PHARMACOLOGY+ St.$Lukes$College$of$Medicine$$William$H.

$Quasha$Memorial$
$ Blk$1$$Lec$1.1$
$ Lecture:! Drug$Development$
Lecturer:$Marcelo$SB$Imasa,$M.D.$
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Date:! August$5,$2016$
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Trans$Team:$ Team$#2$
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$ ! !
Topic!Outline$ !
Introduction$ IV.! Full!Drug!Development! 2.$SERENDIPITY
I.! Approaches!to!Drug! A.! Phase!III!
Discovery!and!Innovations! B.! Phase!IV!
! E.g.!penicillin!discovery!by!Alexander!Fleming!
II.! Preclinical!Drug! V.! Historical!Foundation! !Viagra initially for hypertension but was discovered during
Development! VI.! Additional!Information! clinical trials that it treated erectile dysfunction
III.! Exploratory!Drug! VII.! References!!
Development! VIII.! Quiz! DRUG!
SERENDIPITY HYPOTHESIS EXPERIMENTS
A.! Phase!I! ! CANDIDATES
B.! Phase!II! $
$
Legend:! PPT!Trans!|!Audio&Trans!|!Book Trans & SLCM 2019 | Subhead Notes! 3.$LARGE$SCALE$SCREENING$
$ ! HypothesisPdriven!researches!
OBJECTIVE$ ! Natural Product Research
$

! Define!pharmacology! ! Screening!of!various!organic!molecules!and!natural!products!
! Define!drugs!and!drug!products! ! Sequence of experimentation and characterization!
! Discuss!the!different!stages!of!drug!development! ! General Steps !
! Describe!downstream!signaling!system!and!the!role!of!second! !Identification or elucidation of a new drug target (target ~ disease)
messengers! !Screening for leads (molecule that can achieve the desirable effects,
! Discuss! the! mechanism! of! drug! action! that! do! not! involve! not exactly drugs since they have not been checked for efficacy,
receptors! selectivity to the disease and safety)
! o!Rational design of a new molecule
o!Screening for biologic activity of natural products, previously
INTRO:$DRUG$RESEARCH$AND$DEVELOPMENT$
! discovered drugs and libraries of chemical or organic molecules
! What is drug research and development? o!Chemical modification of a known active molecule, resulting in a
!Screening for biologic activity of large numbers of (1) natural me-too analog (Me too drugs are drugs that have undergone simple
products, (2) banks of previously discovered chemical entities, or chemical alteration of the pharmacokinetic properties of the original
(3) large libraries of peptides, nucleic acids, and other organic prototype)
molecules& Development$History$and$Chemistry$
! Why need it? First! macrolide! antibiotic,$ erythromycin,! was! discovered!
!Imagine&medicine&without&research&and&development& over! 60! years! ago! in! 1949! at! Eli! Lilly! by! McGuire,! who!
o!Many patients will continue to suffer pain and disfigurement (e.g. isolated!erythromycin!from!the!metabolic!products!of!a!strain!
from rheumatoid arthritis)& of! the! actinomycetes! Saccharospora& erythraea,& formerly!
o!Rise in mortality and morbidity rate of diseases (e.g. breast known! as! Streptomyces& erythreus,& found! in! soil! samples!
cancer, heart failure) collected! from! the! Philippines! by! Filipino! scientist! Abelardo$
o!Rise in the complications of diseases (e.g. diabetes mellitus) Aguilar.! It! was! first! marketed! by! Eli! Lilly! in! 1952! under! the!
!Better& drug& delivery& systems& (e.g.& drinking& aspirin& in& tablet& brand! name$ Ilosone! to! overcome! penicillinPresistant! S.&
form&rather&than&in&powder&form)& aureus.&Erythromycin!is!unstable!in!acidic!environment!and!is!
o!Once daily dosing instead of taking medications 3-4x a day poorly!absorbed!
!Antibiotic&resistance&(one&of&the&biggest&problems&today)&& ! !
$
Table$1.$Some!plantPderived!drugs!that!have!gone!large!scale!screening!
SOURCE$ DRUG$ CLINICAL$USE!
Pacific!Yew! Paclitaxel! AntiPcancer!
Tree!
Opium! Morphine,!Opioids,!and! Analgesic,!antitussives,!
Opiates! antidiarrheal!
Willow!tree! Acetylsalicylic!acid! Analgesic,!antipyretic,!
antithrombotic!
Belladonna! Atropine! Mydriatic!
Autumn!crocus! Colchicine! Treatment!of!gout!
Velvet!bean! LPDOPA! Treatment!of!
Parkinsonism!
Ordeal!bean! Physostigmine! Tx!of!glaucoma,!
atropine!poisoning!
! antidote!
Fig.$1.$Overview!of!R&D!(Research!and!Development).!See!how! Cinchona! Quinine! AntiPmalarial!
it!looks!like!a!funnel!filtering!out!the!many!compounds!to!only!1P2! Indian! Rasagiline! Antihypertensive!
products$ snakeroot!
I.$APPROACHES$TO$DRUG$DISCOVERY$$ Tea! Theophylline! Bronchodilator,!
respiratory!stimulant!
AND$INNOVATIONS$ !
!

4.$DIRECTED$RESEARCH$
! Based on what we already know
Directed!
Serendipity !Cellular$ and$ Molecular$ Biology:$ understanding! how! cell!
Research
works! in! the! molecular! level:! channels,! carrier! molecules,!
enzymes,!structural!proteins,!receptors,!other!proteins!
Folklore! Largescale! o!Drugs& have& been& developed& against& the& NaBglucose&
Use Screening! transporter& 2& so& as& to& INDUCE& glucosuria& and& remove&
NEW! glucose& from& the& body& (glucosuria& & when& blood& glucose&
DRUG levels&exceed&180mg%&and&get&excreted&in&the&urine)&
!Applied$ Cellular$ Molecular$ Biology:$ understanding! the!
$ molecular!basis!of!disease$
1.$FOLKLORE$USE$
!Immunotherapy - like monoclonal antibodies that are directed
! Digitalis! P! known! since! 1700s! as! a! cure! for! heart! disease!
symptoms!and!as!a!diuretic$ against the substances or ligands produced by cancer cells.
!Digoxin!!used!for!certain!cases!of!heart!failure! Immunotherapy is currently in a lot of clinical trials against broad
! Periwinkle! (Catharanthus& roseus)& Initially! screened! as! a! drug! spectrum of cancer in comparison with the conventional
for!diabetes!mellitus!but!was!found!to!be!not!useful!for!DM! chemotherapeutic agents that are quite specific.
!Now! the! source! of! anticancer! drugs! like! vincristine,!
vinblastine!and!vinorelbine.!
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PHARMACOLOGY$|$Lecture$#1.1$|$By$Camacho,$Sison|$Checked$by$Conde! Page!1!of!4!
PHARMACOLOGY$|$Lecture$#1.1$|$Drug$Development$|$Version$#3$
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! To! suggest! specific! toxicities! to! be! monitored! during! clinical!
PROCESS!OF! trials! (e.g.,! hearing! loss,! neurotoxicity,! QPTc! prolongation,!
CANDIDATE!DRUG!
DISCOVERY MOLECULE allergenicity)!
! Investigate! toxicities! that! are! unethical! to! examine! in! humans!
! (Carcinogenicity,! Clastogenicity,! Mutagenicity,! Teratology/!
*Candidate Drug Molecule drug that will be formulated and tested in
reproductive! toxicity,! Overdosage! and! toxicity! profile)!
preclinical and clinical trials since it produces the desirable effects
*Clastogenic agent that can cause disruption or breakages of the
OVERVIEW:$DRUG$DEVELOPMENT$ chromosome!

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!
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Fig.$ 2.!The!development!and!testing!process!required!to!bring!a! III.$EXPLORATORY$DEVELOPMENT:$PHASES$I$&$II$
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drug! to! market! in! the! USA.! Note:$ Picture! lifted! from! Katzung.!
Number! of! subjects! may! vary! from! lecture.! Please$ ignore$ the$
numbers$here.$
$
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& preclinical&
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
(well 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
Drug!Candidate
! 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
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.

A.$ PHASE$1:$
Assay! Deveopment!of! Animal! ! The effects of the drug as a function of dosage are established in a
Scale!Up! Development*:! Dosage! Pharmacology!and!
Synthesis Parent!and! Formulation** toxicology
small number of healthy volunteers
Metabolites
$ !Maximum tolerated dose
*Assay development ~ identity test !Prevent severe toxicity
**Dosage formulation recipe of the drug + excipients like fillers, solubilizers, ! Determine the probable limits of the safe clinical dosage range
disintegrants, etc. !Remember: You are not yet treating the disease!
$ ! Defining&parameters
PRECLINICAL$PHARMACOLOGY$AND$TOXICOLOGY! ! Pharmacokinetic measurements
$ ! Exception:&Cancer/cytotoxic&or&highly&toxic&agents&$
Objectives:! !Administered& to& cancer& patients& who& did& not& respond& to&
! Identify!target!organs/tissues previous&therapy&and&are&not&treatment&naive$
! Identify!need!for!specialized,!safety!monitoring! !Administered to volunteers
! Identify!toxicological!profile!
! Select!starting!doses/!regimens! B.$ PHASE$2$
!initial dose to be tried in humans: one hundredth to one tenth of ! Done in hospital or wards
the no-effect dose in animals2! ! Patients with the target disease to determine its efficacy (proof of
$ concept)
Types$of$Toxicity$Studies! ! Used&for&safety&and&to&determine&adverse&effects&(related&and&
1.! Acute!and!multiple!dose!(subchronic)! unrelated)
2.! Chronic!and/or!carcinogenicity! ! Highest rate of drug failures!! only 25% move on to phase 3
3.! Genetic!toxicology!(in!vitro/in!vivo)!
Table$3.$Preclinical!Testing!and!Exploratory!Development
4.! Reproductive!toxicity!(segments!I,!II,!III)!
! Preclinical! $ Phase!I! Phase!II!
5.! Specialized!studies!(inhalation,!phototoxicity,!arthropathy,! testing! $
allergenicity)! Years! 3.5! $ 1! 2!
$ Test! Laboratory! $ 20P80! 100P300!
Other$studies$that$provide$useful$information! Population! and!animal! $ Healthy! Patient!
1.! Safety!pharmacology! studies! File! volunteers! volunteers!
2.! Pharmacokinetics! Purpose! Assess! IND*$ Primary:! Primary:!
3.! Toxicokinetics!! safety!and! at! Safety! Efficacy!
biological! FDA$ ! Proof!of!
$
Purpose$of$Animal$Toxicity$Studies:! activity! Dosing,! Concept!
PK**,!PD***,! !
! To!identify!potential!human!toxicities!!
Bioavailability! Safety!
! To!design!specific!animal!tests!to!further!define!a!toxicity!or!its! Success! 5000! 5!enter!trials!
mechanism! Rate! compounds!
*Investigational!New!Drug!|!**!Pharmacokinetics!|!***Pharmacodynamics!
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PHARMACOLOGY$|$Lecture$#1.1$|$Drug$Development$|$Version$#3$
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EXPLORATORY DEVELOPMENT V.$HISTORICAL$FOUNDATION$
MANUFACTURING SCALE UP2
!

! Nuremberg$ trial$ for! Nazi! war! crimes,! included! human!

! 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$
! !Thalidomide$ tragedyP! increase in the incidence of a rare birth
! Phase!III,!FDA!Approval,!Phase!IV!
! and legs)
A.$ PHASE$3$
! Most expensive phase, multicentered
! Patients with the target diseaseusually thousandsto 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
! Used&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&product&being&approved
!Can&be&skipped&if&it&has&a&convincing&phase&2&data
& !
B.$ PHASE$4$
! AKA PMS (Post Marketing Surveillance)
! Used&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
experimentations!
! Nuremberg$Code:!first!documented!code!of!ethics!for!human!
research!
! Nuremberg$Code$(1947):!Essential!Elements!
!Voluntary!Informed!Consent!
!Favorable!risk/benefit!analysis!for!the!subject!
!Research!should!be!for!the!good!of!society!
!Subjects! right! to! stop! or! withdraw! without! undue! pressure/!
denial!of!care!
! Kefauver$Amendments$(Kefauver-Harris amendments)!
defect called phocomelia (shortening or complete absence of arms
!Proof!of!effectiveness!of!drugs!before!marketing!
! Tuskegee$Syphilis$Study$(1932g1972)$
!US!GovernmentPfunded:!record!the!natural!history!of!syphilis!
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!Equitable!!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$
$

!SGLT2 may increase risk of metabolic acidosis and severe UTI ! Types$of$Toxicity!
!Thus, Phase 4 can check for other long-term side effects and infrequent
toxicities
!Acute!!tested!for!all!drugs!by!giving!incrementing!doses!to!
lethal!level!in!two!species!(rodent!and!non!rodent)!
! Lifetime of a patent is 20 years in the USA
!Gives the pharmaceutical company the right to market drug !Chronic! ! conducted! 2! to! 4! weeks! (subacute)! and! 6! to! 24!
without competition after the expiry of which other companies weeks!(chronic)!in!two!species!
may make generic versions !Reproductive!toxicity!!
!Average effective patent life for major pharmaceuticals was 11 "!Teratogenesis!P!developmental!defects!in!somatic!tissue!of!
years fetus! tested! by! treating! pregnant! animals! of! two! species!
!Patent is already applied for during the time of animal testing during!early!pregnancy!or!when!organogenesis!occurs)!
! Drugs may be WITHDRAWN from the market if serious adverse events or "!Mutagenesis!!defects!induced!at!any!age!and!will!result!to!
reactions are shown to be caused by the drug heritable! abnormalities.! Tested! using! Ames! Test! and!
!E.g.& Rofecoxib& (Vioxx,& a& blockbuster& painreliever& was& Dominant!Lethal!Test!
withdrawn&since&it&increases&the&risk&of&heart&attack& ! Generic$Drugs!
!Only! available! commercially! after! the! expiry! of! the! patent! of!
Table$4.$Full!Drug!Development the!innovator!drug!
! Phase!III! FDA! Phase!IV!
!Must! demonstrate! bioequivalence! (same! content,! purity! and!
Approval!
bioavailability)!with!the!innovator!
Years! 3! 2.5! P!
Test! 1000!to! FDA! Depends&on&a&
! Orphan$Drugs!
Population! 3000! Review! particular& !Drugs!for!rare!diseases!(diseases!that!affect!only!<!200,000!
patient! and! endpoint& people)!
volunteers! Approval! !Government!provides!tax!relief!and!other!incentives!!!
Purpose! Safety!with! P! Additional!PostP !
longPterm! Marketing! VII.$REFERENCES$
use! File! Testing! !

NDA*! Required!by! ! Dr.!Imasas!PowerPoint!and!Voice!

at!FDA! the!FDAk! ! [1]!Katzung,!B.,!Masters,!S.,!Trevor,!A.,!Basic!and!Clinical!
Submission!of! th
Pharmacology!12 !edition!
periodic!reports!
! [2]SLCM!Batch!2019!Trans!
including!any!
case!of! !
adverse! !
reaction! !
Safety! !
Success! 5!enter! 1!Approved! !
Rate! trials! !
*New!Drug!Application!
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PHARMACOLOGY$|$Lecture$#1.1$|$Drug$Development$|$Version$#3$
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VIII.$QUIZ$
!

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!
accomplished?!
a).!Phase!1!
b).!Phase!2!
c).!Phase!3!
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!
removes!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!FDAs!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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