PHARMACOGENETICS · President Obama, State of the Union 2015 Tonight (Jan 2015) I am launching the...

PHARMACOGENETICSTESTING IN CLINICAL PRACTICE

Do you have your DNA passport?

Prof Dr Ron van SchaikInternational Expertcenter Pharmacogenetics

Dept. Clinical Chemistry

Erasmus MC Rotterdam

The Netherlands

NVF lezingUtrecht, 22-11-2019

Pharmacogenetics

DNA analysis

to explain/ to predict

the response of a

patient to drug therapy

Personalized Medicine

President Obama, State of the Union 2015

Tonight (Jan 2015)

I am launching the

Precision Medicine

Initiative: $215.000.000

Medical need…Professor van Schaik,

I have a problem…

Metabolism of drugs

Blood

Blood

Liver

Metabolism of drugs

Cytochrome

P450 enzymes

Dose

Kidney function

Liver

metabolizing

capacity

Time

Dru

g c

on

ce

ntra

tion

in b

loo

d

Dose

Ultra-Rapid metabolism

Slow metabolism

Dose

5-7% of all hospitalizations is are due to

Adverse Drug Reactions (Lazarou

1998). ADRs are the 5th cause of death.

Only 25-60% of all drugs prove to be

effective in treatment

Intestinal

uptakeMetabolism by

the liver

Interindividual variation

in drug metabolism

ADVERSE DRUG REACTIONS

SUBTHERAPEUTIC

Therapeutic window

Metabolism of drugs

CYP3A4

36%

CYP2D6

19%

Cytochrome P450 enzymes: 80% of all drugs

CYP3A4

30-40%

CYP2D6

20%CYP2C9

16%

CYP1A2

11%

CYP2C19

8%

CYP2E1

4%

CYP2B6

3%

Anti-depressives

Antipsychotics

Beta-blockers

Tamoxifen

Anti-coagulation

(warfarin, acenocoumarol)

Anti-depressives

Clopidogrel (Plavix)

Proton Pump Inhibitors

Oncology drugs

Psychiatric drugs

Cyclosporin, tacrolimus

& many, many more

Efavirenz

10

20

40

30

0.1 100101 MRS

CYP2D6 activity in Caucasian population

Ultra-rapid

(UR)~ 2-5 %

Intermediate (IM)

~10-15 %

Normal (NM/EM)

60-70 %

50

60

Perc

enta

ge

ofin

div

idua

l

CYP2D6 enzyme activity(metabolic ratio: debrisoquine→ 4OH debrisoquine)

Slow / Poor (PM)5-10 %

(Slide (adapted) ;courtesy of M. Schwab)

Drugs that are substrate for CYP2D6Pain

codeine

dextrometorfan

dihydrocodeine

ethylmorphine

hydrocodone

norcodeine

oxycodone

tramadol

ADHDAtomoxetine (Staterra)

Anti-arrhytmicsaprindine

encainide

flecainide

mexiletine

N-propylajmaline

procainamide

propafenone

sparteine

Anti-dementiagalanthamine

nicergoline

Anti-depressivesamitryptyline

clomipramine

desipramine

imipramine

nortryptiline

citalopram

desmethylcitalopram

fluoxetine

fluvoxamine

maprotiline

mianserin

minaprine

mirtazapine

paroxetine

venlafaxine

Antidiabeticsfenformine

Anti-estrogenstamoxifen

Antihypertensivesdebisoquine

guanoxan

indoramin

Anti-emeticsdolasetron

ondansetron

tropisetron

Anti-histaminicsmequitazine

promethazine

Appetite inhibitorsdexfenfluramine

Antipsychoticshaloperidol

perphenazine

risperidon

thioridazine

zuclopenthixol

ß - blockersalprenolol

bufuralol

bunitrolol

bupranolol

carvedilol

metoprolol

propanolol

timolol

Ca-antagonistsperhexiline

MAO inhibitorsamiflamine

brofaromine

Recreational drugsmethoxyamfetamine

MDMA, MDME

cinnarizine

flunarizine

(Zanger et al 2003)

Clinical application

PsychiatryAntidepressants

& CYP2D6

Imipramine therapy (antidepressive): CYP 2D6 substrate

Hospitalization

Start

therapy

1 week

22:00

1 week

1st conc 2nd conc

1 week

3rd conc 4th conc

1 week 1 week

~ 50% patients: dose adjustment

based on drug concentration in blood

Time in academic hospital: 4-6 weeks

Fig. 2g

0 1 2 >20

100

200

300

400

500

600

700

800

900

n=11 n=90n=69 n=11

CYP2D6 SGD

IMI

do

se (

mg

/day) Imipramine dosis na bereiken van stabiele therapie

((Paul Schenk et al 2008 Mol Psychiatry)

30% of

standard

dose

Active copies of CYP2D6

Imip

ram

ine

do

se

(mg/d

ay)

Imipramine Desipramine 2OH-desipramineCYP2C19 CYP2D6

Imipramine therapy for depression

(Stingl et al 2013 Mol Psychiatry)

Genotype vs non-genotype guided treatment

(Hall Flavin 2013 Pharmacogenomics)

ConventionalDNA

guided

Clinical application

CardiologyMetoprolol

& CYP2D6

Dosing Guidelines KNMP:

PM: 25% of standard dose

IM: 50% of standard dose

UM: 250% of standard dose

(www.pharmgkb.org)

CYP2D6: NM IM PM

S-m

eto

pro

lol p

lasm

a c

oncentra

tion (n

g/m

l)CARDIOLOGY: CYP2D6 and metoprolol

500

400

300

200

100

0

Clinical application

PainCodeine/Tramadol

& CYP2D6

Pain medication: CYP2D6 & Codeine/Tramadol

Codeine

Morphine

UGT2B7

Morphine-glucuronide

CYP2D6X

No pain relief

Tramadol

O-desmethyl

tramadol

CYP2D6

No pain relief

X

Clinical application

Anti-coagulation

Clopidogrel (PLAVIX)

& CYP2C19

Clopidogrel

(prodrug)

Active

metabolite

CYP2C19(CYP3A4, CYP3A5)

Clopidogrel (Plavix): activation by CYP2C19

Meta-analysis

Geisler et al 2011 Pharmacol & Ther:

CY2C19*2 carriers are at risk

Test for CYP2C19 variants: Negative → clopidogrel (€)

Positive → prasugrel (€€€)

Clopidogrel (Plavix): activation by CYP2C19

Erasmus MC Rotterdam:

Every patient gets

Prasugrel (€€€)

instead of clopidogrel (€)

Antonius ZKH N’gein:

Every patient is tested

for CYP2C19 (€ 80/patient)

before starting clopidogrel

Anonymous ZKH:

Every patient gets

Clopidogrel (without testing)

Ticagrelor or prasugrel

Clopidogrel for CYP2C19*1/*1

Else ticagrelor or prasugrel

* p <0.05

*

Ticagrelor or prasugrel

Clopidogrel for CYP2C19*1/*1

Else ticagrelor or prasugrel

Clinical application

Lipid metabolism

Statins & SLCO1B1

OATP1B1SLCO1B1*5

hepatocyte

CYP3A4

simvastatin

blood

Drug transporters: SLCO1B1 and statinsSLCO1B1 521T>C (*5)

hepatocyte

CYP3A4

blood

Drug transporters: SLCO1B1 and statinsSLCO1B1 521T>C (*5)

>160 drugs now

with PGx info in

the drug label

Where could PGx help you?% with variant alleles

Psychiatry: Antidepressants, antipsychotics CYP2D6, 2C19, 1A2, 3A4 60%

Cardiology: Clopidogrel (Plavix) CYPC19 15%

Metoprolol CYP2D6 40%

Statins SLCO1B1 (521T>C) 20%

Warfarin CYP2C9, VKORC1 20%

Oncology: Tamoxifen (breast) CYP2D6 10%

Capecitabine / 5-FU DPYD (*2A) 2-3%

6-mercaptopurine (ALL) TPMT 11%

Irinotecan (colon) UGT1A1 15%

Neurology Phenytoin CYP2C9, 2C19 20%

Clobazam CYP3A4, 2C19 20%

Dermatology Azathioprine TPMT 11%

Pain Codeine, tramadol, oxycodon CYP2D6 40%

Internal Medicine Azathioprine (Crohns) TPMT 11%

HIV Efavirenz CYP2B6 5%

Abacavir HLA-B*5701 4%

Organ Tx Azathioprine TPMT 11%

Tacrolimus/cyclosporin CYP3A5, 3A4 20%

www6.erasmusmc.nl/farmacogenetica

www.erasmusmc.nl/farmacogenetica

www6.erasmusmc.nl/farmacogenetica

CE-IVD test

2 independent platforms

(of which 1 CE-IVD)

TAT 3 – 5 days

In collaboration with

hospital pharmacy/

clinical pharmaclogy

“Here is my sequence …” (The New Yorker, 2000)

Dutch Pharmacy PGx working group:

Evidence-based dosing guidelines

per genotype for > 90 drugs

Rating evidence: 1 – 4 (RCT)

Rating Clinical effect: A - F (death)

“Here is my sequence …”

(The New Yorker, 2000)

https://www.nhg.org/actueel/nieuws/nhg-

standpunt-farmacogenetica