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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
Manufacturing
Initial Synthesis of
chemical
Research and
development
FDA Expects
Review
data
Drug appears on
the mark
et
Lab and
animal
Studies
Testing in healt
hy 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.