Transcript SLCO1B1 - PGXL Laboratories

The Next Generation:
New Genes and Panels at PGXL
Kristen K. Reynolds, PhD
VP Laboratory Operations
Copyright 2012 PGXL Laboratories, Louisville KY
All materials herein are the exclusive property of PGXL Laboratories
2012 Q4 New Genes
CYP3A4/3A5: Statins, benzodiazepines, Ca++ channel blockers
CYP1A2: Antidepressants, antipsychotics
SLCO1B1: Statin-induced myopathy risk
SLC6A4 (Serotonin transporter): SSRI antidepressant sensitivity/resistance
SULT4A1: Olanzapine
OPRM1: Opioid sensitivity/resistance (expected December 2012)
CYP3A4 and CYP3A5
CYP3A4 and 3A5
• Together metabolize 50% of all medications
• 80% redundancy of function
• Genetic variants in each
– decrease enzyme function (clearance)
– Increased risk of dose-dependent adverse events
CYP3A4/5
master
drug list
CYP3A4/CYP3A5 Substrates
PSYCHIATRY
Benzodiazepines
Alprazolam
Xanax
Midazolam
Versed
Triazolam
Halcion
Antipsychotics
Quetiapine
Seroquel
Ziprasidone
Geodon
Buspirone
Buspar
Lurasidone
Latuda
Carbamazepine
Various brands
Antidepressants
Desvenlafaxine
Pristiq
Vilazodone
Viibryd
Trazadone
Desyrel
Nefazadone
Serzone
Reboxetine
Edronax
Nortriptyline
Pamelor, Aventyl
CARDIOLOGY
Quinidine
Ticareglor
Rivaroxaban
Statins
Atorvastatin
Lovastatin
Mevastatin
Simvastatin
Ca Channel Blockers
Amlodipine
Diltiazem
Felodipine
Lercanidipine
Nifedipine
Nisoldipine
Nitrendipine
Verapamil
Various brands
Brilinta
Xarelto
Lipitor
Mevacor, Advicor
Compactin
Zocor, Vytorin, Caduet, Simcor
Norvasc
Cardizem
Plendil
Zanidip
Adalat
Sular
Various brands
Various brands
OTHER
Antimicrobials/antivirals
Clarithromycin
Erythromycin
Telithromycin
Indinavir
Nelfinavir
Ritonavir
Saquinavir
Biaxin
E-Mycin
Ketek
Crixivan
Viracept
Norvir
Fortovase
Steroids
Estradiol
Hydrocortisone
Progesterone
Testosterone
Various brands
Various brands
Various brands
Various brands
Chemotherapeutics
Vincristine
Docetaxel
Oncovin
Taxotere
Pain Management
Cyclobenzaprine
Fentanyl
Alfentanil
Flexaril
Actiq, Duragesic
Alfenta
Immunosuppressants
Cyclosporine
Tacrolimus
Gengraf
Prograf
CYP3A4/5 significant variants
• CYP3A4*22
– Decreased dose requirements for tacrolimus,
cyclosporin, simvastatin, atorvastatin, lovastatin,
midazolam
– 4-8% frequency
• CYP3A5*3
– Decreased dose requirements vincristine, tacrolimus,
cyclosporin
– 90% freq Cauc, 50% AA, 60% Asians
3A4 Interpretation
CYP3A4
Phenotype
Extensive
Metabolizer
CYP3A4
Phenotype
Partially
Decreased
Metabolizer
CYP3A4
Phenotype
Decreased
Metabolizer
CYP3A4
Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Normal metabolic clearance expected. Common CYP3A4 medications below.
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Decreased metabolic clearance expected with increased risk of dose-dependent side
effects. Common CYP3A4 medications below.
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Decreased metabolic clearance expected with increased risk of dose-dependent side
effects. Common CYP3A4 medications below.
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Adjust Dosage
*22
Decreased metabolic clearance expected Simvastatin
Decreased with increased risk of dose-dependent side
Atorvastatin
Metabolizer effects.
Lovastatin
Tacrolimus
Adjustment
max 10-20 mg, or consider
alternative statin if also
SLCO1B1 *5/*5 genotype
max 10-20 mg
max 10-20 mg
decrease by up to 40%
3A5 Interpretation
CYP3A5
Phenotype
Extensive
Metabolizer
CYP3A5
Phenotype
Partially
Decreased
Metabolizer
CYP3A5
Phenotype
Decreased
Metabolizer
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Genotype consistent with the highest baseline enzymatic activity for CYP3A5. Patients with
this genotype represent only 1% of the population. Maintenance dosages for most
CYP3A5 drugs may be at the higher end of the typical dose range. Common CYP3A5
medications below.
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Genotype consistent with intermediate CYP3A5 enzymatic activity and represents
approximately 20% of the population. For PDMs, maintenance dosages for most CYP3A5
drugs are lower than extensive metabolizers and are higher than decreased metabolizers.
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Genotype consistent with reduced CYP3A5 enzymatic activity and represents the majority
(60-80%) of the population. For DMs, maintenance dosages for most CYP3A drugs are
lower than extensive metabolizers. Common CYP3A5 medications below.
SLCO1B1
statin myopathy risk
• Statin therapy reduces risk of CV events
• Statin therapy can lead to muscle weakness
and ultimately muscle breakdown with
rhabdomyolysis
• GWAS studies revealed a single genetic
determinant of statin induced myopathy
N Engl J Med 2008;359:789-99.
SLC01B1
OATP1B1
• ~35% of population are carriers of the SLC01B1*5 allele
– Myalgia/muscle cramps
• Myopathy on 40mg/day:
– SLCO1B1 *1/*5, OR = 2.6
– SLCO1B1 *5/*5, OR = 5.2
• Most frequently associated with simvastatin > atorvastatin
> pravastatin
Vanderbilt Algorithm
Wilke et al. Clin Pharmaco Ther 2012;92(1).
SLCO1B1 Interpretation
SLCO1B1
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Phenotype
No Increased RiskNormal OATP1B1 transporter function. No increased risk of statin-induced myopathy expected at
low to moderate doses (10-40 mg). Consider 10-20 mg dose if also CYP3A4*22 carrier.
SLCO1B1
Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Adjust Dosage
2.6 Fold
Increased
Myopathy
Risk
Reduced OATP1B1 transporter function.
Increased risk of statin-induced myopathy.
Simvastatin
Atorvastatin
SLCO1B1
Phenotype
Adjustment
max 10-20 mg and consider monitoring CK
levels, or consider alternative statin if also
taking verapamil or diltiazem. Consider low
10-20 mg dose of alternative statin if
patient also CYP3A4*22 carrier.
max 10-20 mg
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Avoid
>5 Fold
Increased
Simvastatin
Myopathy Risk
Alternative Consideration
pravastatin, lovastatin,
fluvastatin, rosuvastatin,
mevastatin
Adjust Dosage
Adjustment
Atorvastatin
max 10-20 mg
SLC6A4
serotonin transporter
SLC6A4 Serotonin Transporter
SLC6A4
• 50-60% depressed patients have recurrence and
20% fail 1st line Rx (SSRIs)
– TRD  increased # of Rx, hospitalization risk, costs (19x higher)
• 75% people carry S or LG
• S/S, S/LG, or LG/LG should be considered for non-SSRI
therapies
Antidepressants
2C19
2C19
2D6
2D6,1A2
2D6
2C19
3A4/5
SSRIs
citalopram
escitalopram
fluoxetine
fluvoxamine
paroxetine
sertraline
vilazodone
Celexa
Lexapro
Prozac
Luvox
Paxil
Zoloft
Viibryd
2D6,1A2,3A4/5
2D6,1A2
2D6,2C19
2D6
2D6
2D6,3A4/5
2D6,3A4/5,2C19
TCAs
amitriptyline
clomipramine
desipramine
doxepin
imipramine
nortriptyline
trimipramine
Elavil
Anafranil
Norpramin
Sinequan
Tofranil
Pamelor, Aventyl
Surmontil
2C19
MAOIs
phenelzine
tranylcyromine
isocarboxazid
moclobemide
Nardil
Parnate
Marplan
Black indicates major pathway; Gray indicates minor pathway
SNRIs
2D6,1A2
duloxetine
2D6
venlafaxine
3A4/5
desvenlafaxine
renal
milnacipran
2D6,1A2,3A4/5 mirtazapine
2B6,1A2
3A4/5
3A4/5
2D6
2D6,1A2
3A4/5
Cymbalta
Effexor
Pristiq
Savella
Remeron
Atypicals (NRIs, NDRIs)
bupropion
Wellbutrin
trazadone
Desyrel
nefazadone
Serzone
maprotiline
Ludiomil
mianserin
reboxetine
Edronax
SLC6A4 interpretations
SLC6A4
Phenotype
Normal Responder
SLC6A4
Phenotype
Intermediate Responder
SLC6A4
Phenotype
Poor Responder
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Normal serotonin transporter expression expected. Patients with the LA/LA genotype are
more likely to respond within the first 4 weeks of therapy, achieve remission, and are less
likely to have adverse effects when treated with SSRIs.
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Carriers of S or LG alleles may have decreased serotonin transporter expression compared
to LA/LA subjects. Possible risk of decreased or slower response to SSRIs or increased risk
of adverse events.
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Decreased serotonin transporter expression expected. Risk of decreased response to
SSRI-based therapies and increased risk of adverse events. Consider non-SSRI
antidepressant therapies, such as SNRIs or tricyclic antidepressants alternatives.
CYP1A2
CYP1A2
• Metabolizes many antidepressants and
antipsychotics
• Inducible by several medications and smoking
• Variants cause altered enzymatic activity, particularly
in the presence of an inducer
• Increased risk of having adverse drug reactions or
therapeutic failure to standard dosages of CYP1A2
medications
CYP1A2 master drug list
CYP1A2
Other
Psychiatry
Ropivicaine
Various brands
Olanzapine
Zyprexa
Lidocaine
Various brands
Clozapine
Clozaril
Theophylline
Aerolate
Imipramine
Tofranil
Zolmipitran
Zomig
Clomipramine
Anafranil
Triamterene
Dyrenium
Mirtazapine
Remeron
Flutamide
Eulexin
Bupropion
Wellbutrin
Tizanidine
Zanaflex
Duloxetine
Cymbalta
Tacrine
Cognex
Promazine
Sparine
Cyclobenzaprine
Flexaril
Asenapine
Saphris
Caffeine
17-beta estradiol
1A2 Interpretation
CYP1A2
Phenotype
Normal Inducer
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Normal metabolic clearance expected. Common CYP1A2 medications below.
This patient’s genotype is consistent with normal CYP1A2 enzymatic activity and normal induction in the presence of an inducer, such as tobacco smoke.
CYP1A2*1A/*1A patients with inducers have 30% lower plasma concentrations of CYP1A2 substrates such as olanzapine.
CYP1A2*1A*1A patients without inducers have a 30% increased plasma concentration over those who have inducers present.
CYP1A2
Phenotype
Hyperinducer
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Rapid metabolism expected, especially in smokers. Consider dose increases for
medications inactivated by CYP1A2 particularly in smokers, or alternative medications not
metabolized by CYP1A2. Common CYP1A2 medications below.
CYP1A2 Hyperinducer: Presence of the CYP1A2*1F allele results in the hyperinduction phenotype. Hyperinduction may yield 20-40% higher CYP1A2 activity
compared to the normal *1A allele in the presence of an inducer, such as tobacco smoke. Patients who are homozygous for the CYP1A2*1F/*1F genotype may
exhibit even higher rates of CYP1A2 enzymatic activity and have been described as ultra-rapid metabolizers for olanzapine. As an example, carriers of CY1A2*1F
with the hyperinduction phenotype may exhibit as much as 50% lower than expected plasma levels of olanzapine, clozapine, and haloperidol, which could lead
to sub-therapeutic response. Hyperinducers may require increased dosages of CYP1A2 substrates due to higher than normal rates of drug metabolism in the
presence of an inducer.
CYP1A2
Phenotype
Non-Inducer
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Normal metabolic clearance not affected by inducers. Consider dose decreases for
medications inactivated by CYP1A2 or alternative medications not metabolized by CYP1A2.
Common CYP1A2 medications below.
SULT4A1
psychosis
• PGXL exclusive provider of SULT4A1 marker
(schizophrenia, bipolar disorder)
SULT4A1
• Brain enzyme that interacts with neurochemicals
• Efficacy advantage with olanzapine
Efficacy
Hospitalization
SULT4A1 Interpretations
Gene
THERAPEUTIC IMPLICATIONS (adapted from published resources)
SULT4A1-1 Consider olanzapine. SULT4A1-1 positive patients have been shown to demonstrate
POSITIVE
enhanced treatment efficacy and reduced hospitalization risk when treated with
olanzapine compared to both SULT4A1-1 negative patients treated with olanzapine and
SULT4A1-1 positive patients treated with risperidone.
SULT4A1-1 SULT4A1-1 negative patients treated with olanzapine do not display the expected efficacy
NEGATIVE advantage compared to other atypical antipsychotics.
How do we implement
these new genes?
Panels and specialty-specific focus
Panels*
PGXL Core
Panel:
Thrombophilia
Panel:
CYP2D6
CYP2C9
CYP2C19
CYP3A4
CYP3A5
CYP1A2
Factor V Leiden
Factor II
MTHFR
*All genes always orderable a la carte
Panel Add-Ons
(build specialtyspecific uses):
VKORC1 (warfarin)
SLC6A4 (SSRIs)
SLCO1B1 (statins)
OPRM1 (opioids)
Specialty Requisition Forms
General Practice - DRAFT
Cardiology - DRAFT
Pain Management - DRAFT
OB/GYN - DRAFT
Psychiatry - DRAFT
Psychosis
Depression
PGXL
Depression
Panel
DRAFT
(Panel +
SLC6A4
add-on)
SLC6A4 S/S
SLC6A4
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Phenotype
Poor Responder Decreased serotonin transporter expression expected. Risk of decreased response to SSRIbased therapies and increased risk of adverse events. Consider non-SSRI antidepressant
therapies, such as SNRIs or tricyclic antidepressant alternatives.
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012
Is olanzapine likely to have increased efficacy?
Yes
See SULT4A1
Does consensus data suggest alternatives to risperidone? Yes
See CYP2D6
Are SSRIs likely to have decreased efficacy and increased Yes
risk of side effects?
See SLC6A4
See below for possible dosage considerations.
STA2R Panel
Report
SULT4A1 rs763120 CC rs5764010 TT
SULT4A1-1
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Phenotype
POSITIVE
Consider olanzapine. SULT4A1-1 positive patients have been shown to demonstrate
enhanced treatment efficacy and reduced hospitalization risk when treated with olanzapine
compared to both SULT4A1-1 negative patients treated with olanzapine and SULT4A1-1
positive patients treated with risperidone.
CYP2D6 *4/*4
CYP2D6
Phenotype
Poor Metabolizer
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Avoid
Alternative Consideration
Adjust Dosage
Adjustment
Risperidone†
Venlafaxine†
Amitriptyline†
Quetiapine, olanzapine, clozapine
Citalopram, sertraline
Citalopram, sertraline
Aripiprazole†
Clomipramine†
Doxepin†
Haloperidol†
Imipramine†
Nortriptyline†
Zuclopenthixol†
10 mg/day maximum
Decrease 50%
Decrease 60%
Decrease 50%
Decrease 70%
Decrease 60%
Decrease 50%, or
flupenthixol, quetiapine,
olanzapine, clozapine
SLC6A4 S/S
SLC6A4
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Phenotype
Poor Responder Decreased serotonin transporter expression expected. Risk of decreased response to SSRIbased therapies and increased risk of adverse events. Consider non-SSRI antidepressant
therapies, such as SNRIs or tricyclic antidepressant alternatives.
CYP2C19 *2/*2
CYP2C19
Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Poor Metabolizer
Decreased metabolic clearance expected.
Adjust Dosage Adjustment
Imipramine†
Sertraline†
Decrease 30%
Decrease 50%
CYP1A2 *1F/*1F
CYP1A2
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Phenotype
HYPERINDUCER Rapid metabolism expected, especially in smokers. Consider dose increases for
medications inactivated by CYP1A2 particularly in smokers, or alternative medications.
Common CYP1A2 medications next page.
*Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to
diminished drug clearance.
2D6 master drug List
CYP2D6
Pain Management
Codeine**
Oxycodone**
Hydrocodone**
Tramadol**
Various brands
Oxycontin, various
Various brands
Ultram, various
Cardiology
Carvedilol
Metoprolol
Propanolol
Coreg
Toprol-XL
Inderal, various
Timolol
Propafenone
Flecainide
Blocadren
Rythmol
Tambocor
Clomipramine
Desipramine
Doxepin
Imipramine
Nortriptyline
Claritin
Aricept
Various brands
Various brands
Trimipramine
Other
Loratadine
Donepezil
Dextromethorphan
Tamoxifen**
** indicates prodrug
Psychiatry
Antidepressants
Fluoxetine
Fluvoxamine
Paroxetine
Venlafaxine
Duloxetine
Maprotiline
Mirtazapine
Amitriptyline
Prozac
Luvox
Paxil
Effexor
Cymbalta
Ludiomil
Remeron
Various
brands
Ananfranil
Norpramin
Sinequan
Tofranil
Pamelor,
Aventyl
Surmontil
Antipsychotics
Haloperidol
Risperidone
Aripiprazole
Zuclopenthixol
Perphenazine
Thioridazine
Iloperidine
Chlorpromazine
Haldol
Risperidol
Abilify
Various brands
Trilafon
Mellaril
Fanapt
Thorazine
Atomoxetine
Amphetamine
Strattera
Adderall
2C19 and 2C9 master drug lists
CYP2C19
Clopidogrel**
Citalopram
Escitalopram
Imipramine
Sertraline
Diazepam
Omeprazole
Esomeprazole
Pantoprazole
Rabeprazole
Lansoprazole
Nelfinavir
Methadone
Carisoprodol**
Voriconazole
Plavix
Celexa
Lexapro, various
Tofranil
Zoloft
Valium
Prilosec
Nexium
Protonix
Aciphex
Prevacid
Viracept
Various brands
Soma
Vfend
CYP2C9
Warfarin
Celecoxib
Ibuprofen
Naproxen
Glyburide
Glipizide
Tolbutamide
Glimepiride
Phenytoin
Fluvastatin
Rosuvastatin
Losartan
Coumadin
Celebrex
Advil, Motrin
Aleve
Diabeta
Glucotrol
Orinase
Amaryl
Dilantin
Lescol
Crestor
Cozaar
Cliff Notes on the Portal
CYP3A4
CYP3A4 is a liver enzyme that, in concert with CYP3A5, metabolizes approximately 50% of medications,
including many of the statins, benzodiazepines, antibiotics, and antipsychotics. Detecting variants of the
CYP3A4 gene that cause altered enzymatic activity can identify patients who may be at increased risk of
having adverse drug reactions while taking standard dosages of 3A4 substrates. Roughly 4-10% of the
general population possesses inherited differences in 3A4 that cause decreased metabolism. These
Decreased Metabolizers may be at increased risk for dose-dependent side effects to drugs normally
inactivated by 3A4.
SLCO1B1
SLCO1B1 is the gene that makes a liver enzyme called OATP1B1, which helps transport statins
medications into the liver more effectively. Roughly 15% of the population possesses the *5 variant, an
inherited form of SLOC1B1 which increases risk of statin-induced muscle damage, or myopathy, by 3 to 5
fold. Risk of myopathy with the *5 variant is most closely associated with simvastatin and to a lesser
extent, atorvastatin. Patients with the *5 variant may need the lowest doses of simvastatin or an
alternative statin to reduce risk of myopathy.
SLC6A4
SLC6A4 is the gene that makes the serotonin transporter in the brain. The role of the serotonin
transporter is to shuttle the potent brain chemical serotonin from one neuron to another. Inhibiting
serotonin transport is associated with improved mood; thus the effectiveness of many antidepressant
drugs (namely selective serotonin reuptake inhibitors, SSRIs) is thought to be due to their inhibition of
the serotonin transporter. Nearly 75% of people have an inherited form of the SLC6A4 gene that can
lead to decreased response to SSRI therapy. The Short (S) and Long G (LG) forms of the transporter are
associated with delayed response to SSRI antidepressants and increased risk of adverse drug reactions
(ADRs) during antidepressant therapy. Patients who possess two copies of the S or LG forms may be
more likely to benefit from non-SSRI therapies.
Questions?
Thank You!
[email protected]
CYP2D6 *4/*4
CYP2D6
Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Poor Metabolizer
Avoid
Codeine**
Hydrocodone**
Oxycodone**
Tramadol**
Tamoxifen**
Amitriptyline †
Venlafaxine †
Risperidone †
Alternative Consideration
Adjust Dosage
Adjustment
Morphine, non-opioid
Hydromorphone, non-opioid
Oxymorphone, non-opioid
Consider active drug, non-opioid
Anastrozole, exemestane, letrozole
Citalopram, sertraline
Citalopram, sertraline
Quetiapine, olanzapine, clozapine
Aripiprazole †
10 mg/day maximum
decrease 50%
decrease 60%
decrease 50%
decrease 50%
decrease 70%
decrease 60%
decrease 70%
decrease 75%, or
atenolol, bisoprolol,
carvedilol
decrease 50%, or
flupenthixol, quetiapine,
olanzapine, clozapine
Clomipramine †
Doxepin †
Flecainide †
Haloperidol †
Imipramine†
Nortriptyline †
Propafenone †
Metoprolol †
Zuclopenthixol †
*Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to diminished
drug clearance.
CYP2D6 Poor Metabolizer (PM): This patient’s genotype is consistent with a lack of
CYP2D6 enzymatic activity. PMs are at increased risk of drug-induced side effects due to
diminished drug elimination of active drugs or lack of therapeutic effect resulting from
failure to generate the active form of the drug, as is the case with pro-drugs.
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012
RESULTS
Gene
X CYP2D6
*4/*4
THERAPEUTIC IMPLICATIONS (adapted from published resources
Phenotype
Poor
Metabolizer
Avoid
Codeine*
Hydrocodone*
Oxycodone*
Tramadol*
Normal metabolic clearance expected.
Oxycodone*
Hydrocodone*
†
Propafenone
Oxymorphone, non-opioid
Hydromorphone, non-opioid
Sotalol, disopyramide,
quinidine, amiodarone
Quetiapine, olanzapine,
clozapine
Citalopram, sertraline
Codeine*
Tramadol*
Tamoxifen*
Morphine, non-opioid
Hydromorphone, non-opioid
Oxymorphone, non-opioid
Citalopram, sertraline
Citalopram, sertraline
Citalopram, sertraline
Methylphenidate
Quetiapine, olanzapine,
clozapine
Flupenthixol, quetiapine,
olanzapine, clozapine
Sotalol, disopyramide,
quinidine, amiodarone
Tramadol*
†
Imipramine
†
Nortriptyline
†
Venlafaxine
Amitriptyline
†
Venlafaxine
†
Risperidone
 CYP2D6
*1/*1
! CYP2D6
*1/*4
Extensive
Metabolizer
Intermediate
Metabolizer
Risperidone
†
†
†
Velafaxine
X CYP2D6
*1/*1xN
Ultra-Rapid
Metabolizer
)
Adjustment
10 mg/day maximum
50%
60%
50%
50%
70%
60%
70%
75%, or atenolol, bisoprolol,
carvedilol
†
Zuclopenthixol
50%, or flupenthixol,
quetiapine, olanzapine,
clozapine
Common CYP2D6 medications next page
Tamoxifen*
Codeine*
Hydrocodone*
Oxycodone*
†
Amitriptyline
†
Clomipramine
†
Paroxetine
†
Atomoxetine
†
Risperidone
Zuclopenthixol
Propafenone
†
†
Alternative Consideration
Morphine, non-opioid
Hydromorphone, non-opioid
Oxymorphone, non-opioid
Consider active drug, nonopioid
Anastrozole, exemestane,
letrozole
Citalopram, sertraline
Citalopram, sertraline
Quetiapine, olanzapine,
clozapine
1,4,6
Adjust Dosage
†
Aripiprazole
†
Clomipramine
†
Doxepin
†
Flecainide
†
Haloperidol
†
Imipramine
†
Nortriptyline
†
Propafenone
†
Metoprolol
†
Amitriptyline
†
Imipramine
†
Nortriptyline
†
Zuclopenthixol
†
Doxepin
†
Flecainide
†
Metoprolol
Haloperidol
†
†
Doxepin
†
Metoprolol
15-60 mg/hr
titrate to pain relief
Avoid CYP2D6 inhibitors, e.g.
paroxetine, or consider
aromatase inhibitor in postmenopausal women
25%
30%
40%
25%
20%
25%
50%, or atenolol, bisoprolol,
carvedilol
30%
70%
60%
150%, or citalopram,
sertraline
based on plasma
measurement, or pimozide,
flupenthixol, fluphenazine,
quetiapine, olanzapine,
clozapine
100%
up to 250%, or atenolol,
bisoprolol, carvedilol
2C19
CYP2C19 *1/*2
CYP2C19
Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Intermediate
Metabolizer
Avoid
Alternative Consideration Adjust Dosage Adjustment
Clopidogrel**
Prasugrel
Imipramine†
Sertraline†
Caution, consider decrease
30%
Caution, consider decrease
30%
*Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to diminished drug
clearance.
CYP2C19 Intermediate Metabolizer (IM): This patient’s genotype is consistent with
reduced CYP2C19 enzymatic activity. IMs are at slightly increased risk of drug-induced side
effects due to diminished drug elimination of active drugs. Patients with reduced CYP2C19
function (IMs) taking clopidogrel may exhibit suboptimal drug activation and may have
increased risk for cardiovascular events compared to CYP2C19 extensive metabolizers.
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012
2C19 all
†
Caution, consider 30%
Caution, consider 50%
†
30%
50%
! CYP2C19
*1/*2
Intermediate
Metabolizer
Clopidogrel*
Prasugrel
Imipramine
†
Sertraline
X CYP2C19
*2/*2
Poor
Metabolizer
Clopidogrel*
Prasugrel
Imipramine
†
Sertraline
X CYP2C19
*17/*17
Ultra-Rapid
Metabolizer
Increased metabolic clearance expected. Possible
7
increased risk of bleeding events with clopidogrel .
 CYP2C19
*1/*1
Extensive
Metabolizer
Normal metabolic clearance expected.
Citalopram
up to 150%
†
Escitalopram
up to 150%
†
Omeprazole
100-200%
†
Esomeprazole
50-100%
†
Lansoprazole
200%
†
Pantoprazole
400%
Common CYP2C19 medications next page
! CYP2C19
*2/*17
Or *3/*17
Intermediate
∫
Metabolizer
Decreased metabolic clearance expected based on
presence of the inactive allele.
Imipramine
†
Sertraline
†
†
Caution, consider 30%
Caution, consider 50%
CYP2C9 *1/*2
CYP2C9
Phenotype
Intermediate
Metabolizer
VKORC1 GG
VKORC1
Phenotype
Low warfarin
sensitivity
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Decreased metabolic clearance expected.
Adjust Dosage
Adjustment
Phenytoin†
Warfarin†
decrease 25%
See below
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Estimated warfarin maintenance dose requirement: 6.20 mg/day‡
Estimated time to steady-state: Delayed, 8-11 days
INRs measured before steady state blood concentrations have been achieved should be interpreted
with caution as they may not be indicative of stable therapy.
**Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to diminished drug
clearance.
CYP2C9 Intermediate Metabolizer (IM): This patient’s genotype is consistent with reduced CYP2C9 enzymatic activity. Reduced CYP2C9
activity leads to lower warfarin dose requirement due to decreased clearance, increased elimination half-life, and increased time to reach
steady-state blood concentrations. The time to reach steady-state affects the timing of INR measurement for optimal interpretation. Time to
reach steady-state is the time period required for the dosage to consistently yield reproducible blood concentrations of warfarin. INR
measurements are most reliable when measured after steady-state has been achieved. INR measurements before steady-state blood
concentrations have been achieved should be interpreted with caution, as they may not be indicative of stable therapy.
VKORC1 Low Warfarin Sensitivity: This patient’s genotype is consistent with higher VKORC1 enzyme expression and higher warfarin dose
requirement.
‡The warfarin maintenance dose estimate was derived using a published formula that accounts for age, gender, weight, and CYP2C9 and
VKORC1 genotypes. This estimate should be viewed as an example of how this information can be taken into consideration by the physician
as part of the overall patient management strategy.
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012
All warf possible
 CYP2C9
*1/*1
Extensive
Metabolizer
Normal metabolic clearance expected.
Common CYP2C9 medications next page. For
warfarin see below.
! CYP2C9
*1/*3
Intermediate
Metabolizer
Decreased metabolic clearance expected.
Phenytoin
†
Warfarin
†
25%
See below
X CYP2C9
*3/*3
Poor
Metabolizer
Decreased metabolic clearance expected.
Phenytoin
†
Warfarin
†
50%
See below
High warfarin
sensitivity
Estimated warfarin maintenance dose requirement: 4.1 mg/day
Estimated warfarin time to steady-state: Average, 6-9 days (flex CYP2C9-specific times)
INRs measured before steady state blood concentrations have been achieved should be interpreted with
caution as they may not be indicative of stable therapy.
‡
Estimated warfarin maintenance dose requirement: 4.6 mg/day
Estimated time to steady-state: Delayed, 8-11 days (flex CYP2C9-specific times)
INRs measured before steady state blood concentrations have been achieved should be interpreted with
caution as they may not be indicative of stable therapy.
‡
Estimated warfarin maintenance dose requirement: 5.6 mg/day
Estimated time to steady-state: Delayed, 12-15 days (flex CYP2C9-specific times)
INRs measured before steady state blood concentrations have been achieved should be interpreted with
caution as they may not be indicative of stable therapy.
X VKORC1
AA
 VKORC1
AG
! VKORC1
GG
Intermediate
warfarin
sensitivity
Low warfarin
sensitivity
‡
X Factor V
Leiden
AA
! Factor II
GA
X MTHFR
677 TT
1298 AA
>9 fold
Increased
Thrombosis
Risk
Positive family history of thrombotic events: avoid
estrogen-containing oral contraceptives and consider
alternative contraceptive (e.g., IUD or progestin-only
contraceptive).
Negative family history of thrombotic events:
avoid additional risk factors (e.g., obesity,
smoking).
2-3 fold Increased Thrombosis Risk
Increased
Risk
Increased risk of hyperhomocysteinemia, coronary artery disease, and thrombosis when folate deficiency is
present. Consider folate supplementation.
Factor V Leiden High Thrombosis Risk: This genotype result revealed that the patient is homozygous for (has two copies of) the
Factor V Leiden (1691 G>A) variant, which has been associated with an increased risk of thromboembolic events.
This variant is found in approximately 4% of individuals in the U.S. Presence of the Factor V Leiden variant increases the risk of
venous thromboembolism (VTE) by 3-8 fold in heterozygous carriers and >9 fold in homozygous carriers.
Factor II Moderate Thrombosis Risk: This genotype result revealed that the patient is heterozygous for (has one copy of) the Factor
II (Prothrombin) 20210 G>A variant, which has been associated with an increased risk of thromboembolic events. This variant is
found in approximately 2% of individuals in the U.S. Presence of the Factor II 20210G>A variant increases the risk of venous
thromboembolism (VTE) by 2-3 fold in heterozygous carriers and >3 fold in homozygous carriers.
MTHFR Increased Risk: Presence of the 677 C>T polymorphism of MTHFR leads to decreased MTHFR enzymatic activity and elevated
homocysteine. This patient’s genotype is consistent with an increased risk of hyperhomocysteinemia, atherosclerotic heart disease,
myocardial infarction, cerebrovascular disease, and venous thrombosis. Additionally, associations between the 677 C>T polymorphism
and increased risk for methotrexate toxicity, increased 5-fluorouracil chemosensitivity, and increased risk of fetal neural tube defects in
pregnant women have also been reported in states of folate deficiency.
 Factor V
Leiden
GG
! Factor V
Leiden
GA
X Factor V
Leiden
AA
 Factor II
GG
No Increased Thrombosis Risk
3-8 fold
Female, Positive family history of thrombotic events:
Increased
avoid estrogen-containing oral contraceptives and
Thrombosis
consider alternative contraceptive (e.g., IUD or
Risk
progestin-only contraceptive).
>9 fold
Positive family history of thrombotic events: avoid
Increased
estrogen-containing oral contraceptives and consider
Thrombosis
alternative contraceptive (e.g., IUD or progestin-only
Risk
contraceptive).
No Increased Thrombosis Risk
Female, Negative family history of thrombotic
events: avoid additional risk factors (e.g., obesity,
smoking).
Negative family history of thrombotic events:
avoid additional risk factors (e.g., obesity,
smoking).
! Factor II
GA
2-3 fold Increased Thrombosis Risk
X Factor II
AA
>3 fold Increased Thrombosis Risk
 MTHFR
677 CC
1298 AA
 MTHFR
677 CC
1298 AC
 MTHFR
677 CC
1298 CC
 MTHFR
677 CT
1298 AA
 MTHFR
677 CT
1298 AC
 MTHFR
677 CT
1298 CC
X MTHFR
677 TT
1298 CC
X MTHFR
677 TT
1298 AC
X MTHFR
677 TT
1298 AA
No Increased Risk of hyperhomocysteinemia, coronary artery disease, or thrombosis
No Increased Risk of hyperhomocysteinemia, coronary artery disease, or thrombosis
No Increased Risk of hyperhomocysteinemia, coronary artery disease, or thrombosis
No Increased Risk of hyperhomocysteinemia, coronary artery disease, or thrombosis
No Increased Risk of hyperhomocysteinemia, coronary artery disease, or thrombosis
No Increased Risk of hyperhomocysteinemia, coronary artery disease, or thrombosis
Increased
Risk
Increased risk of hyperhomocysteinemia, coronary artery disease, and thrombosis when folate deficiency is
present. Consider folate supplementation.
Increased
Risk
Increased risk of hyperhomocysteinemia, coronary artery disease, and thrombosis when folate deficiency is
present. Consider folate supplementation.
Increased
Risk
Increased risk of hyperhomocysteinemia, coronary artery disease, and thrombosis when folate deficiency is
present. Consider folate supplementation.