Are You Ready for
Pharmacogenomics?
Bruce Matthias
June 3, 2010
MUSE International Conference
Definition
Tailoring drug therapy to individual
patients based on their own unique
molecular characteristics such as
individual differences in drug metabolizing
enzymes, drug transporter activity,
receptor sensitivity, etc. (genetic profile)
Background
• 1956 – Kalow – patients were identified that
did not exhibit a typical response ot
succinylcholine due to a genetic “variation”
• 1956 – Carson – excess hemolysis
opbserved in “primaquine-sensitive”
individuals
• 1959 – Evans – detailed “slow inactivators”
and “rapid inactivators” of isoniazid
• 1959 – Fredrich Vogel – uses term
“pharmacogenetics”
• 2003 – Human Genome Published
Single Nucleotide Polymorphisms
(SNP’s)
• Human genome contains between 30,000
and 40,000 distinct genes.
• Genetic variation most commonly occurs as
random variations between the nucleotide
sequences of different individuals
• Single base-pair substitutions that occur with
a frequency of greater than or equal to 1% in
a population are referred to as single
nucleotide polymorphisms (SNP’s)
• To date 1.4 million SNP’s have been identified
• More than 60,000 occur in the coding regions of
proteins
• Genes that code for the CYP enzymes 2A6, 2C9,
2C19, 2D6 and 3A4 have shown to be
polymorphic with functional variations on a
significant percentage of ethnic groups.
• The most common and best studied
polymorphisms to date are those that affect drug
pharmacokinetics and pharamcodynamics
Variability in Drug Response
• Pharmacokinetics
– Absorption
– Distribution
– Metabolism
– Excretion
• Pharmacodynamics
– Drug target response
CYP2D6 - CYP2C19
•
CYP2D6 is involved in the metabolism of:
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•
Codeine (pro-drug)
Prozac
Zoloft
Paxil
Effexor
Hydrocodone
Amitriptyline
Claritin
Cyclobenzaprine
Tagamet
Tamoxifen (pro-drug)
CYP2C19 is associated with the metabolism of:
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Carisoprodol
Diazepam
Dilantin
Premarin
Prevacid
Plavix
By analyzing the variation in the two genes, the test predicts whether an individual will
metabolize these drugs more quickly or more slowly than average. These variations can help the
physician identify how a patient's metabolism works. If the test reveals that a patient metabolize
drugs rapidly or slowly, the doctor may consider adjusting your drug dosages or switching to a
non 2D6 or 2C19 metabolized drug. This information can help to maximize the likelihood of
therapeutic effectiveness and minimize the risk of adverse drug reactions.
AmpliChip CYP450
• The first CYP2D6 and CYP2C19 genotyping test
with FDA clearance.
• The AmpliChip CYP450 Test has greater than 99%
accuracy for detection and genotype call rate.
• Covers clinically relevant polymorphisms known to
impact drug metabolism.
• With its broad coverage of 27 alleles for CYP2D6
and three alleles for CYP2C19, the AmpliChip
CYP450 Test is relevant for racially diverse
populations.
AmpliChip CYP450 Results
Using a simple blood test, analysis of the data can be accomplished in
eight hours:
 The majority of people are extensive metabolizers (normal) who
can be administered drugs following standard dosing practices.
 Some people are poor metabolizers with a deficiency in drug
metabolism, which could lead to life-threatening drug accumulation
and severe adverse reactions.
 Some people are intermediate metabolizers, meaning that they
metabolize drugs at a slower-than-normal rate—somewhere
between the rates of poor and extensive metabolizers.
 Ultra-rapid metabolizers are those who break down drugs at faster
rates than extensive metabolizers. These people may experience
either no effect or less-than-expected effectiveness from their drug
therapy. In the case of pro-drugs, the opposite phenomenon would
occur.
Clopidogrel (Plavix) DNA Test - CYP2C19
Several recent landmark studies have proven the
importance of 2C19 genotyping in treatment using
clopidogrel or Plavix. Researchers have found that
patients with variations in a gene called
cytochrome P-450 2C19 (CYP2C19) have a 3.58
times greater risk for major adverse cardiovascular
events such as death, heart attack, and stroke; the
risk was greatest in CYP2C19 poor metabolizers.
The abstract is available in the online verison of
the New England Journal of Medicine.
Population Frequency of Cytochrome P450
(CYP) 2C19 Metabolizer Types
• There is wide variability among populations.
People of Asian and African ancestry have a
greatly increased prevalence of poor metabolizer
status.
• CYP2C19 is not just involved in the metabolism of
clopidogrel, it metabolizes many other medications
including antidepressants, barbituates, proton
pump inhibitors, antimalarial and antitumor drugs.
Who Should Be Tested
• The CYP2C19 test for clopidogrel or
Plavix is considered appropriate for any
patient taking or considering this
medication.
• The process is simple. You can order
testing directly if you have a physician
prescription or your healthcare provider
can request testing for you.
Warfarin Sensitivity (CYP2C9 & VKORC1 )
• Warfarin overdosing can result in life-threatening
• Up to 1 percent mortality and 15 percent morbidity due to
bleeding complications.
• Mutations in the CYP2C9 and VKORC1 genes. The common
CYP2C9 gene mutations (*2 and *3) with the VKORC1 gene
promoter mutation (c.-1639G>A), are estimated to account for
40-63 percent of the variability in therapeutic warfarin dose.
• VKORC1 stands for Vitamin K epoxide reductase, complex 1
gene. Warfarin inhibits the product of this gene (VKOR), a
key enzyme in the vitamin K cycle
TPMT
ThioPrine MethylTransferase
• Methylates anticancer drugs such as mercaptopurine and
azathioprine
• Several SNP’s have been identified for TMPT which can
alter its activity of methylation that is involved in both
activation and metabolism of mercaptopurine
• Altered enzyme activity will affect the concentration of both
active and toxic metabolites
• NTI – life threatening myelosuppresion is a major concern
NAT2
N-AcetylTranferase 2
• Involved in the metabolism of several agents
(hydralazine, isoniazid, procainamide, dapsone)
• Has multiple phenotypes
– Fast/rapid
– Intermediate
– Slow
• Recognition of variation dates back to 1960’s
prior to the idea of the NAT2 enzyme or the idea
of genotyping
FDA
• As a result of demonstrated clinical impact
of polymorpisms in the CYP2C9 and
TMPT, the FDA recommends that patients
be tested for the presence of the variants
before receiving warfarin or azathioprine
• The FDA currently suggests that NAT2
genotyping may be useful in tuberculosis
patients being treated with a combination
of rifampin, isoniazid, and pyrazinamide
CYP1A2
Controls the Clearance of Clozapine
• Poor 1A2 metabolizers are a risk of
several potentially fatal toxicities including
agranulocytosis, seizures and myocarditis
• Patients with higher-than-normal 1A2
activity are at increased risk of treatment
failures
UGT1A1
UDP-GlucuronosylTranferases
• Patients that are homozygous for the UGT1A1*28 allele
have impaired metabolism of the active form (SN-38) of
the anticancer agent irinotecan that can result in severe,
dose-limiting toxicity (diarrhea, neutropenia).
• The FDA currently recommends an assessment of a
patient’s level of UGT1A1 activity prior to the initiation of
irinotecan therapy
Pharmacogenomic Data extracted
from FDB
GNN
DDXCN_DRUG_DES
C
DXID_DESC100
DDXCN_REF
COLCHICINE/PROBENECID
COLCHICINE
Hemolytic Anemia from Pyruvate Kinase and G6PD
Deficiencies
DICUMAROL
COUMARIN
ANTICOAG.
Bleeding Risk Associated with Vitamin-K-Epoxide Reductase
(Warfarin-Sensitive) Gene
MEDWATCH 08/17/07
COLCHICINE/PROBENECID
COLCHICINE
Hemolytic Anemia from Pyruvate Kinase and G6PD
Deficiencies
WARFARIN SODIUM
COUMARIN
ANTICOAG.
Bleeding Risk Associated with Vitamin-K-Epoxide Reductase
(Warfarin-Sensitive) Gene
MEDWATCH 08/17/07
ISONIAZID
ISONIAZID
Slow Acetylator due to N-acetyltransferase Enzyme Variant
ISONIAZID PI, 10/01 (WEST)
ABACAVIR SULFATE
ABACAVIR
HLA-B 5701 Positive Status
ZIAGEN PI, 07/08
WARFARIN SODIUM
COUMARIN
ANTICOAG.
Poor Metabolizer due to Cytochrome p450 CYP2C9 Variant
MEDWATCH 08/17/07
ABACAVIR SULFATE
ABACAVIR
HLA-B 5701 Positive Status
ZIAGEN PI, 07/08
CARBAMAZEPINE
CARBAMAZEPINE
HLA-B 1502 Positive Status
MEDWATCH 12/12/07
WWW.G6PD.ORG
WWW.G6PD.ORG
REDUCING ADRS AND SAVING MONEY
More than 50% of Americans have gene
based variations that can be tested for and
that increase the risk of an ADR.
The wide use of DNA Drug Sensitivity
Testing has the potential to save tens of
thousands of lives, prevent hundreds of
thousands of serious events that initiate or
extend hospital stays, and save hundreds
of millions of dollars in health care costs.
Fifty-nine percent of drugs most commonly
cited in ADR studies are processed by
enzymes with genes known to have poor
metabolizer variants. This is compared to
7% of a random selection of the top selling
drugs. (JAMA 286:2270 2001).
Currently available tests help predict a
patient's response to many prescription,
OTC (over-the-counter) and herbal
medicines including those used to treat
depression, anxiety, seizures and
psychoses; blood pressure,
anticoagulation and other heart medicines;
anti-diabetic agents, and many pain
relievers.
Many known drug drug interactions are
based on a knowledge of the drug
metabolizing systems that have a high
level of genetic variation. When those
variations are present in individuals taking
more than one drug the chance of having
an adverse drug reaction is greatly
increased.
Hospitalized psychiatric patients who are
poor metabolizers cost $4,000 - $6,000
more in medical care compared to patients
with an average metabolizer genotype.
ALL antidepressants and antipsychotics
are processed by enzymes with a high
incidence of poor metabolizers. Journal of
Clinical Psycopharmacology 20:246 2000
Review – What We Know
• We know that genetic differences can
affect drug response in patients
• We have identified specific SNP’s that
produce specific responses
• We can now identify patients that have
specific Genotypes
• Where do we go from here?
Ideal (future) Genetic Profile
• Integrated within EMR (Inpatient and
Ambulatory)
• Demo recalled
• Audit trail
• Accessible to all caregivers
• Integrated with PHA and POM to provide
Clinical Decision Support
• Database updated by other vendor
supplier
Prototype (current) Genetic Profile
Options
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Integrate within PHA Patient Data Screen
Demo recall on Pharmacy Profile
Audit trail (basic)
Access based on PHA module access
Clinical Decision Support can be Integrated
with PHA and POM by utilizing RULES
• Database updated manually based on
literature review
Current State
• Currently No Genetic Profile Application
/Routines in MEDITECH or LSS
• Limited data available from Formulary
service or Other Vendors
• No Pharamcogenomic data incorporated
into Other Vendor Order Sets
Customer Defined Screen
• Query Types – Group response
• Single query multiple response vs Multiple
Queries with single response
• Single Query easier to maintain but allows
inappropriate selections.
• Multiple queries require additional query
build and screen modifications for added
genetic traits
Prototype (sample) Genetic Profile
WarfarinDosing.com - Profile
Clinical Decision Support Rules
• Suggest ordering appropriate Genetic
Screening – if not already on Genetic
Profile (Include reason for testing )
• Review Genetic Profile and warn user
regarding potential adverse effects (i.e.
Warfarin – bleeding)
• Suggest alternate therapy when
appropriate (i.e. Effient vs Palvix or H2
antagonist vs PPI)
Pharmacogenomic Rules may meet the
“rules” requirement for “Meaningful Use”
Other Clinical Decision Support
• Black box warnings include PGEN
recommendations
• Use Free text headers and reminders to
instruct evidence based PGEN practice
• Use POM Imbedded links to facilitate
reference availability as well as functional
PGEN dosing sites
Dosing Algorithms
• PGEN dosing algorithms are very complex
and must take a number of factors into
consideration
• Currently several vendors are offering
dosing software that utilizes PGEN data
• Future integration will be key to provide
accurate patient dosing
Resources
• www.GeneMedRx.com
• www.warfarindosing.org
IMBEDDED LINKS
OE Order Set Dictionary –
Headers/Reminders
Adding a Link
Remember Lab
Be sure to coordinate efforts for
Pharmacogenetic testing with your Lab
Department. It will be important for the
physicians to be able to order the tests as
recommended in the evidence
Conclusion
As more patients have genetic profiles performed and
more information is available about medications and
their interactions with different genetic profiles, we will be
able to tailor a regimen with specific medications and
doses for the patient based on the patient’s genetic
make-up. This customization will be in addition to other
commonly acceptable variables used today (age, weight,
sex). The Hippocratic Oath states first do no harm. With
genetic testing, many of the worst side effects from
medications may be more predictable and can prevent
patient deaths from occuring.
QUIZ
Name each of the following terms|
1.
2.
3.
4.
5.
SNP
VKORC1
NAT2
TMPT
UGT1A1
Questions?
Bruce.matthias@theingroup.com