lect 1 side effects and their role in drug development

7/30/2019 Lect 1 Side Effects and Their Role in Drug Development

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Side Effects and their role in

Drug DevelopmentChris Benham

DDD Code: 3PHA0002


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Therapeutic drugs

A balance between efficacy and adverseeffects

Risk / Benefit

Unmet medical need


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Aims

Explore role of side-effects of molecules in the processof drug development

Limiting side-effects

Side effects and screening Side effects in clinic and in market

Exploiting side-effects Rational applications

Exploiting serendipity

Illustrate by examples


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PerceptionUsers Values


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Car driving more dangerous than rock-climbing?


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Motor-cycling more dangerous thansmoking?


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Playing soccer more dangerous thantaking the Pill?


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PerceptionUsers ValuesMortality per person per annum

0.0000001

0.000001

0.00001

0.0001

0.001

0.01

0.1

1

Motor-cycling

Smoking

Power-boating

Cardriving

Rock-climbing

Influenza

Car-racing

Leukemia

Heavydrinker

Soccer

OCs

Canoeing

Tornados

Earthquakes

Skiing

A

mateurboxing

Probabilit

Most risk


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Risk / Benefit

Eliminate drug induced harm- life expectancy increases

? Positive effects of medication- life expectancy increases

?


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The four most dangerous words in medicine:

First do no harm

By Clifton Leaf, FORTUNE senior editor-at-largeFebruary 9, 2006: 11:21 AM EST

A Business view
http://money.cnn.com/2006/02/09/news/economy/fda_fortune/[email protected]://money.cnn.com/magazines/fortunehttp://money.cnn.com/2006/02/09/news/economy/fda_fortune/[email protected]


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Show me a drug without side-effects and I shallshow you a drug that doesnt work

Anon

What is the appropriate trade-off between risk and benefit?


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Lecture 1

Overview of side-effect issues

Cardiovascular examples

- Minoxidil

- Sildenafil

References :- as cited on slides- Rang HP (2006) Drug Discovery and Devpt. ChurchillLivingstone ISBN 0443 064202


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Strategies for new drugdevelopment

Identify unmet need in therapeutic area

Where existing therapies exist

- identify new mechanistic approach withpromise of improved efficacy/ response rate

- improve therapeutic index of existingmechanistic approach by developing newmolecules

- Greater efficacy- Reduced side effects or both


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Difficulties in identifying new therapeuticmechanisms

Pain

Cox inhibitors Opioids (mu)

NA uptake blockers N type Ca channel block

(CaV 2.2) Steroids Na channel block TNFalpha mAb TRPV1 (capsaicin)

agonist

Migraine

5-HT1B/1D agonists CGRP antagonists

Beta blockers GABA (valproate) Cox inhibitors

Few mechanistic approacheswork in the clinicFinding new ones is very riskySo try to improve existing ones

Mechanisms that work


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Economics requires expandeduses

Total cost of developing a new drug ~$1Bn

developing failures is the major cost- most new targets will fail

Less risky route to increase sales is toexpand current indications

Particularly attractive if molecule has

multiple receptor targets

Exploit other in vivo actions of molecule


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Exploiting side-effects to treat new patientgroups

On target effects- side effects have the same molecularmechanism as the intended effect

Off target effects- side-effects are due to other molecular actionsof the drug

Polypharmacy- Drugs developed empirically using in vivomodels may have multiple actions


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Exploiting On target effects

Cardiovascular drugs often have other utilitiesbecause.

Large research effort

Smooth muscle in other places

Targets on additional cells

Minoxidil and sildenafil examples where Phase1data lead to new indication


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Medicine requirements

Effective

Safe

Well tolerated

Side-effects

Aims of Phase 1Clinical Studies

Careful observation can identifyuseful unexpected effects


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EXAMPLE 1:K CHANNEL OPENERS


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Minoxidil

Potassium channel opener

Acts on vascular smooth muscle KATPchannels

Developed as anti-hypertensive


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KATP in smooth muscle cells

ATP

KATP

K

+

-

KATP are closed by ATP

+

Openers

CromakalimPinacidil

Diazoxide

Minoxidil

Channels normally kept closed by ATPIn vascular smooth muscle

Do blockers ..Glipizide, tolbutamide

Affect blood pressure?

Opening K channels- Hyperpolarises- Relaxes smooth muscle


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KATP in pancreatic b cells

VDCC

Ca2+ +

Extracellular glucose

insulin

-

ADP ATP

+

KATP

K+

-

GLUT1 GLUT2

Intracellular glucose

Food +

KATP are closed by ATP


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Minoxidil

Potassium channel opener

Acts on vascular smooth muscle KATP channels

Developed as anti-hypertensive

Anti-hypertensive profile not better than existingtherapy- limited use in severe hypertension

Side-effects seen in Phase1/2- water retention- hypertrichosis


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Minoxidil

Now marketed for male pattern baldness

- topical application avoids b.p. changes

- Available over the counter

Observed thickening of hair growth- differentiation of follicular keratinocytes- prolongs growing phase of follicle- probably K channel opening effect


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EXAMPLE 2:PHOSPHODIESTERASE

INHIBITORS


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Phosphodiesterase inhibitors

24 phosphodiesterases identified

PDE 1-11 with further ABC sub-division

Varying selectivity for cGMP and cAMP

Molecular definition in the 1990s

cGMP selective PDEs of interest to boostactions of endogenous nitric oxide


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Sildenafil

Project initiated in 1985 by Pfizer using zaprinastas a lead

Zaprinast moderately selective PDE5 inhibitor

( known only as cGMP selective over cAMPat time) Aim to produce an angina treatment

- dilating coronary arteries- by potentiating effects of nitric oxide

1600 molecules including sildenafil by 1989

Entered phase 1 in 1991 at Sandwich


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Sildenafil

Phase 1 data showed no potential fortreating coronary artery disease

Male volunteers reported unexpected side-

effect Entered Phase 2 for male erectile

dysfunction in 1993, at end of trials males

and partners protested Approved by FDA in 1998

5.3 M prescriptions in first 6 months

McCullough 2002, Rev Urol. 4(Suppl 3): S26S38


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Selectivity of Sildenafil mechanismof action

PDE5 expressed at high levels in corpuscavernosum smooth muscle

PDE5 is predominant isoform in CC

No other significant cGMP breakdownroutes in this tissue

So PDE5 inhibition leads to rise in cGMPin this tissue

NANC th ti di i


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NANC parasympathetic nerve endings incorpus cavernosum

NO

NO

Ca

Ca nNOS

NO

GTP cGMP

G cyclase

arginine

Smooth muscle cell

relaxation

5GMP PDE 5

sildenafil X

NonAdrenergicNonCholinergic nerve ending


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Sildenafil side-effects

Rare cases of myocardial infarction not thoughtto be drug induced- sexual activity has Relative risk of MI of 2.9- about 1% of MI are due to sexual activity

Headache - cerebral vascular Flushing Blue tinted vision

- role of cGMP in cone visual transduction

- sildenafil 10 fold less potent for PDE6 in retina

Competitors positionned on pharmacokinetics


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Other side effects


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Could development have beenrational rather than serendipitous?

Pilot experiments on the actions of drugs

injected into the human corpus

cavernosum penis.

Brindley GS.Seven drugs that are known to relax smooth muscle

(phenoxybenzamine, phentolamine, thymoxamine,imipramine, verapamil, papaverine, naftidrofuryl)

caused erection when injected intracavernosally.by relaxing vascular and trabecular smoothmuscle within the cavernosal space.

Br J Pharmacol. 1986 Mar;87(3):495-500.

Papaverine was known to be a PDE inhibitor at this time
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Brindley+GS%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Brindley+GS%22%5BAuthor%5D


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Summary

Overview of side-effect issues

Cardiovascular examples

- Minoxidil- Sildenafil

Two examples where unexpected side-effects lead to products that filled anunmet need

lect 1 side effects and their role in drug development

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