lead Optimization

• Formulation and Delivery

Lead Optimization

1.Quantitative structure activity relationship (QSAR)- Lead Optimization

Quantitative Structure Activity Relationship (QSAR)

The derived function

group is used as a guide to select best

candidate for drug design.

Reflects the property of

binding cavity on protein target.

Derive a functional group that

links biological activity

2.Structure Activity Relationship

Pharmacological assay for lead assessment

Optimization of pharmacological

properties

Determination of Potency,

selectivity and MOA

Data into next optimization

cycle

Lead Optimization

3.Animal PK/PD-Lead Optimization

Animal pharmacokinetics (ADME) and pharmacodynamics (PD) assess the general pharmacology and mechanisms of action of

drugs..

Lead molecules are administered via different routes: intravenous (iv), intraperitoneal (ip),

subcutaneous (sc), intramuscular (im), rectal, intranasal (IN), inhalational, oral , trans

dermal, topical, etc

The main models used are rodents including mouse and rat, but larger animals such as

dogs, pigs, and, more rarely, monkeys, are also used under certain circumstances.

3.Animal PK/PD-Parameters

• PK/PD studies rely heavily on analytical methods and instrumentation. The recent innovation and progress in

mass spectroscopy, (whole-body) imaging, and chromatography technology (HPLC, LC-MS, GC-MS) have tremendously increased the quantity and quality of data

generated in PK/PD experiments.

A large number of parameters is assessed. Here is a partial list:

(ADME); bioavailability (F) and protein binding; stability and half-life (t1/2); maximum serum concentration

(Cmax); total exposure or area under the curve (AUC); clearance (Cl); volume of distribution (Vd); drug drug

interactions; onset of drug action; multicompartmental analysis of blood, liver, and other tissues.

Principles and applications of LC-MS in new drug discovery

4.Toxicity-Lead Optimization

The toxicity is the degree to which a substance or mixture of substances can harm human or animals.

Acute Toxicity

Acute toxicity involves harmful effects in an organism through a single or

short-term exposure.

Chronic ToxicityChronic toxicity is the ability of a

substance or mixture of substances to cause harmful effects over an

extended period.

LeadLead

Formulation and Delivery

Formulation and Delivery

Preclinical Studies

Pre-Clinical Studies

Once the drug is designed it have to be tested In vitro [ in laboratory conditions-glass wares].

In vivo [in animals (rodents and non rodents, lab models)].

Difference between In Vivo And In Vitro

In Vivo

In Animals

Generates Pharmacokinetic, Pharmacodynamic and toxicokinetic data

Gives an understanding of dose, dose range, side effects, drug receptor binding capabilities,

Objective of Preclinical Studies

Pharmacokinetic Studies

Toxicokinetic Studies

Pharmacodynamic Studies

Importance Of Pharmacokinetic Studies

Research and selection of a promising molecules Formulation Dosage

Toxicology and safety assessment

Dosing recommendation for age groups and

subgroup population

Effect of meals and dosing

Importance of Toxicokinetic Studies

Toxicokinetic Studies

Single dose Toxicity

Repeated-dose

toxicityReproductive

toxicityGenotoxic potential Carcinogenicity Safety

pharmacology.

Coordination of preclinical and clinical studies.

Coordination of preclinical and clinical

studies

Drug information journal Vol. 35, pp. 321-336,2001

Investigational New Drug Application

(INDA)•What is an INDA?

Sponsors

IND

FDA

To initiate the conduct of

clinical trials

Contents of INDA

INDA

Table of content

Cover Letter

Introductory Statement and

General Investigational

Plan

Investigator’s Brochure

Clinical Protocol

Chemistry Manufacturing and Controls Information

Pharmacology and Toxicology

Information

Previous Human Experience

Additional Information

Clinical Trials

Phase I:- Studies in normal healthy

volunteers to understand

pharmacokinetics

Phase II: Dose ranging efficacy safety studies to determine the

optimal dose for a particular indication

Phase III:Large scale multicentre

comparative studies to assess efficacy safety of

the study drug v/s currently accepted

treatment.

Phase IV: Post Marketing

Studies.

Clinical Trial – Phase I

Phase 1

Types of Phase I Trial:

SAD (Single Ascending Dose )studies

Small l group of people receives single dose.

Adverse Event –Nil,Escalation of dose

Continued till intolerable side effects start showing

MAD (Multiple Ascending Dose) studies

.In these studies, a group of patients receives multiple low

doses of the drug

The dose is subsequently escalated for further groups, up to a

predetermined level.

Continued till intolerable side effects start showing .

Phase II

Phase 2

Rigid and well-controlled

small population between 100-300.

Double blind studies using

placebo or standard

treatment are done.

Efficacy and safety are evaluated.

Pharmacokinetic and other

pharmacological studies are

done.

Types of Phase II Studies

Phase 2 Trials

Phase IIA

is specifically designed to assess

dosing requirements (how much drug should

be given).

Phase IIB

is specifically designed to study efficacy (how well the drug works at

the prescribed dose(s)).

Phase III

Phase 3

Done in a large

population- above 300

Evaluation of efficacy and

safety profile (initial risk

benefit assessment)

Identification of the

disease sub types for

which drug is effective.

Comparison with other standard

drugs.

Pharmacokinetics with

others drugs and Quality

of life (depends)

are evaluated.

Done while the New Drug Application (NDA) is submitted to FDA.Studies which start pre-launch but which are not intended to form part of Regulatory dossier are referred to as Phase III-b.The data of this study also submitted to FDA.

Types of Phase III

Difference between Phase I,II and III Trials

Phase 1

• Safety• Dose Ranging

Phase 2

• Safety • Efficacy• Dose• Route

Phase3

• Efficacy vs. standard

• Defined endpoints

The formal request to be allowed to market a drug.Sponsor submit NDA to FDA after phase III trials are competed.Have to submit everything that is known about the drug to date, all protocols, case report forms.Regulation for NDA are found in 21 CFR 314.

New Drug Application (NDA)

New Drug Application (NDA)

Drug Discover

y and develop

ment

Preclinical

Clinical

FDA

ManufacturingInitial

Synthesis of

chemical

Research and

development

FDA Expects

Review

data

Drug appears on the

market

Lab and

animal

Studies

Testing in

healthy

volunteers

Company

address

FDA Conce

rns

Post marketing Surveillanc

eIRBTesting in disesed

individual

Advisory-Hearing may be called

Follow up Studies and inspection

Large scale studies with diseased

individuals

IND NDA FDA

Phase IV

Phase 4

S.No Phases No of PeoplePopulation

Group Safety/Efficacy Goal

1 Phase I 20-100Healthy Individuals Safety

The main goal of a Phase 1 trial is to discover if the drug is safe in humans. Researchers look at the pharmacokineticsof a drug. How is it absorbed? How is it metabolized and eliminatedfrom the body?

They also study the drug’s Pharmacodynamic: Does itcause side effects? Does it produce desired effects?

Dose ranging studies ,Safety Studies

2 Phase II 100-500Diseased Individuals

Safety and efficacy

In Phase 2 trials researchers evaluate the candidate drug’s effectiveness Examine the possible short-term side effects (adverse events) and risks associated with the drug.

Researchers also analyze optimal dose strength and schedules for using the drug.

S.No Phases No of PeoplePopulation

Group Safety/Efficacy Goal

3 Phase III 1000-5000Diseased Individuals

Safety and efficacy and benefit-risk relationship

This phase of research is key in determining whether the drug is safe and effective.

It also provides the basis for labeling instructions to help ensure proper use of the drug (e.g., information on potential interactions with other medicines).

4 Phase IV >5000Real Life Population

Ongoing monitoring of safety of drug

These trials can be set up to evaluate long-term safety or how the newmedicine affects a specific subgroup of patients.