drug development lecture 12

7/28/2019 Drug Development Lecture 12

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Drug Development andInvestigational new

drug applications


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Insight

Deciding factors in creating a new drug

Finding a suitable target

Creating a ligand for the target

Testing

Clinical trials

Finding new uses

What can go wrong

Histories of some drugs


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Drugs And Their Use

To Cure Disease

To Suppress Disease To Prevent Disease

To Diagnose Disease


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SOURCES OF NEW DRUGS

Chemical modifications of a known

molecule

Random screening of new chemical

Rational drug designing

Biotechnology and cloning of genes


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SOURCES OF NEW

CHEMICAL ENTITIES Molecular

modeling

Combinational

chemistry

Mixing of

chemicals

Proteins from

biotechnology

Genetic medicines

Serendipity (by

chance / luck)


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Investigational New Drug Process

An Introduction

Definitions

Types of INDs Phases of an Investigation


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Introduction

The main purpose of anInvestigational New Drug (IND)application is to provide the data

showing that it is reasonable to begintests of a new drug on humans.


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Introduction

During a new drug's early preclinicaldevelopment, the sponsor's primarygoal is to determine if the product is

reasonably safe for initial use inhumans and if the compoundexhibits pharmacological activity that

justifies commercial development.


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Introduction

When a product is identified as a viable

candidate for further development, the

sponsor then focuses on collecting the

data and information necessary toestablish that the product will not expose

humans to unreasonable risks when used

in limited, early-stage clinical studies.


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Note The IND is not anapplication for marketing

approval. investigational newdrug An ind application containinglaboratory study results of the drug

candidate is submitted to the fda torequest permission to conductstudies in humans.


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Definitions

Clinical investigation means anyexperiment in which a drug isadministered or dispensed to one or

more human subjects.

Investigator means an individualunder whose immediate direction the

drug is administered or dispensed toa subject.


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Definitions

Sponsor means a person who takesresponsibility for and initiates a clinicalinvestigation.

Sponsor-Investigator means anindividual who both initiates and conductsan investigation and under whoseimmediate direction the investigational

drug is administered or dispensed. Theterm does not include any person otherthan an individual


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Types of INDs

An Investigator IND is submitted by aphysician who both initiates and conductsan investigation, and under whose

immediate direction the investigationaldrug is administered or dispensed. Aphysician might submit a research IND topropose studying an unapproved drug, or

an approved product for a new indicationor in a new patient population


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Types of INDs

Emergency Use IND allows theFDA to authorize use of anexperimental drug in an emergency

situation that does not allow time forsubmission of an IND in accordancewith rules. It is also used forpatients who do not meet the criteria

of an existing study protocol, or if anapproved study protocol does notexist.


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Types of INDs

Treatment IND is submitted forexperimental drugs showing promisein clinical testing for serious or

immediately life-threateningconditions while the final clinicalwork is conducted and the FDA

review takes place.


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Pre-clinical

Research

Some ethics / protocols

Ethics and Protocols


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The pre-clinical research and development

The pre-clinical phase represents bench (invitro) and then animal testing (in vivo), whichinclude toxicity, metabolism andcarcinogenicity.

The first priority for a new drug is to test if it has

any toxicity.

Many promising drugs fail the toxicity testing.

Any sings of carcinogenicity would prevent

the drug being taken any further.


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Toxicity testing should include a large

variety of different in vitro and in

vivo tests designed to reveal different

types of toxicity.

Toxicity from the drug may be linked to

the minor impurities from the

synthetic route. It is important to

establish the manufacturing synthesis

as quickly as possible


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Toxicity testing should include a

large variety of different in vitro andin vivo tests designed to revealdifferent types of toxicity.

There is no foolproof for toxicitytesting. New and unexpected toxiceffects may appear during laterclinical trials, which will require thedevelopment of a new test.


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The Thalidomide Tragedy:

Thalidomide was launched in WestGermany in 1958 by the companyChemie Grunenthal under the name

Contergan. It was sold withoutprescription and was later sold inforty countries, apart from the US. Itwas first realized in 1961 that the

drug was a teratogen and hadcaused what commonly called seallimbs.


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Thalidomide

N

NH

O

O

O

O

*


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Thalidomide

The thalidomide tragedy is a landmark in

drug regulation. It is instrumental in the

implementation of more strict clinical

testing requirements, which is partlyresponsible for the overall cost increase of

drug development.


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Thalidomide

The thalidomide tragedy would probablynever have occurred if, instead of usingthe racemate, the (R)-enantiomer had

been brought on to the market. Instudies it was shown that after i.p.administration only the (S)-enantiomerexerts an embryotoxic and teratogenic

effect. The (R)-enantiomer is devoid of anyof those effects under the sameexperimental conditions.


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Thalidomide


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Thalidomide

Most drugs consist of chiral molecules,and often only one of the mirror imageforms is of interest. The other form may

even be harmful. This was the case, forexample with the drug thalidomide, whichwas given in the 1960s to pregnantwomen. One mirror image form helped

against nausea, while the other one - as itwas discovered too late - could cause fetaldamage.


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Contd.

The proposal that the thalidomide tragedy

could have been avoided if the singleenantiomer had been used is misleading,

for two reasons:


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Contd

It is based on unreliable biological data.The study purporting to show the (S)-enantiomer is more teratogenic were in the

mouse, a species that is generallyregarded as unresponsive, and involvedvery high doses. However, early work inthe rabbits, the species that is most

sensitive to thalidomide, showed clearlythe equal teratogenic potency of itsenantiomers


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Contd

The chiral centre in thalidomide is unstable

in protonated media and undergoes a

rapid configurational inversion. Therefore,

even if there were differences in thetoxicity of the enantiomers of thalidomide,

their rapid racemisation in vivo would blunt

them such that they could not be exploited


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The issues with animal

testing

Animal toxicity tests do not always

highlight potential problems and the toxic

properties in test animals may differ from

those ultimately observed in humans.

The Fialuridine (FIAU) clinical trial in theUS in 1993 that resulted in five deaths


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Animal rights campaigners against animalexperimentation.

Campaigns against Huntington Life

Sciences (HLS) in Cambridgeshire, UK.

and against the building of the 18 million

pound animal laboratory at OxfordUniversity.


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Clinical Trials

Before clinical testing in human subjects,

the pharmaceutical company has to

submit an Investigational New Drug

application (IND) to the FDA forpermission. FDA will review the findings

from the preclinical studies to make sure

that there is no unreasonable risks in theclinical trials.


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The clinical trial phase is from the time

from the beginning of human trials to the

submission ofNew Drug Application

(NDA) to the FDA for the permission tomarket the drug


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Ethical guidelines for clinical trials

Clinical trials are covered by the provisions

of the Declaration of Helsinki, adopted in

1964, which provides guidelines for all

biomedical research involving humansubjects. This recognizes that medical

progress is based in part on experiments

involving human subjects, and that thisinvolves some hazard..


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A degree of risk is more acceptable if the

aim of the research is diagnostic or

therapeutic for the patient than if it is pure

medical research from which the trialpatient does not benefit


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The World Medical Association

guidelines drawn up in response to the

Helsinki Declaration enshrine the

principle of informed patient consent:'each potential subject must be adequately

informed of the aims, methods, anticipated

benefits and potential hazards of the studyand the discomfort it may entail.


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He or she should be informed that he orshe is at liberty to withdraw his or her

consent to participation at any time. The

physician should then obtain the subject'sfreely-given informed consent, preferably

in writing


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Clinical trial is the longest and most

expensive part of drug development.

During the clinical trials, volunteers takethe candidate drug to determine if it is safe

for the people and effective for the disease

in question.

The clinical trials take place in three

phases, and the trials can be stoppedduring any stages by FDA if there are

safety concerns.


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How to proceed further

A sponsor shall submit an IND to FDA if

the sponsor intends to conduct a clinical

investigation with an investigational new

drug A sponsor shall not begin a clinicaltrial until the investigation is subject to an

approved IND application. A sponsor shall

submit a separate IND for any clinicalinvestigation involving an exception from

informed consent.


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Phases of Investigation

An IND may be submitted for one or more

phases of an investigation. The clinical

investigation of a previously untested drug

is generally divided into three phases.Although in general the phases are

conducted sequentially, they may overlap.

The three phases of an investigation areas follows:


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Phase 1

Healthy Volunteers - 20-50 Subjects

Phase 1 includes the initial introduction of

an investigational new drug into humans.

These studies are usually conducted in

healthy volunteer subjects.


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Phase 1

Healthy volunteers - 20-50 subjects

These studies are conducted to determine

1. Metabolic and Pharmacologic action2. Side effects associated with increasing

doses

3. To gain early evidence on effectiveness


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Physico-chemical properties

Predict permeation rate of a moleculeknowing its physical properties

Predict most effective route of

administration of a drug. Methods of creating constant plasma drug

concentrations.

Show how the liver affects drug potency. Show how drugs can compartmentalise

within the body.


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Factors which influence effective drug concentration

Absorption ExcretionFree available

drug

MetabolismBound

drug

Re-distributionto other tissues


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Diffusion through membranes (Permeability)

Amount diffusing depends on:

Depends on concentration gradient (C)

Area of membrane (A)

Permeability coefficient (P)

=P x A x C

P depends on nature of

membrane (phospho-lipid)

permeant moleculeThus

Fat soluble molecules pass through easily

Small molecules pass through easily

Which compounds diffuses through phospholipid bilayers


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CO2

Urea

Na+

Glucose

Glycerol

Acetic acid

Butyric acid

Antidiuretic hormone (a peptide)

Trypsin

Inulin (glucose polymer)ATP

H+

H20

CO2

Urea

Glycerol

Butyric acidH2O

Na+Glucose

Aceticacid

Antidiuretic hormoneTrypsinInulin

ATPH+

Which compounds diffuses through phospholipid bilayers

Impermeant Permeant


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PHASE-2 STUDIES

50-300 Patients

It includes

1. Early controlled clinical studies

2. Effectiveness of the drug for a particular

indication

3. To determine side effects and risksassociated with the drug


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Phase 3

250 -1000 Patients

Multi Centric Study

Phase 3 intended to gather

1. Additional information abouteffectiveness and safety

2. Benefit-risk relationship

3. To obtain adequate basis forextrapolating the results to the generalpopulation


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PHASE-4 STUDIES

Post Licensing studies

2,000 -10,000 Patients

Surveillance for safety and efficacy

Further formal therapeutic trial

Special comparison with other drugs


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Stages Of Drug Development

6.5Years

1.5Years

2Years

3.5Years

1.5Years

EarlyResearch /PracticalTesting

Laboratoryand animalStudies

Evaluationof Biologicaland SafetyStudies

Phase IHealthyVolunteers

ClinicalTrials

Phase IIPatients

Phase IIILarge GroupPatients

RegulatoryApproval

SUCCESS RATE OF NEW


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SUCCESS RATE OF NEW

DRUGS

5000

Compound

Tested

5 In

Clinical

Trials

1Approved


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Liver

Arterial

VenousPortal

Gastro-

intestinal

tract

First pass effect


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The fraction of administered

dose reaching systemic circulation

for intravenous: 100%

for non-parenteral: ranges from 0 to 100%

for different drugs

Bioavailability


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Bioavailability

Dose

Destroyed

in gut

Not

absorbed

Destroyed

by gut wall

Destroyed

by liver

to

systemic

circulation


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Drug metabolism

Body has a large number of enzymes tochemically modify toxins

Drugs are treated as toxins

Also, hormones and other signalling substances

inactivated in same way.


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Metabolism of drugs and

toxins

Large number of enzymes found in:

Liver (most important)

Kidneys

Plasma

Lungs

other tissuesFew drugs excreted without some metabolism

Aim to make the molecule less reactive


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Drug metabolism

Via

Phase I reactions

Phase II reactions


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Phase I

Aim to make the molecule more reactive for

phase II reactions

Usually simple changes to moleculeeg

oxidation

hydroxylation

hydrolysisamination or deamination

methylation


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Drug metabolism


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Phase II

Aim to make the molecule more readily excreted

Make the molecule larger and more charged

egsulphonation

conjugation with monosaccharide

conjugation with amino-acid, eg glycine


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Enzyme induction

Many of these enzymes are used constantly in

normal body function

For others, genes present but no transcription.Drug or toxin can induce the manufacture of

these enzymes

ie enzyme induction

Develops over several days


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Gender

Diet Other drugs

Species (cf, rabbits, goats and humans)

Race, eg lactase in Asians

Disease (eg liver)

Individual variations in

drug metabolism

Variability between


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Daily Dose (mg/kg)

P

lasmaAntibiotic

Conc

n(mg/L)

0 5 10 150

10

20

30

40

50

60

Variability betweenindividuals


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Drug excretion


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Objectives

Know the main routes of excretionRelate these to the physiological function of the

corresponding organ

Show the basic principles of chemical

inactivation of drugsPredict how drug potency changes when drug

metabolism varies


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Pla

smaConce

ntration

Time


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Excretion routes

RenalLungs

Skin (sweat)

Bile

Faeces


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Renal excretion

R l ti


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Renal excretionDepends on filtration and selective re-absorptionProportion of filtrate excreted depends on:

Amount filtered (small if plasma protein bound)

Amount re-absorbed in nephron

Higher if lipid soluble

also pH dependent if weak acid or baseif low molecular weight

For some drugs further secretion eg frusemide.

Concentrating mechanism useful in treating renaland urinary tract infections - reduces other side

effects

Manipulating renal


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Manipulating renalexcretion

Weak acid - HAc

Uncharged

Fat soluble

Membrane diffusible Acidifyie, more H+

H+ + Ac-HAcpH=7

Manipulating renal


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Manipulating renalexcretion rate

H+ + Ac-

Acidify H+

HAc


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Bilary excretion

Liver

Arterial

VenousPortal

Gall

bladder

Bile

Gastro-

intestinal

tract


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Bile excretion

Hepatic excretionMainly conjugated metabolites

Some drugs before entering general circulation


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Pulmonary excretion

Volatile fat soluble molecules

Low MW e.g.

CO2Ketones (eg Acetone) from diabetics

Ethanol (breathalyser)Gaseous anaesthetics

Concentration in alveolar proportional to

plasma concentration


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Other sites

Any place where have secretion including

SweatMilk

Saliva

Faeces

Not usually important

Question


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Question

Why do you see much smaller

variations in hormone levels, etc?

Because of negative feedbackregulation

Complexity of


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p ymetabolism

C l k d


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Can also make drugs

more toxic

D ti ti


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Drug activationDrug metabolism may activate and inactive drug

Called a Prodrug

Might be because the prodrug:

More easily absorbed

Longer shelf life

Broken down in the GITMore palatable

Easier to make

eg phenacetin (converted to paracetamol)

But problemsReduced enzyme activity reduce effectiveness

By-products may have adverse effects

Effectively have 2 drugs increasing idiosyncratic

effects

Conclusions


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Conclusions

Drugs exist only transiently

Rate of decline depends on:

Metabolism

Phase I & II

Excretion

Several routes

Complex Highly variable


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P d


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Uses

To improve absorption and by-pass liverinactivation

Improve palatability or reduce gastric orintestinal irritation

Increase duration of action through slowactivation

Selective targeting (activated in target tissue)

Manufacturing convenience

Problems Reduced enzyme activity reduce effectiveness

By-products may have adverse effects

Effectively have 2 drugs increasing idiosyncratic

Prodrugs

drug development lecture 12

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