DNA-Guided Anti-Platelet Management with the ... - Genomas

LABORATORY OF
PERSONALIZED HEALTH
LPH
Personalized Medicine in Real Time
DNA-Guided
Clopidogrel (Plavix
® ) Management
Pharmacogenetic Foundations and Case Study
1

Clopidogrel (Plavix
® )
Leading AntiPlatelet Drug
Thienopyridine antiplatelet drug
Irreversibly inhibits ADP receptor
Marketed as Plavix ® , Sanofi-Aventis/BMS
Second largest selling drug in the world,
$9.5B sales 2008
>22 million prescriptions issued in 2007
Indicated to prevent death, MI, and stroke
in patients with cardiovascular disease
Dosing: Recent MI, stroke, PAD: 75 mg daily
ACS: 300 mg x 1 75 mg daily
Label Revision May 2009: Pharmacogenetics Section
Variance on potency related to CYP2C19 gene polymorphisms
Pharmacogenetic testing can identify genotypes of CYP2C19
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Clopidogrel Activation to Metabolite
CYP2C19 Essential in Metabolite Formation
CYP2C19
Clopidogrel
ProDrug, Inactive
Requires metabolism
by CYP2C19 for
antiplatelet activity
Active metabolite
Metabolite, Active
Far more potent as
P2Y12 blocker than
clopidogrel
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Clopidogrel Mechanism of Action
Pharmacokinetics and Pharmacodynamics
Cytochrome
p450 2C19
Clopidogrel
Active
metabolite (thiol(
thiol)
ADP
2PY12
Resting
platelet
X
Activation
4

Clopidogrel Response
Wide Range of Efficacy: Resistant Quartile
Number of Patients
20
18
16
14
12
10
“Resistance”=31%
8
6
4
2
0
Number of Patients
“Resistance”=31%
5 uM ADP aggregation
after 300 mg loading
dose
20
18
16
14
12
10
8
6
4
2
0
-30--20 -20--10 -10-0 0-10 10-20 20-30 -30--20 30-40 -20--10 40-50 -10-0 50-60 0-10 >60 .10-20 20-30
Change in Aggregation
Change in Aggrega
Gurbel, et al. Circulation 2003;107(23):2908-13.
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CYP2C19 Genotypes, Phenotypes
10 Alleles
green=Functional yellow=Deficient red=Null blue=Ultra
Allele
*1
*2
*3
*4
*6
*7
*8
*9
*10
*17
Change
Reference
Splicing defect
Stop codon
Start codon
Arg 132 Glu
Splicing defect
Trp 120 Arg
R 144 H
P 227 L
Promoter
Metabolizer
Phenotype
Functional
Null
Null
Null
Null
Null
Null
Deficient
Deficient
Ultra
Antidepressants
Escitalopram (Lexapro ® )
Citalopram (Celexa ® )
Anti-epileptics
Phenytoin (Dilantin ® )
Diazepam (Valium ® )
Proton Pump Inhibitors
Omeprazole (Prilosec ® )
Lansoprazol (Prevacid ® )
Esomeprazole (Nexium ® )
AntiPlatelet ProDrug
Clopidogrel (Plavix ® )
6

CYP2C19 Carrier Status
N=577 Referrals to Lab Personalized Health
non-carrier
single carrier
double carrier
7

Frequency of CYP2C19 *17 allele
Patients Referred: Pharmacogenetic Consult
Patients
41
308
576
Non-carriers
Single carriers
Double carriers
N = 925
Allele frequency = 21.1 %
Carrier frequency = 37.7%
HW p-value = 1.0 (perfect)
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CYP2C19 Genotypes, Phenotypes
Population Frequencies
Allele
Genomic
position
(NCBI
website‡)
Amino Acid
Change or
other effect
Enzymatic
Activity
Frequency %
Native
European Asian African American
*1 wild-type Reference common common common common
Oceana
Not
common
Mixed
Other
common
*2 19154 G>A Splicing defect Null 9-15 21-39 10-25 19 57 8-25
*3 17948 G>A Trp 212 X Null 0-2 0-13 0-2 0 25 0.1
*4 5001A>G Start codon Null Rare 0.4 Rare Rare Rare Rare
*5 19294 T>A Arg 433 Trp Null Rare Rare Rare Rare Rare Rare
*6 12748 G>A Arg 132 Glu Null Rare Rare Rare Rare Rare Rare
*7 19294 T>A Splicing defect Null Rare Rare Rare Rare Rare Rare
*8 12711 T>C Trp 120 Arg Null Rare Rare Rare Rare Rare Rare
*9 12784 G>A Arg 144 His Null Rare Rare Rare Rare Rare Rare
*10
19153 C>T Pro 227 Leu Decreased Rare Rare Rare Rare Rare Rare
*17 4195C>T
Promoter
variant
Increased 18-27 1.4-4.0 19-24 ? ? ?
‡
http://www.ncbi.nlm.nih.gov/gene/1557
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Epidemiology CYP2C19 Polymorphisms
Association with Higher Event Rates
Death, MI, Stroke
Carriers, N=395 12%
Noncarriers, N=1064
8%
Mega, et al. NEJM 2009;360:354-62
62
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HILOmet
PhyzioType System: CTM3
Case Report and Clinical Management Utility
Patient CTM3 is a 74-year old Caucasian, diabetic man,
hx. severe coronary arterial disease who manifested:
14 PTCAs, 7 stents, recurrent restenoses over 8
yrs; on clopidogrel 75 mg/d, high platelet reactivity
________________________________________________
HILOmet
Combinatorial
Genotype
2D6 2C9 2C19
*1 *1 *1 *1
*2 *2
_________________________________________________
*3 *1
DRUG
CYP
CYPARRAY
BIO-CLINICAL
METABOLISM
HIGH
Ruaño, Hirst, McKay et al, Connecticut Medicine 2012
LOmet
HILO
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PHP Personalized Health Portal
Anti-Thrombotic Management: Patient CTM3
CYP2C19 Genotype
*1/*1
*1/*2, *1/*3
Antiplatelet Therapy Option to Consider
Clopidogrel 75 mg/day
Clopidogrel 225 mg/day or Consider alternatives:
Prasugrel 5 or 10 mg/day or Ticagrelor 90 mg/day, b.i.d.
*2/*2, *2/*3, *3/*3
*1/*17
*2/*17, *3/*17
Consider alternatives:
Prasugrel 5 or 10 mg/day or Ticagrelor 90 mg, b.i.d.
Clopidogrel 75 mg/day with Rapid Effect
Consider alternatives:
Prasugrel 5 or 10 mg/day or Ticagrelor 90 mg, b.i.d.
*17/*17
Clopidogrel 75 mg/day with Rapid Effect or Consider alternatives:
Prasugrel 5 or 10 mg/day or Ticagrelor 90 mg, b.i.d.
Note: Interpretations of the March 2010 clopidogrel label revision have become
incorporated into recent clinical guidelines. Recommendations regarding patients
heterozygous for null alleles call for supra-normal clopidogrel dosing levels.
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DNA-Guided Anti-Platelet Rx
CYP2C19 Individualized Decision Support
Post Cardiac Event
High Risk Patients
CV Prophylaxis
CYP2C19
Status
Functional
Null
Clopidogrel
ALTERNATIVES
Clopidogrel
Prasugrel
Ticagrelor
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LPH Laboratory of Personalized Health
CLP Clinical Lab Partners: CT Distributor
Pioneering high complexity
pharmacogenetics laboratory +
clinical practice
Anchor for commercialization of
PhyzioType Systems throughout
New England and nationally
Referral Center for Institute of
Living + Mood Disorders Program
CT-wide CLP distribution and
reimbursement agreement
$1.4M reimbursable revenue 2011
Reimbursement rate >95%
1044 Patients referred in 2011
3059 PhyzioType tests in 2011
Used by 206 Clinicians in 2011
LABORATORY OF
PERSONALIZED HEALTH
LPH
Licensed by CT Dept of Public
Health (#CL-0644) + R.I.
CLIA certified and registered
(Clinical Laboratory Improvement
Amendments)
ID #07D1036625 CMS (Centers for
Medicare and Medicaid)
4 successful biannual inspections
(most recent June 2011)
53 patient service centers in CT
Subsidiary of Hartford Healthcare
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LPH Laboratory of Personalized Health
CLIA Lab, Clinical Launchpad
Physician
Clinician
CLP Patient
Service
+ Billing
Laboratory of
Personalized
Health
1 2 3
Personalized
Health
Portal
Physician requests
HILOmet
PhyzioType System
and sends patients
for blood draw or
buccal swab to CLP
centers.
Phlebotomist
acquires sample and
enters the
requisition into the
CLP system,
including activation
of claims.
Messengers bring
blood or buccal
swab sample to LPH
for DNA extraction
and clinical
genotyping.
Genomas prepares
reports + drug
selection guidance,
uploads into the
Portal, sends hard
copy reports to
clinician.
P A Y O R S
CLP files 3 claims per HILOmet PhyzioType System with payors based on
generic molecular diagnostic codes.
CLP remits payment to Genomas at a contractually agreed upon rate per
component test.
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LABORATORY OF
PERSONALIZED HEALTH
LPH
Thank You !
LPH@genomas.net
860-545
545-45894589
www.genomas.com
Personalized Medicine in Real Time
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