Gruyere ARL Septembre 05.PPT

LA PHARMACOGENETIQUE OU UNE
PRESCRIPTION MEDICAMENTEUSE
ADAPTEE A CHACUN: UTILISATION
ACTUELLE ET FUTURE
Chin Bin EAP, Dr ès Sciences
Privat-Docent & Maître d’Enseignement et
de Recherche,
Gruyères, ARL, Septembre 2005
Questions auxquelles tente de répondre la
pharmacogénétique / pharmacogénomique:
Peut-on:
-
comprendre,
- prévoir,
- prévenir,
l’apparition de toxicité, d’effets indésirables ou
d’inefficacité thérapeutique survenant chez certains
individus, lors de la prise de doses standards
de médicaments?
PREMIER EXEMPLE CONNU DE
PHARMACOGENETIQUE
Décès par anémie hémolytique, suite à l’ingestion de fèves:
Connu depuis l’antiquité:
Pythagore (510 avant JC):
«... danger représenté par l’ingestion de fèves pour
certaines personnes ».
Lucretius Caro (auteur romain):
« Ce qui peut être nourriture pour certains, peut être un
poison
féroce pour d’autres »
DEFICIENCE EN GLUCOSE-6-PHOSPHATE
DEHYDROGENASE (SUITE)
Pendant la deuxième guerre mondiale, développement de
crises hémolytiques aiguës chez certains soldats américains,
en particulier ceux d’origine africaine, prenant l’antimalarique
primaquine.
« Primaquine induces intravascular hemolysis in about 10 % of
Negroes, but rarely in Caucasians....demonstrating an
abnormality in the direct oxidation of glucose in the red blood
cells of primaquine
- sensitive subjects. This abnormality affects
glucose
- 6
- phosphate dehydrogenase activity. »
Carson et al., Science 124:484-485, 1956
FATE OF DRUGS IN THE ORGANISM
PHARMACOKINETICS
- Absorption
- Distribution
-Metabolism
- Elimination
==>
==>
==>
==>
Glycoprotein P
α1-acid glycoprotein
Cytochromes P450
Glycoprotein P
PHARMACODYNAMICS
-Interaction with receptors, enzymes,
ions channels, lipoproteins, …
Isoformes principaux de la famille des
cytochromes P450 impliqués dans le
métabolisme des médicaments
CYP 1 A
CYP 2 C
CYP 2 E
CYP 2 D
CYP 3 A
Genetic polymorphism of CYP2D6
~ 7% Poor metabolizers
0 «active»
CYP2D6
~ 90% Extensive metabolizers
1 or 2 «active»
CYP2D6
~ 1-10% Ultrarapid metabolizers
3 to 13 «active»
CYP2D6
Dalén et al, CPT, 1998
Dalén et al., Clin Phamacol Ther 63, 453-464 (1998)
After
paroxetine
Before
paroxetine
100%
(R)-methadone
p = 0.032
80%
100%
80%
(108)
60%
60% (97)
40%
40% (110)
(184)
(276)
(61)
20%
(104) PM
20%
0% (129)
0%
-20%
-20%
Original concentrations (in %)
(138) PM
(56)
Concentrations in % of the original values
(in brackets: original concentrations in
ng/ml)
Begré et al., J Clin Psychopharmacol , 22:211-25, 2002
Isoformes principaux de la famille des
cytochromes P450 impliqués dans le
métabolisme des médicaments
CYP 1 A
CYP 2 C
CYP 2 E
CYP 2 D
CYP 3 A
Clozapine
Metabolism by cytochrome P4501A2
Very large interindividual variability of CYP1A2
activity (over 10 fold)
Therapeutic plasma level: 350 ng/ml for nonresponse (Perry et al., 1991)
Fast dissociation from the dopamine receptor
(Kapur and Seeman 2001)
Plasma levels > 1000 ng/ml: increased risks of
adverse effects on the central nervous system
(confusion, delirium, generalized seizures)
Clozapine plasma level to dose ratio mesured in one patient (A) with a slow and
in four patients (B,C,D,E) with a very rapid CYP1A2 activity compared to a
general population of patients receiving clozapine
Patient A
(4.25,4.5]
(4,4.25]
(3.75,4]
(3.5,3.75]
(3.25,3.5]
(3,3.25]
(2.75,3]
(2.5,2.75]
(2.25,2.5]
(2,2.25]
(1.75,2]
(1.5,1.75]
(1.25,1.5]
(1,1.25]
(.75,1]
10
9
8
7
6
5
4
3
2
1
0
(.5,.75]
(.25,.5]
<= .25
Number of observations
Patients B,C,D,E
Clozapine blood levels / clozapine dose (ng * day / ml * mg)
Patient A: Low metabolism and overdosage
üSuspicions of overdosage (300 mg/day: 1300 ng/ml)
üCafeine plasma clearance (CYP1A2 activity): 0.32 ml / min per Kg
(general population: 0.3 to 3.33 ml / min per Kg)
üDNA sequencing of the CYP1A2 gene
(5’- flanking region, 7 exons, exons
- introns junctions)
üMutation in intron 6 responsible for defective mRNA processing
üAnalysis of 100 unrelated Caucasians: No other carrier (rare
mutation)
Allorge et al., Br J Clin Pharmacol, 56: 341-44, 2004
Clozapine plasma level to dose ratio mesured in one patient (A) with a slow and
in four patients (B,C,D,E) with a very rapid CYP1A2 activity compared to a
general population of patients receiving clozapine
Patient A
(4.25,4.5]
(4,4.25]
(3.75,4]
(3.5,3.75]
(3.25,3.5]
(3,3.25]
(2.75,3]
(2.5,2.75]
(2.25,2.5]
(2,2.25]
(1.75,2]
(1.5,1.75]
(1.25,1.5]
(1,1.25]
(.75,1]
10
9
8
7
6
5
4
3
2
1
0
(.5,.75]
(.25,.5]
<= .25
Number of observations
Patients B,C,D,E
Clozapine blood levels / clozapine dose (ng * day / ml * mg)
Patients B,C,D,E : High metabolism and
non-response
ü4 patients non-responders with low blood levels (<< 350 ng/ml)
clozapine doses up to 900 mg/day
ü3 patients: + fluvoxamine (strong CYP1A2 inhibitor)
ü1 patient dose increase up to 1400 mg/day
üImprovement of the clinical state (marked for two
patients)
üCafeine plasma clearance (CYP1A2 activity): 3.33 to 4.17 ml / min per Kg
(general population: 0.3 to 3.33 ml / min per Kg)
üDNA sequencing of the CYP1A2 gene
ü3 Homozygous for the CYP1A2*1F allèle, 1 heterozygous
Eap et al., J Clin Psychopharmacol, 24, 214-219,2004
Isoformes principaux de la famille des
cytochromes P450 impliqués dans le
métabolisme des médicaments
CYP 1 A
CYP 2 C
CYP 2 E
CYP 2 D
CYP 3 A
NON-REPONSE A LA QUETIAPINE / METABOLISME RAPIDE
ü Patient schizophrène non-répondeur à la quetiapine (malgré
que dose montée jusqu’à 1200 mg/j)
ü Quetiapine 1200 mg/j: taux plasmatique bas pour la dose:
51 ng/ml (taux recommandé: 70 – 170 ng/ml)
ü Réponse au traitement après remplacement de la
quetiapine par l’amisulpride (800 mg/j, taux plasmatique de
598 ng/ml, correspondant à la dose)
ü Génotype CYP2D6 ultrarapide et phénotype CYP3A4/5
ultrarapide
ü Quetiapine métabolisée par CYP2D6 et CYP3A4/5,
ü Amisulpride éliminée principalement par clearance rénale.
Manuscrit en préparation
25
1OHMID / MID ratios
20
15
10
5
0
Before
grapefruit juice
After
grapefruit juice
Benmebarek et al., Clin Pharmacol Ther 2004; 76:55-64
Cinétique méthadone avant et après jus de pamplemousse
1000
(R )-methadone plasma levels
(ng/ml)
Après Pamplemousse
Avant Pamplemousse
100
-1
4
9
14
19
Time (hours)
Benmebarek et al., Clin Pharmacol Ther 2004; 76:55-64
24
ou
FATE OF DRUGS IN THE ORGANISM
PHARMACOKINETICS
- Absorption
- Distribution
-Metabolism
- Elimination
==>
==>
==>
==>
Glycoprotein P
α1-acid glycoprotein
Cytochromes P450
Glycoprotein P
PHARMACODYNAMICS
-Interaction with receptors, enzymes,
ions channels, lipoproteins, …
Association of Multidrug Resistance in Epilepsy with a
Polymorphism in the Drug-Transporter Gene ABCB1
Asra Siddiqui et al., N ENGL J MED 348;15
APRIL 10, 2003
Marzolini et al.,
Clin Pharmacol Ther
2004
Neff MW et al., PNAS, vol 101(32), 11725-30, August 10, 2004
ADVERSE DRUG REACTIONS
27 drugs identified as frequently cited in adverse drug
reaction studies
59 % metabolized by at least 1 enzyme with a variant
known to cause poor metabolism
Only 7 to 22 % of randomly selected drugs known to be
metabolized by enzymes with this genetic variability
(range, p = 0.006 – 0.001)
Phillips KA, JAMA 2001;286, 2270-2279
Apparition d'une aplasie médullaire chez un homme d'une soixantaine
d'année traité par l'azathioprine après avoir bénéficié d'une greffe cardiaque
Schutz et al., Lancet 1993, 341,436
Second example of a successful pharmacogenetics test:
Thiopurine S-methyl Transferase or TPMT
-Thiopurines such as 6-mercaptopurine and azathioprine are used to
treat acute lymphoblastic leukemia and inflammatory bowel disease
- People with deficient or intermediate TPMT activity risk toxicity
including
myelosuppression, at standard thiopurine doses
-Testings for low activity TPMT has been introduced in clinical
practice for more than 10 years now in the US as well as in other
countries.
- It has been shown to be cost-effective in certain health settings
Patient No (%)
Group of patients
UM
3
EM
(3)
Hospitalisation
days per years
Total coast
per years
26
12’000 U$
72 (72)
17
8’300 U$
IM
13 (13)
11
6’000 U$
PM
12 (12)
24
12’000 U$
Chou et al., J Clin Psychopharmacol, 20 (2000) 246-251
CYP2D6 genotype by AmpliChip ®
Advantages:
Validated method with a high number of alleles
analysed (33 alleles)
Redundant analyses (increase confidence)
Shorter time analysis than classical method (8
hours without DNA extraction)
CYP2D6 genotype by AmpliChip ®
Disadvantages:
Other rare alleles not analysed (> 20 alleles).
Analytical sensitivity 99.2 %
Acceptable chance of misclassification for a
genetic test ? (different situation than for a
research protocol)
Duplications (CYP2D6*1/*Xx2): prediction of less
than half of UM (determined by phenotyping).
Price (about 1700 SFrs for CYP2D6 and CYP2C19
determination, without reimbursement)
Ideally shorter analysis time needed
Closed system
Genetic-based dose adjustments
% of standard
dosage 250
200
150
100
50
0
CYP2D6
c
PM
c
t
IM
EM
UM
c
t
c
t
t
Kirchheiner et al.
ip
ra
D mi
M ox ne
Tr apr e p
im ot in
D ipr ilin
es a e
m
N i pr i n
or a m e
C tr i
lo ip n
m ty e
ip l i
Pa r a n e
m
Ve r o x i n
n e e
A laf tin
m a e
itr x i
i n
M p ty e
ia lin
ns e
er
in
Pe
Zu rph
c l en
o a
Th pe n zin
i o th e
A rid ixo
rip a l
z
Fl ipra ine
u z
H pen ole
al t
o p ix
er ol
P
R er ido
is a l
p e zi
rid ne
on
e
Im
% dose adjustment of a standard dose
CYP2D6-based dose adjustments for
antidepressants and antipsychotics
200
150
Ultrarapid
100
Extensive
50
Intermediate
0
Poor
metabolizer
Mol Psychiatry 2004; 9: 442-473
THE CASE OF ATOMOXETINE (STRATTERA®)
-
-
Atomoxetine: first non-stimulant drug approved by
FDA for treatment of attention-deficit /
hyperactivity disorder (ADHD)
In vitro data showed that CYP2D6 is a major
metabolizing enzyme for atomoxetine
Phase I studies showed that plasma elimination
half-life is 4 hours in EMs and 19 hours in PMs
THE CASE OF ATOMOXETINE (STRATTERA®)
-
In Phase II and III studies, atomoxetine dosing was
initiated and capped at lower doses in PMs than in
EMs, or included patients were genotyped at the
initial
visit, and the genotypes stored in sealed envelopes,
to
in
-
be opened in case of emergency.
Response to treatment was lower among EMs than
PMs
For all studies, (including open-label and long-term
studies), 5% of EMs and 7% of PMs discontinued
because of an adverse event.
THE CASE OF ATOMOXETINE (STRATTERA®)
The following adverse events occurred in at least 2% of
PMs and were either twice as frequent or statistically
significantly more frequent in PM patients compared
with EMs
Decreased appetite (23% of PMs, 16% of EMs)
Insomnia (13% of PMs, 7% of EMs)
Sedation (4% of PMs, 2% of EMs)
Depression (6% of PMs, 2% of EMs)
Tremor (4% of PMs, 1% of EMs)
Early morning awakening (3% of PMs, 1% of EMs)
Pruritus (2% of PMs, 1% of EMs)
Mydriasis (2% of PMs, 1% of EMs).
Drug Discovery World Spring 2005, 9-18
VIOXX Merck (MSD)
Introduced in the US market in 1999 (approximately 1.8 billion $)
3 year colon cancer study showed a slight increase in the risks of
heart attack and stroke: Voluntary withdrawal from the market in fall
2004
Immediate loss of 28 billion $ in the company market value !! MSD
stock price is recovering slowly after the the company received
FDA permission to place Vioxx back on the market with a strict
« Black box » drug safety warning.
« What is needed is a diagnostic test sufficiently powerful to predict
COX-2 inhibitor toxicity in advance of heart and stroke. More
generally, a diagnostic that could be used to help physicians make
more evidence-based decisions on risk/benefit ratios for individual
patients would be transformative in medicine.
M Schena and W Greene Drug Discovery World, Spring2005, 9-18
Drug Discovery World Spring 2005, 9-18
LOTRONEX® (alosetron hydrochloride)
Glaxo-SmithKline Beecham
Introduction: February 2000
Indication: Irritable bowel syndrome (chronic or recurrent abdominal
pain and discomfort, irregular bowel function such as diarrhea,
constipation, or alternating diarrhea and constipation). Unknown
cause
19 MIO subjects with this disease in the US
Approval by FDA: Feb 2000
LOTRONEX® (alosetron hydrochloride)
Glaxo-SmithKline Beecham
Several gastrointestinal side-effects, specifically ischemic colitis
and complications of constipation (hospitalization, blood transfusion
and/or surgery and some fatilities (clinical trials: incidence of 3 /
1000)
Widrawal: November 2000
Reintroduction: June 2002, with narrower indication: only women
with severe diarrhea-predominant IBS who have failed to
conventional therapy, whose IBS symptoms are chronic (generally
lasting six months or longer), and who had other gastrointestinal
medical conditions ruled out, which could have explained their
conditions.
L e a r n if Y O U H a v e a C la im
(m a k e r o f L o tron e x )
T he K ah
on b eh a
p o p u la r
sy n d ro m
A g a in s t G la x o S m it h K lin e
D r u g P u lle d A f t e r O n ly N in
n G a u t h ie r L a w G r o u p is in v e
lf o f u s e r s o f L o t r o n e x ( a lo s e
p r e s c r ip t io n d r u g u s e d t o t r e
e in w o m e n .
e M o n th s o n M a rk e t
s t ig a t in g p o s s ib le le g a l a c t io n s
t r o n h y d r o c h lo r id e ) , t h e o n c e a t o n e fo rm
o f ir r it a b le b o w e l
D O
Y O U
Q U A LIF Y ?
H a v e y o u o r a f a m ily
m e m b e r ta k e n L o tro n e x ?
Y e s
O v e r t h e p a s t 3 0 y e a r s , o u r t e a m h a s b e e n r e s p o n s ib le f o r b r in g in g ju s t ic e a n d
d o lla r s t o t h o u s a n d s o f c lie n t s f r o m c la s s a c t io n a n d in d iv id u a l s e t t le m e n t s .
i
j
k
l
m
n
d is t r ib u t in g
N o
j
k
l
m
n
m illio n s o f
Development of an anti-obesity drug
Roses et al., Nature Review Genetics, 5, 645-656, 2004
QUESTION SOMETIMES ASKED:
-
If I perform a pharmacogenetic test, I adapt the dose
according to the genotype, will it spare me to do other
tests (e.g. therapeutic drug monitoring, blood pressure,
bilirubin level, coagulation time determinations or other
clinical evaluations) later on ?
ANSWER: NO, OTHER TESTS ARE
NEEDED !
Metabolic clearance
Enzyme C
Metabolic clearance
Enzyme D
Metabolic clearance
Enzyme B
Renal clearance
Transporters
Metabolic clearance
Enzyme A
Drug blood
concentration
Age, development,
weight, size
percentage body fat,
nutritional status
Compliance
Smoking
Alcohol
Diet
Pollutants
Food effects
Comedications
Physiological disorders
(Commorbid diseases, impaired
organ function)
Thompson C, Am J Psy 2000; 157: 338-343
PRESENT SITUATION
TDM
TDM
TDM
TDM
Clinical evaluations
FUTURE ?
TDM
TDM
Clinical evaluations
Genotyping
Phenotyping
TDM
TDM
Clinical evaluations
Side effects
Efficacy
LA MEDICATION N’EST PAS DESTINEE A…
MAIS A …