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PHARMACOLOGY + St.$Luke’s$College$of$Medicine$ – $ William$H.$Quasha$Memorial $ $ $ Lecture: ! Blk$1 $–
PHARMACOLOGY +
St.$Luke’s$College$of$Medicine$ – $ William$H.$Quasha$Memorial $
$
$
Lecture: !
Blk$1 $– $Lec$1.1 $
Drug$ Development $
$
Date: !
August$5,$2016 $
_ $
Lecturer: $
Marcelo$SB$Imasa,$M.D. $
_ $
Trans$Team: $
!
Team$#2 $
_ $
$
!
!
Topic!Outline $
!
Introduction $
I. ! Approaches!to!Drug!
Discovery!and!Innovations !
II. ! Preclinical!Drug!
Development !
III. ! Exploratory!Drug!
Development !
A. ! Phase!I !
B. ! Phase!II !
IV. ! Full!Drug!Development !
A. ! Phase!III !
2
.$ SERENDIPITY
B. ! Phase ! IV !
V. ! Historical!Foundation !
VI. ! Additional!Information !
VII. ! References! !
− ! E.g.!penicillin!discovery ! by!Alexander!Fleming !
• !Viagra – initially for hypertension but was discovered during
clinical trials that it treated erectile dysfunction
VIII.
!
Quiz !
DRUG!
SERENDIPITY
HYPOTHESIS
EXPERIMENTS
!
CANDIDATES
$
$
Legend: !
PPT!Trans! |! Audio&Trans ! |! Book Trans & SLCM 2019 | Subhead Notes !
OBJECTIVE $
3.$ LARGE$SCALE$SCREENING $
− ! Hypothesis P driven!researches !
− ! “Natural Product Research”
$
− ! Define!p harmacology !
− ! Define!drugs!and!drug!products!
− ! Discuss!the!different!stages!of!drug!development!
− ! Describe!downstream! signa ling!system!and!the!role!of!second!
messengers !
− ! Discuss! the! mechanism! of! drug! action! that! do! not! involve!
receptors !
INTRO: $ DRUG$RESEARCH$AND$DEVELOPMENT $
!
− ! What is drug research and development?
• !Screening for biologic activity of large numbers of (1) natural
products, (2) banks of previously discovered chemical entities, or
(3) large libraries of peptides, nucleic acids, and other organic
molecules &
− ! Why need it?
• !Imagine&medicine&without&research&and & development &
o !Many patients will continue to suffer pain and disfigurement (e.g.
from rheumatoid arthritis) &
o !Rise in mortality and morbidity rate of diseases (e.g. breast
cancer, heart failure)
o !Rise in the complications of diseases (e.g. diabetes mellitus)
• !Better& drug& delivery& systems& (e.g.& drinking& aspirin& in& tablet&
form&rather&than&in&powder&form) &
o !Once daily dosing instead of taking medications 3-4x a day
• !A ntibiotic&resistance & (one&of&the&biggest&problems&today) & &
− ! Screening!of!various!organic!molecules!and!natural!products!
− ! Sequence of experimentation and characterization !
− ! General Steps !
• !Identification or elucidation of a new drug target (target ~ disease)
• !Screening for leads (molecule that can achieve the desirable effects,
not exactly “drugs” since they have not been checked for efficacy,
selectivity to the disease and safety)
o !Rational design of a new molecule
o !Screening for biologic activity of natural products, previously
discovered drugs and libraries of chemical or organic molecules
o !Chemical modification of a known active molecule, resulting in a
me-too analog (“Me too” drugs are drugs that have undergone simple
chemical alteration of the pharmacokinetic properties of the original
prototype)
Develo pment$History$and$Chemistry $
First! macrolide! antibiotic, $ erythromycin ,! was! discovered!
over! 60! years! ago! in! 1949! at! Eli! Lilly! by! McGuire,! who!
isolated!erythromycin!from!the!metabolic!products!of!a!strain!
of! the! actinomycetes! Saccharospora& erythraea ,& formerly!
known! as! Streptomyces& erythreus,& found! in! soil! samples!
collected! from! the! Philippines! by! Filipino! scientist! Abelardo$
Aguilar .! It! was! first! marketed! by! Eli! Lilly! in! 1952! under! the!
brand! name $ Ilosone ! to! overcome! penicillin P resistant! S.&
aureus.& Eryth romycin!is!unstable!in!acidic!environment!and!is!
poorly!absorbed !
!
!
$
Table$1.$ Some ! plant P derived!drugs!that!have!gone!large!scale!screening !
SOURCE $
DRUG $
CLINICAL$USE !
Pacific!Yew!
Paclitaxel !
Anti P cancer !
Tree !
Opium !
Morphine,!Opioids,!and!
Opiates !
Analgesic,!antitussives,!
antidiarrheal !
Willow!tree !
Acetylsalicylic!acid !
Analgesic,!antipyretic,!
antithrombotic !
Belladonna !
Atropine !
Mydriatic !
Autumn!crocus !
Colchicine !
Treatment!of!gout!
Velvet!bean !
L
P DOPA !
Treatment!of!
Parkinsonism !
Ordeal!bean !
Physostigmine !
Tx!of!glaucoma,!
atropine!poisoning!
!
antidote !
Fig.$1.$ Overview!of!R&D!(Research!and! Development) .!See!how!
it!looks!like!a!funnel!filtering!out!the!many!compounds!to!only!1P 2!
Cinchona !
Quinine !
Anti P malarial !
Indian!
Rasagiline !
Antihypertensive !
products $
snakeroot !
Tea !
Theophylline !
Bronchodilator,!
I.$ APPROACHES$TO$DRUG$DISCOVERY$ $
AND$INNOVATIONS $
respiratory!stimulant !
!
!
Directed!
Serendipity
Research
Folklore!
Largescale!
Use
Screening!
NEW!
4.$ DIRECTED$RESEARCH $
− ! Based on what we already know
• !Cellular$ and$ Molecular$ Biology:$ understanding! how! cell!
works! in! the! molecular! level:! channels,! carrier! molecules,!
enzymes,!structural!proteins,!receptors,!other!proteins !
o !Drugs& have& been& developed& against& the& NaB glucose&
transpo rter& 2& so& as& to & INDUCE & glucosuria& and& remove&
glucose& from& the& body & (glucosuria& – & when& blood& glucose&
DRUG
levels&exceed&180mg%&and&get&excreted&in&the&urine)&
• !Applied$ Cellular$ Molecular$ Biology:$ understanding! the!
$
1.$ FOLKLORE$USE $
− ! Digitalis! P ! known! since! 1700s! as! a! cure! for! heart! disease !
symptoms!and!as!a!diuretic $
• !Digoxin! – ! used!for!certain!cases!of!heart!failure !
− ! Periwinkle! ( Catharanthus& roseus)& Initially! screened! a s! a! drug!
for!diabetes!mellitus ! but!was!found!to!be!not!useful!for!DM !
• !N ow! the! source! of! anticancer! drugs ! like! vincristine,!
vinblastine!and!vinorelbine. !
molecular!basis!of!disease $
• !Immunotherapy - like monoclonal antibodies that are directed
against the substances or ligands produced by cancer cells.
Immunotherapy is currently in a lot of clinical trials against broad
spectrum of cancer in comparison with the conventional
chemotherapeutic agents that are quite specific.
P HARMACOLOGY $ |$Lecture$# 1.1 $ |$ Drug$Development $ |$Version$# 3 $ ! PROCESS!OF! CANDIDATE!DRUG!
P
HARMACOLOGY $ |$Lecture$# 1.1 $ |$ Drug$Development $ |$Version$# 3 $
!
PROCESS!OF!
CANDIDATE!DRUG!
DISCOVERY
MOLECULE
*Candidate Drug Molecule – drug that will be formulated and tested in
preclinical and clinical trials since it produces the desirable effects
− ! To! suggest! specific! toxicities! to! be! monitored! during! clinical!
trials! (e.g.,! hearing! loss,! neurotoxicity,! Q P Tc! prolongation,!
allergenicity) !
− ! Investigate!toxicities!that!are!unethical!to!examine!in!humans!
(Carcinogenicity,! Clastogenicity,! Mutagenicity,! Teratology/!
reproductive! toxicity,! Overdosage! and! toxicity! profile ) !
*Clastogenic – agent that can cause disruption or breakages of the
chromosome !
OVERVIEW:$DRUG$DEVELOPMENT $
Limitations of Preclinical Testing
− ! Time-consuming and expensive
− ! Large numbers of animals may be needed
− ! Extrapolations of therapeutic index and toxicity data are reasonably
predictive for many but not for all toxicities
− ! Rare adverse effects are unlikely to be detected
Table$2.$ Preclinical!Testing $
Years !
3.5
!
Test$Population $
Laboratory!and!animal!studies !
Purpose $
Assess!safety!and!biological!activity !
Success$rate $
5,000!compounds !
Cost $
84M!to! 335M!USD !
$
III.$ EXPLORATORY$DEVELOPMENT:$ PHASES $ I$&$II $
Fig.$ 2 .!T he!development!and!testing!process!required!to!bring!a!
drug! to! market! in! the! USA.! Note:$ Picture! lifted! from! Katzung.!
Number! of! subjects! may! vary! from! lecture.! Please$ ignore$ the$
numbers$here. $
$
− ! Start of Clinical Testing $
− ! Phase I and II open label (you know what you are giving) research
designs
− ! Before beginning the Clinical Trials, you have first to apply for an
$
II
.$ PRECLINICAL$DRUG$DEVELOPMENT $
!
− ! Preclinical = non human, Clinical = human
− ! Some& drugs& such& as& herbal /food $ supplements & are& labeled&
with& “no& therapeutic& claims”& have& not& undergone& p r eclinical&
nor&clinical&testing.&They&are&only&based&on&testimonials. &
− ! Define the limiting toxicities of drugs and the therapeutic index
• !Therapeutic index is the ratio of the toxic dose to the effective dose
(we’ll learn more about it in the future lectures). The HIGHER it is, the
SAFER the drug.
− ! Objective is to estimate the risk associated with exposure to the
drug candidate
IND (Investigational New Drug) Application at the FDA (Food
and Drug Administration) $
Investigational New Drug includes $
− ! Information on the composition and source of drug
− ! Chemical and manufacturing information
− ! All data from clinical preclinical/animal studies
− ! Proposed plans for clinical
− ! Names and credentials of physicians who will conduct the trials
− ! Compilation of key preclinical data relevant to the study of the drugs
in humans that have been made available to investigators and their
institutional review boards.
Drug!Candidate
Assay!
Deveopment!of!
Animal!
Scale!Up!
Development*:!
Dosage!
Pharmacology!and!
A. $ PHASE$1: $
− ! The effects of the drug as a function of dosage are established in a
small number of healthy volunteers
Synthesis
Parent!and!
Formulation**
toxicology
Metabolites
• !Maximum tolerated dose
$
*Assay development ~ identity test
** Dosage formulation – “recipe” of the drug + excipients like fillers, solubilizers,
disintegrants, etc.
$
PRECLINICAL$PHARMACOLOGY$AND$TOXICOLOGY !
$
Objectives : !
− ! Identify!target!organs/tissues
− ! Identify!need!for!specialized,!safety! monitoring !
− ! Identify!toxicological!profile !
− ! Select!starting!doses/!regimens !
• !initial dose to be tried in humans: one hundredth to one tenth of
the no-effect dose in animals 2 !
• !Prevent severe toxicity
− ! Determine the probable limits of the safe clinical dosage range
• !Remember: You are not yet treating the disease!
− ! De fining&parameters
− ! Pharmacokinetic measurements
− ! Exception:& Cancer/cytotoxic&or&highly&toxic&agents&$
• !Administered& to& cancer& patients & who& did& not& respond& to&
previous & therapy & and&are&not&treatment&naive $
• !Administered to volunteers
$
Types$of$Toxicity$Studies !
1. ! Acute!and!multiple!dose!(subchronic)!
2. ! Chronic!and/or!carcin ogenicity !
B. $ PHASE$2 $
− ! Done in hospital or wards
− ! Patients with the target disease to determine its efficacy (“proof of
concept”)
− ! Us ed&for&safety&and&to&determine&adverse&effects & (related&and&
unrelated)
− ! Highest rate of drug failures ! ! only 25% move on to phase 3
3. ! Genetic!toxicology!(in!vitro/in!vivo) !
4. ! Reproductive!toxicity!(segments!I,!II,!III)!
5. ! Specialized!studies!(inhalation,!phototoxicity,!arthropathy,!
allergenicity) !
Table$3 .$ Preclinical!Testing ! and! Exploratory ! Development
!
Preclinical!
$
Phase! I !
Phase! II !
testing !
$
Years !
3.5
!
$
1
!
2
!
$
$
Test!
Laboratory!
20
P 80!
100
P 300!
Other$studies$that$provide$useful$information !
$
Population !
and!animal!
Healthy !
Patient !
1. ! Safety!pharmacology !
2. ! Pharmacokinetics !
3. ! Toxicokinetics! !
File!
studies !
volunteers !
volunteers !
IND*$
Purpose !
Assess!
Primary:!
Primary:!
at!
safety!and!
Safety !
Efficacy !
FDA $
$
biological!
!
“Proof!of!
activity !
Dosing, !
Concept” !
Purpose$of$Animal$T oxicity$Studies : !
− ! To!identify!potential!human!toxicities! !
− ! To!design!specific!animal!tests!to!further!define!a!toxicity!or!its!
mechanism !
PK**,!PD***,!
!
Bioavailability !
Safety !
Success!
5000!
5!enter!trials !
Rate !
compounds !
*Investigational!New!Drug!|!**!Pharmacokinetics!|!***Pharmacodynamics!

P HARMACOLOGY $ |$Lecture$# 1.1 $ |$ Drug$Development $ |$Version$# 3 $

!

EXPLORATORY DEVELOPMENT MANUFACTURING SCALE UP 2

! Ongoing clinical trials ! Scale-up manufacturing research (large production of the drug)

Formulation issues during clinical trials

Drug delivery system (e.g. capsule, tablet, injectable) and/or salt selection and development

Manufacturing issues during scape up

IV.$ FULL$DEVELOPMENT :$PHASES$III$&$IV $

!

! Phase!III,!FDA!Approval,!Phase!IV !

!

A. $ PHASE$3 $ ! Most expensive phase, multicentered ! Patients with the target disease—usually thousands—to further establish and confirm safety and efficacy !Corrects& over/under& estimation& due& to& a& small& study& population

& !Certain toxic effects like those caused by immunologic processes, may first become apparent in this phase

! Us ed&to&verify& effectiveness ! Random Clinical Trial !Double-blind and crossover techniques ! Drug is formulated as intended for the market !Designed to minimize errors caused by placebo effects, variable course of the disease, etc. ! Application is made for permission to market the new agent to& FDA , if successful ! New Drug Application (NDA) !Basis&of&drug&p roduct&being&approved !Ca n&be&skipped&if&it&has&a&convincing&phase&2&data

&

B. $ PHASE$4 $ ! AKA PMS (Post Marketing Surveillance) ! Us ed&to&verify&effectiveness ! Constitutes monitoring the safety of the new drug under actual conditions of use in large numbers of patients ! Low incidence drug effects are not generally detected before phase 4 no matter how carefully the studies are executed !SGLT2 – may increase risk of metabolic acidosis and severe UTI !Thus, Phase 4 can check for other long-term side effects and infrequent toxicities ! Lifetime of a patent is 20 years in the USA !Gives the pharmaceutical company the right to market drug without competition after the expiry of which other companies may make generic versions !Average effective patent life for major pharmaceuticals was 11 years !Patent is already applied for during the time of animal testing ! Drugs may be WITHDRAWN from the market if serious adverse events or reactions are shown to be caused by the drug !E.g.& Rofecoxib& (Vioxx ®,& a& blockbuster& painreliever& was& withdrawn&since&it&increases&the&risk&of&heart&attack&

Table$4 .$ Full!Drug!Development

 

Phase!III !

 

FDA!

Phase! IV !

Approval !

Years !

3

2.5

P

Test!

1000!to!

FDA!

Depends&on&a&

Population !

3000!

Review!

particular&

patient!

and!

endpoint &

volunteers !

Approval !

Purpose !

Safety!with! long P term! use !

P

Additional!Post P Marketing! Testing! Required!by! the!FDAk! Submission!of! periodic!reports! including!any! case!o f ! adverse! reaction ! Safety !

File!

 

NDA*!

at!FDA !

Success!

5!enter!

1!Approved !

Rate !

trials !

*New!Drug!Application !

V.$ HISTORICAL$FOUNDATION $

!

! Nuremberg$ trial$ for! Nazi! war! crimes, ! included! human! experimentations ! ! Nuremberg$Code :!first!documented!code!of!ethics!for!human! research !

! Nuremberg$Code$(1947) :!Essential!Elements !

!Voluntary!Informed!Consent!

!Favo rable!risk/benefit!analysis!for!the!subject !

!Research!should!be!for!the!good!of!society!

!Subject’s! right! to! stop! or! withdraw! without! undue! pressure/! denial!of!care ! ! Kefauver$Amendments$ ( Kefauver-Harris amendments ) !

!Thalidomide$ tragedy P ! increase in the incidence of a rare birth defect called phocomelia (shortening or complete absence of arms and legs) !Proof!of!effectiveness!of!drugs!before!marketing! ! Tuskegee$Syphilis$Study$(1932 g 1972) $

!US!Government P funded:!record!the!natural!history!of!sy philis!

in!600!blacks!who!were!never!told!about!the!study!

!1947! penicillin! was! introduced! as! cure! for! syphilis! but! this! cure!was!withheld!from!the!participants ! ! Belmont$report$(1979):$3!Ethical!Principle ! !Respect$for$Persons !

o

!Informed!consent !

o

!Vulnerable! population !

!Beneficence $

o

!Benefits!outweighs!harm !

o

!Minimize!harm !

!Justice$ $

o

!Equitable!distribution!of!benefits!and!burdens!

o

!E quitable!≠!Equal ! !Those& who& will& benefit& must& bear& the& burden& of& the& treatment&while&under&the&study !

!

Other Laws:

! Pure Food and Drug Act of 1906: unsanitary and unethical practices in the meat-packing industry $ ! Federal Food, Drug, and Cosmetic Act of 1938: reaction to deaths associated with the use of a preparation of sulfanilamide

VI.$ADDITIONAL$INFORMATION $

$

! Types$of$Toxicity ! !Acute! – ! tested! for!all!drugs!by!giving!incrementing!doses!to! lethal!level!in!two!species!(rodent!and!non!rodent)! !Chronic! – ! conducted! 2! to! 4! weeks! (subacute)! and! 6! to! 24! weeks!(chronic)!in!two!species ! !Reproductive!toxicity! ! " !Teratoge nesis ! P ! developmental!defects!in!somatic!tissue!of! fetus! tested! by! treating! pregnant! animals! of! two! species! during!early!pregnancy!or!when!organogenesis!occurs) ! " !Mutagenesis! – ! defects!induced!at!any!age!and!will!result!to! heritable! abnormalities.! Tested! using! Am es! Test! and! Dominant!Lethal!Test ! ! Generic$Drugs ! !Only!available!commercially!after!the!expiry!of!the!patent!of! the!innovator!drug ! !Must!demonstrate!bioequivalence! (same! content,!purity!and!

bioavailability)!with!the!innovator !

! Orphan$Drugs ! !Drugs!for!rare!diseas es!(diseases!that!affect!only!<!200,000! people) ! !Government!provides!tax!relief!and!other!incentives! ! !

V I I.$ RE F ERENCES $

!

! Dr.!Imasa’s!PowerPoint!and!Voice ! ! [1]! Katzung,!B.,!Masters,!S.,!Trevor,!A.,!Basic!and!Clinical! Pharmacology!12 ! edition ! ! [2] SLCM!Batch! 2019!Trans !

th

$

P HARMACOLOGY $ |$Lecture$# 1.1 $ |$By$ Camacho,$Sison $ |$Checked$by$ Conde $

Page! 3 ! of! 4 !

P HARMACOLOGY $ |$Lecture$# 1.1 $ |$ Drug$Development $ |$Version$# 3 $

VII I .$ QUIZ $

!

1.!Pharmacokinetics!is: ! a)!The!study!of!biological!and!therapeutic!effects!of!drugs ! b)!The!study!of ! absorption,!distribution,!metabolism!and!excretion! of!drugs ! c)!The!study!of!mechanisms!of!drug!action ! d)!The!study!of!methods! of!new!drug!development !

2.!On!what!subjects!are!drugs!undergoing!Phase!2!Clinical!Trial!

tested!on? ! a).!animals ! b).!healthy!human!volunteers ! c).!widespread!differentiated!population ! d).!people!with!the!target!disease !

3.!When!does!a!company!seek!permission ! to!market!a!product!to! the!general!public? !

a).!following!completion!of!Phase!1

b).!following!completion!of!Phase!2

c).!following!completion!of!Phase!3

d).!following!completion!of!Phase!4 !

 

4.! After ! what!phase!is!the!FDA!approval!of!the!new!drug! accomplishe d? !

a).!Phase!1

b).!Phase!2 !

c).!Phase!3

!

! d).!Phase!4 ! ! ! 1.!b.!Pharmacokinetics!is!about!what!the!body!does!to!the!drug !
!
d).!Phase!4 !
!
!
1.!b.!Pharmacokinetics!is!about!what!the!body!does!to!the!drug !
(i.e.!the!body!absorbs!it!from!the!dosage!form,!distributes!it!to!
reach!its!site!of!action,!metabolizes!it!usually!to!inactivate!it!and!
remo ves!or!excretes!it!from!the!body)!
2.!d.!Phase!2!clinical!trials!are!done!to!the!people!with!the!target!
disease!to!test!its!efficacy !
3.!c.!After!Phase!3!right!after!the!FDA’s!approval ! (seeking!
permission!=!“New!Drug!Application . ” ! You!apply!for!an!IND!or!
“Investigational!New!Drug!Application”!before!you!start!doing!
clinical!trials!(i.e.!before!Phase!1) !
4.!c .!Phase!3 .!Phase!4!is!done!AFTER!the!drug!has!been!
approved. !
!
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Gamot!para!sa!mga!Hopia !
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