Transcript CYP2D6 - PGXL Laboratories

Brad Esarey
VP Business Operations
A need for
Personalized
Medicine
PGx Integration:
Role of the Clinical Laboratory
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Catalyze the delivery of biotechnology products to
healthcare consumers
Overcome barriers to genotyping
Develop genetic profiling strategies to maximize
sensitivity and specificity of predicting phenotype
Provide availability of testing
Develop methods to reduce technical difficulty, cost
Improve interpretations
Pharmacogenetics
Links differences in gene structure
(inherited polymorphism) to drug
metabolism and response
Genetic
Drug metabolism
polymorphism
& response
(Genotype)
(Phenotype)
Why is this important ?
~60% of meds in top 20
list causing ADRs are
linked to a genetic
variation
122 drugs have FDA box
warnings related to
genetics
Explanatory Use
Predictive Use
Decision for
Drug Treatment
Decision for
Drug Treatment
Standard Drug
and Dose
CYP Genotyping
Dose Adjustment According
to Efficacy and Adverse Events
Drug Selection and Dosage
Based on Genotype
Therapy Refractoriness
or Adverse Events
CYP Genotyping
Further Adjustment According
to Efficacy and Adverse Events
PGXL Enables Transformation
Intuitive
Medicine
Precision
Medicine
Indicators Suggest: Diagnostic services will trump therapeutics (Clayton M
Christenson in: The Innovator’s Prescription, MacGraw Hill, 2009)
Applications of
pharmacogenomics
• Individualizing drug therapy
selection
• Predicting adverse reactions,
dosing, response
• Identify increased sensitivity to drug
interactions
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Clinical Applications of Pharmacogenetic
Information
• Anti-coagulation
– Warfarin
– Plavix (clopidogrel)
• Psychiatry
– Anti-depressants
• Oncology
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– KRAS
– Tamoxifen
– EGFR’s
• Pain management
– Codeine
– Hydrocodone
– Oxycodone
Medications and metabolic pathways
CYP2C9
CYP2C19
CELECOXIB
IBUPROFEN
NAPROXEN
GLYBURIDE
GLIPIZIDE
TOLBUTAMIDE
GLIMEPIRIDE
PHENYTOIN
FLUVASTATIN
LOSARTAN
CELEBREX
ADVIL, MOTRIN
ALEVE
DIABETA
GLUCOTROL
ORINASE
AMARYL
DILANTIN
LESCOL
COZAAR
CYP2C9/VKORC1
WARFARIN
COUMADIN
CLOPIDOGREL
CITALOPRAM
ESCITALOPRAM
IMIPRAMINE
SERTRALINE
OMEPRAZOLE
ESOMEPRAZOLE
PANTOPRAZOLE
RABEPRAZOLE
LANSOPRAZOLE
DIAZEPAM
NELFINAVIR
PLAVIX
CELEXA
VARIOUS BRANDS
TOFRANIL
ZOLOFT
PRILOSEC
NEXIUM
PROTONIX
ACIPHEX
PREVACID
VALIUM
VIRACEPT
Medications and CYP2D6 metabolic pathway
ANTIDEPRESSANTS
AMITRIPTYLINE
CLOMIPRAMINE
DESIPRAMINE
DOXEPIN
IMIPRAMINE
NORTRYPTYLINE
VARIOUS BRAND NAMES
ANAFRANIL
NORPRAMIN
SINEQUAN
TOFRANIL
PAMELOR, AVENTYL
ANTI-PSYCHOTICS SSRI’S
ARIPIPRAZOLE
FLUOXETINE
MAPROTOLINE
PAROXETINE
RISPERIDONE
ABILIFY
PROZAC
LUDIOMIL
PAXIL
RISPERIDOL
BETA-BLOCKERS
CARVEDILOL
METOPROLOL
PROPANOLOL
COREG
TOPROL-XL
VARIOUS BRAND NAMES
OPIOIDS
CODEINE
OXYCODONEOXYCONTIN
HYDROCODONE
DESTROMETHORPHAN
TRAMADOL
NAMES
CODEINE PHOSPHATE
VARIOUS BRAND NAMES
VARIOUS BRAND NAMES
ULTRAM, VARIOUS BRAND
SNRI’S
ATOMOXETINE
VENLAFAXINE
STRATTERA
EFFEXOR
OTHERS
DONEPEZIL
FLECANIDE
FLUVASTATIN
LORATIDINE
PROPAFENONE
TAMOXIFEN
ARICEPT
TAMBOCOR
LESCOL
CLARITIN
RYTHMOL
VARIOUS BRAND NAMES
Vision: enable transition of pharmacogenetic
diagnostics into actionable healthcare results
Mission and Core Business Strategies:
• Provide Clinical Diagnostic Services
(healthcare providers for direct patient care)
• Support Development of Diagnostics
(discovery & translation of biological markers)
Product Lines
Cardiovascular:
Pain Management:
- Opiods
- Anticoagulation
- HTN/CHF
Oncology:
- Cancer therapy
- Prevention
Respiratory:
- Asthma
- COPD
PGXL is uniquely positioned
Behavioral Health:
- ADHD
- Schizophrenia
- Depression
Current Test Menu
MOLECULAR ONCOLOGY
- CYP2D6 tamoxifen
- KRAS
- BRAF
-BCR/ABL (quantitative)
-
BCR/ABL Kinase Domain mutations
JAK2 (quantitative)
BCL1
BCL2
PML-RARα
c-KIT
EGFR
EGFR (FISH)
HER2/neu (FISH)
ALK (FISH)
DPD/TYMS
TPMT
PHARMCOGENETICS
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CYP1A2
CYP2C9
CYP2C9/VKORC1
CYP2C19
CYP2D6
NAT2
HLA-B*1502 Carbamazepine sensitivity
HLA-B*5701 Abacavir sensitivity
5-HTTLPR Serotonin Transporter
MTHFR
Factor II (Prothrombin 20210 G>A)
Factor V Leiden
Hepatitis-B Virus DNA Quantitative
THERAPEUTIC DRUG MONITORING
- MPA,serum
- MPA + MPA-G, serum
PGx of Warfarin Overview
• Quick review of the problem
• Review of Pharmacokinetic Basics
• Application of knowledge
FDA Updates Coumadin Label
Genetic Information may improve initial dosing estimate for individual
patients
The U.S. Food and Drug Administration announced today the
approval of updated labeling for the widely used blood-thinning drug,
Coumadin, to explain that people's genetic makeup may influence
how they respond to the drug.
The labeling change highlights the opportunity for healthcare
providers to use genetic tests to improve their initial estimate of what
is a reasonable warfarin dose for individual patients. Testing may
help optimize the use of warfarin and lower the risk of bleeding
complications from the drug.
U.S. Food and Drug Administration August 16, 2007
Reynolds K et al. Pers Med 2007;4(1):11-31.
• Pharmacogenetics of Warfarin
– Inactivated and eliminated via Cytochrome
P4502C9 metabolism
• 40% of populations have deficient CYP2C9
– Inhibits Vitamin K epoxide reductase complex
• > 70% of population have decreased VKOR and
are more sensitive to warfarin
• Dose effectiveness
should be assessed
at steady-state
3.00
S-Wa rfa rin (m g/L)
• CYP2C9 *2 and *3
– delay time to reach
steady-state
– Increase blood
concentration
2.40
CYP2C9*1/*3
1.80
CYP2C9*1/*2
1.20
0.60
CYP2C9*1/*1
0.00
0
3
6
9
12
15
18
Time (days)
Linder et al. J Thrombosis & Thrombolysis
2002;14:227-232
Confidential
21
24
27
30
Variables influencing maintenance dose.
Optimal WARFARIN dose can be calculated based on AGE, GENDER,
WEIGHT and PHARMACOGENETICS
Zhu Y et al. Clin Chem 2007;53(7):1199-1205.
Impact of Testing
• Estimate Maintenance Dose Requirement
Guides dose selection
• Estimate of Time to Reach Steady-state
Avoid Mis-interpretation of INR’s
Avoid Premature Dosage Changes
© Copyright 2007 Pharmacogenetics Diagnostic Laboratory, LLC. All rights reserved. Duplication of material prohibited.
Application of
Pharmacogenomics to
Anti-platelet therapy
Antiplatelet Response
• Clopidogrel (Plavix) is a pro-drug which is
converted to an active metabolite by
hepatic cytochrome P4502C19
(CYP2C19).
• ~ 30% of patients have deficiency in
CYP2C19
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Influence of CYP2C19 on Clopidogrel
Response
Incidence of Adverse events in patients prescribed standard dosages of
Clopidogrel by CYP2C19 Phenotype.
PHENOTYPE
Stent Thrombosis
EM
CV death, MI,
Ischemic Stroke
8%
(BASELINE)
8.9%
1.4%
IM
10%
2.4%
PM
12.7%
5.7%
Mega et.al., JAMA. 2010;304(16);1821-1830.
0.9%
Applications of PGx in Pain
Management
• Pharmacokinetics: genetic variation in
cytochrome P450’s
– Decreased drug clearance
• Mis-interpretation of over compliance
– Ultra-rapid drug clearance
• Mis-interpretation of drug diversion
• Mis-interpretation of poor compliance
Cytochrome P4502D6 Substrates
• Pain management
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Hydrocodone
Oxycodone
Methadone
Propoxyphene
Codeine
Others ….
• In addition many drugs commonly co-prescribed
with pain management medications
– Antidepressants
– Anti-anxiety
Genetic polymorphism of CYP2D6
• Ultra-rapid metabolizers (UM)
– 3 – 7 % of population
• Extensive metabolizers (EM)
– 55 – 60 % of population
• Intermediate metabolizers (IM)
– 25 – 30% of population
• Poor Metabolizers (PM)
– 5 – 10 % of population
Example: Codeine
• Principal metabolism by CYP2D6
• Pro-drug to morphine
• CYP2D6 PM: in adequate morphine
• CYP2D6 UM: morphine poisoning
Case Report:
Neonatal Morphine Overdose
• Full-term healthy male infant showed intermittent
periods of difficulty in breastfeeding and lethargy
starting on day 7
• Day 11 pediatric visit baby regained birth weight
• Day 12 gray skin and milk intake had fallen
• Baby found dead on day 13
• Postmortem analysis showed no anatomical
anomalies
Koren et al. Lancet 2006;368:704.
Toxicology Results
• Blood concentration of morphine = 70 ng/mL
– neonates breastfed by mothers receiving codeine typically
have morphine serum concentrations of 0–2.2 ng/mL
• Day 10 breast milk morphine concentration = 87 ng/mL
– Typical range after repeated maternal codeine doses of 60
mg every 6 h is 1.9–20.5 ng/mL
• The mother was prescribed 2 weeks codeine 30 mg +
acetaminophen 500 mg (Tylenol #3) after birth for
episiotomy pain
– 4 tabs first day, but only 2 tabs daily thereafter because of
maternal somnolence and constipation
Koren et al. Lancet 2006;368:704.
CYP2D6 Genotype Analysis
CYP2D6 *1/*2xN
(gene duplication)
=
Ultra-rapid Metabolizer
(UM)
• Leads to increased formation of morphine from codeine
• Maternal grandfather, the father, and the infant had 2
functional CYP2D6 alleles (Extensive Metabolizer, EM)
• The maternal grandmother was a UM
Koren et al. Lancet 2006;368:704.
Clinical Case Conclusions
• The clinical and laboratory picture was consistent
with neonatal death from opioid toxicity
• Most of the analgesic and CNS depressant
effects of codeine are secondary to its
metabolism to morphine by CYP2D6
• Neonates invariably have impaired capacity to
metabolize and eliminate morphine
Koren et al. Lancet 2006;368:704.
Case Conclusions, cont’d
• Codeine is a commonly used analgesic after labor
– Episiotomy
– Caesarean section
• American Academy of Pediatrics lists codeine as
compatible with breastfeeding, despite lack of sufficient
published data to support this recommendation
• Inherited differences in CYP2D6 can be life-threatening
for some breastfed babies
“Codeine cannot be considered as a safe drug for all infants
during breastfeeding”
• CYP2D6 UM frequency
– 1.5 - 2% in Caucasians and Asians
– 14% in African Americans
– 29% in Ethiopians
Koren et al. Lancet 2006;368:704.
Strategies to manage breastfeeding while on codeine
Action
Avoid codeine; use
alternative
Advantages
Avoids potential
neonatal toxicity
Disadvantages
Potential uncontrolled
pain
Minimizes potential
Avoid high-dose
codeine (240mg/d) for neonatal toxicity
more than a few days
Uncontrolled pain;
dose still too high for
UMs
Avoid breastfeeding Avoids potential
neonatal toxicity
while on codeine
Inform and monitor Early Intervention and
prevention of serious
for signs of opioid
toxicity
toxicity
Loss of breastfeeding
benefits
Genotype mothers
for CYP2D6
Parental anxiety and
false-positive toxicity
Predicts risk of excess Expensive, not
morphine production
presently routine
Adapted from Koren et al. Lancet 2006;368:704.
CYP2D6 Genotyping
Routine CYP2D6 testing IS available
Metabolizer status (phenotype)
can be predicted
Predicts risk of toxicity, therapeutic failure, and
promotes optimal outcomes for patients
Other CYP2D6 Genotyping
Considerations
• CYP2D6 metabolizes 20-25% of all current
medications
• CYP2D6 inactivates medications
– antidepressants, antipsychotics, beta- blockers, antiarrhythmics
• CYP2D6 activates medications
– opioids, tamoxifen
• CYP2D6 is inhibited by medications
– antidepressants (SSRIs in particular), antipsychotics, certain
antimicrobials, quinidine, amiodarone
• CYP2D6 is induced by medications
– rifampin, carbamazepine, phenobarbital, ritonavir
Consultation Services
• PGXL provides state-of-the-art interpretive reports with
actionable guidance
• PGXL medical directors are available for clinical
consultation with ordering practitioners before and after
testing
• Ongoing VIP review consultation after 50-100 patients
tested
• Educational lecture series and/or CME events as needed
Diagnostic Testing
• Clinical testing is available
• Must be performed by high-complexity
CLIA-certified laboratory
• 5-7 business day TAT
• Whole blood or cheek swab samples
• Genotype result with phenotype
interpretation
Patient Information: Genetic Drug Sensitivity Testing
Why test my genes before prescribing a drug?
Just as gene variation controls hair or eye color, it also controls how the body reacts to certain drugs. Before
prescribing one of those drugs, your physician may give you a genotype test to make sure the drug will be safe and
effective for you. A genotype is an analysis of some aspect of your genetic make-up. Knowing your genotype will
help you and your doctor choose the most effective treatment path.
What is CYP450?
CytochromeP450, abbreviated CYP450, is a complex of genes that controls liver enzymes that digest certain
drugs. Those drugs include Plavix®, Coumadin®, warfarin, beta blockers, common pain medications and
antidepressants, among many others. Different genes within the CYP450 complex control the metabolization of
different drugs. CYP2C19, for example, indicates Plavix sensitivity, and CYP2C9 is commonly analyzed before
prescribing Coumadin/warfarin.
What will the test tell me?
Specifically, how quickly your body filters a given drug out of your bloodstream. A high metabolizer flushes drugs
out of the body quickly, and might never realize any benefit from taking a “normal” dose. A poor metabolizer is just
the opposite, with a “normal” dose building to potentially dangerous levels. Understanding how quickly you will
metabolize a drug helps your doctor calculate the safest, most effective dose for you.
What is required to perform this test?
You will need to provide a DNA sample using a buccal swab. A buccal swab is a sterile cotton swab made for DNA
collection. You gather DNA simply and painlessly by rubbing the buccal swabs on the insides of your cheeks. The
swabs are then sealed and shipped to the lab for testing.
What happens to my DNA once the test is complete?
Your privacy is assured. Samples and genetic information are stored securely in accord with HIPAA and other
government regulations.
Is there a cost for this test?
This is a routine clinical laboratory test covered by Medicare and most private insurance plans. There may be a copay, depending on the specifics of your policy.
How do I get my test results?
Results will be sent to your doctor 3-5 business days after your sample is collected.
All tests are performed by PGXL Laboratories, Louisville, KY – 877-564-2199 – CLIA License 18D0983143.
The Actual In-service
DON’T
DO’S
• Four swabs per test
• One swab at a time
• Two swabs per
cheek
• Thirty seconds per
swab
• One minute dry
•
•
•
•
Blood is ok
Swabs in envelope
Envelopes in Ziploc
Forms in Pouch
QUESTIONS?
THANK YOU!