pharmacogenetics · president obama, state of the union 2015 tonight (jan 2015) i am launching the...
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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