Download PGXL-Multidrug-report-example-11172014

PGXL
Laboratories
201 E. Jefferson
Street
Louisville, KY 40202
Phone: (502) 569-1584 Laboratory Director:
Linder PhD
CLIA#: 18D0983143
KY State License #:
200251 [email protected]
Mark W.
Sex: M
PGXL Laboratories
Name: Test, Patient
Example, Physician
DOB: 7/15/1955 Age: 59 Accession
Client ID #:
#: PG-14-01698
Client: PGXL Laboratories
Collected: 11/14/2014
Received: 11/17/2014
Reported: 11/17/2014
Specimen Type : Buccal Swab
Reason for Referral : Depression
Final PGXL Interpretive Report
Therapeutic implications adapted from published resources:
CYP2D6 phenotype:
POOR METABOLIZER
Avoid:
Alternative Considerations:
Adjust Dosage:
Adjustment:
Codeine**
Morphine, non-opioid
Aripiprazole†
decrease 50%
Hydrocodone**
Hydromorphone, non-opioid
Clomipramine†
decrease 50%
Oxycodone**
Oxymorphone, non-opioid
Doxepin†
decrease 60%
Tramadol**
Consider active drug, non-opioid
Flecainide†
decrease 50%
Tamoxifen**
Anastrozole, exemestane, letrozole
Haloperidol†
decrease 50%
Amitriptyline†
Citalopram, sertraline
Imipramine†
decrease 70%
Venlafaxine†
Citalopram, sertraline
Nortriptyline†
decrease 60%
Risperidone†
Quetiapine, olanzapine, clozapine
Propafenone†
decrease 70%
Metoprolol†
decrease 75%, or atenolol,
bisoprolol
Vortioxetine†
maximum 10mg/day
Zuclopenthixol†
decrease 50%, or flupenthixol
quetiapine, olanzapine,
clozapine
CYP2C19 phenotype:
POOR METABOLIZER
Avoid:
Alternative Considerations:
Adjust Dosage:
Adjustment:
Clopidogrel**
Prasugrel, Ticagrelor
Citalopram†
Maximum 20mg/day
Imipramine†
decrease 30%
Sertraline†
decrease 50%
CYP2C9 phenotype:
INTERMEDIATE METABOLIZER
Decreased metabolic clearance
Adjust Dosage:
Adjustment:
expected.
Phenytoin†
decrease 25%
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ent name: Test, Patient
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Warfarin†
Adjust based on multiple factors
VKORC1 phenotype:
INTERMEDIATE WARFARIN SENSITIVITY
Average VKORC1 enzyme expression and average warfarin dose requirement expected.
Warfarin Dose Information:
Estimated warfarin maintenance dose requirement: 5.5 mg/day‡
Estimated time to warfarin steady-state: Delayed, 11-15 days
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
steadystate blood concentrations have been achieved should be interpreted with caution, as they may not be indicative of
stable therapy.
CYP3A4 phenotype:
EXTENSIVE METABOLIZER
Normal metabolic clearance expected. Common CYP3A4 medications below.
CYP3A5 phenotype:
DECREASED METABOLIZER
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.
CYP1A2 phenotype:
HYPERINDUCER
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.
SLC6A4 phenotype:
POOR RESPONDER
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.
SLCO1B1 phenotype:
2.6 FOLD INCREASED MYOPATHY RISK
Reduced OATP1B1 transporter function.
Adjust Dosage:
Adjustment:
Increased risk of statin-induced myopathy.
Simvastatin
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.
Atorvastatin
max 10-20 mg
Factor V Leiden phenotype:
NO INCREASED THROMBOSIS RISK
Factor II phenotype:
2-3 FOLD INCREASED THROMBOSIS RISK
MTHFR phenotype:
INCREASED RISK
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Increased risk of hyperhomocysteinemia, coronary artery disease, and thrombosis when folate deficiency is present. Consider
folate supplementation.
COMT phenotype:
HIGH ACTIVITY
The COMT Val/Val genotype results in increased COMT activity and decreased dopamine levels in the prefrontal cortex.
Compared to patients with the Met allele, Val/Val patients with depression are less likely to achieve remission when treated with
SSRI antidepressants, and Val/Val patients with schizophrenia are less likely to demonstrate improved cognitive effects when
treated with antipsychotics. Val/Val patients may benefit from agents that increase dopamine availability including
methylphenidate and amphetamine.
OPRM1 phenotype:
Adjust Dosage:
INTERMEDIATE OPIOID RESPONDER / NORMAL NALTREXONE RESPONDER
Morphine, increase up to 10%
Opioid response: Higher than average doses of morphine typically required (may also apply to other active opioids, eg,
hydromorphone, oxymorphone). Note: Formation of active opioid metabolites (e.g., morphine) from prodrugs (eg, codeine) is
dependent on CYP2D6 activity.
Naltrexone response: In patients treated with naltrexone for alcohol dependence, those with the AG genotype have a 15% lower
average relapse rate compared to the typical on-treatment relapse rate. Overall, relapse rate among G allele carriers is 25%
compared to 54% in patients with AA genotype.
**Prodrug: PM lack of efficacy due to failure to produce active metabolite, UM at risk of toxicity from increased active metabolite;
†Active drug: PM risk of adverse events due to diminished drug clearance, UM risk of subtherapeutic response.
CYP2D6 *4/*4 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.
CYP2C19 *2/*2 Poor Metabolizer (PM):
This patient’s genotype is consistent with significantly reduced CYP2C19 enzymatic activity. PMs are at increased risk of
drug-induced side effects due to diminished drug elimination of active drugs. Patients with no CYP2C19 function (PMs)
taking clopidogrel lack adequate antiplatelet response and remain at risk for cardiovascular events, including thrombosis,
myocardial infarction, stroke, and death.
CYP2C9 *1/*3 Intermediate Metabolizer (IM):
This patient’s genotype is consistent with reduced CYP2C9 enzymatic activity. Reduced CYP2C9 activity leads to lower
dose requirement (e.g., warfarin) due to decreased clearance, increased elimination half-life, and increased time to reach
steady-state blood concentrations.
VKORC1 Result: GA Intermediate Warfarin Sensitivity:
‡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.
CYP3A4 *1/*1 Extensive Metabolizer (EM):
This patient’s genotype is consistent with normal CYP3A4 enzymatic activity. In general, extensive metabolizers can be
administered drugs which are substrates of the CYP3A4 enzyme following standard dosing practices.
CYP3A5 *3/*3 Decreased Metabolizer (DM):
This patient's genotype is 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.
CYP1A2 *1F/*1F
Hyperinducer:
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Presence of the -163 C>A variant (present in *1F, *1L, *1J hyperinducer alleles) 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 hyperinducer alleles may exhibit even higher rates of CYP1A2
enzymatic activity and have been described as ultra-rapid metabolizers for olanzapine. As an example, carriers of
CYP1A2*1F with the hyperinduction phenotype may exhibit as much as 50% lower than expected plasma levels of
olanzapine and clozapine, 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.
SLC6A4 Result: S/S Poor Responder:
Patients with S/S, S/LG, and LG/LG genotypes may be less likely to achieve remission of depression, more likely to have a
higher number of antidepressant trials, and are more likely to experience adverse effects when treated with selective
serotonin reuptake inhibitors (SSRIs) compared to non-SSRIs.
SLCO1B1 *1/*5 Moderate Myopathy Risk:
This patient's genotype is consistent with decreased OATP1B1 transporter function and is associated with an increased risk
of simvastatin-induced myopathy at 40 mg doses. The FDA recommends avoiding 20mg simvastatin dose when the patient
is co-prescribed verapamil or diltiazem. Consider low dose alternatives to simvastatin in patient who also carry the
CYP3A4*22 variant allele.
Factor V Leiden Result: GG, no variant Normal Thrombosis Risk:
This genotype result revealed that the patient does not possess the Factor V Leiden (1691G>A) variant, which is consistent
with no increased risk of thromboembolic events.
Factor II Result: GA, heterozygous 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 677(C>T): TT, homozygous variant MTHFR 1298(A>C): AC, heterozygous 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.
COMT Result: Val/Val High activity:
COMT is an enzyme that degrades dopamine and norepinephrine, primarily in the prefrontal cortex. The Val allele has higher
enzymatic activity resulting in higher dopamine degradation and lower dopamine concentrations as compared to the Met
allele. Lower prefrontal dopamine in Val/Val patients is associated with impaired cognitive function and working memory
deficits. Val/Val homozygotes are less likely to achieve remission of symptoms when treated with psychotropic medications
and may benefit from agents that increase dopamine availability such as methylphenidate and amphetamine.
OPRM1 Result: AG Intermediate Opioid Responder/Normal Naltrexone Responder:
This patient's genotype is consistent with higher than average doses of active opioids (e.g., morphine, hydromorphone,
oxymorphone) for therapeutic effect. Formation of active opioid metabolites (e.g., morphine) from prodrugs (e.g., codeine) is
dependent on CYP2D6 activity. In patients treated with naltrexone for alcohol dependence, those with the AG genotype
have a 15% lower average relapse rate compared to the typical on-treatment relapse rate. Overall, relapse rate among G
allele carriers is 25% compared to 54% in patients with AA genotype. The AG genotype is found in approximately 30% of
Caucasians, 20% of African Americans, and 50% of Asians.
This test should not be used as the sole means of treatment decision making, and should be regarded by the
ordering physician as adjunctive to the overall patient management strategy. These genotyping results do not
eliminate the necessity to account for non-genetic factors that can influence dose requirements for or responses to
medications that are metabolized by these enzyme systems. Drug-drug and drug-gene interactions that lead to
enzymatic inhibition or induction may lead to altered metabolism. Results should always be interpreted in context
with the clinical picture and all co-administered medications.
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CYP2D6 common medications
Psychiatry
Antidepressants
Amitriptyline
Atomoxetine
Clomipramine
Desipramine
Doxepin
Duloxetine
Fluoxetine
Fluvoxamine
Imipramine
Maprotiline
Mirtazapine
Nortriptyline
Paroxetine
Trimipramine
Venlafaxine
Vortioxetine
Elavil, Levate
Strattera
Ananfranil
Norpramin
Sinequan
Cymbalta
Prozac
Luvox
Tofranil
Ludiomil
Remeron
Pamelor, Aventyl
Paxil
Surmontil
Effexor
Brintellix
Antipsychotics
Amphetamine
Aripiprazole
Chlorpromazine
Haloperidol
Iloperidone
Lisdexamfetamine
Perphenazine
Risperidone
Thioridazine
Zuclopenthixol
Adderall, Dexedrine
Abilify
Thorazine
Haldol
Fanapt
Vyvanse
Trilafon
Risperdal
Mellaril
Cisordinol, Clopixol
Pain Management
Codeine**
Hydrocodone**
Oxycodone**
Tramadol**
Various brands
Lortab, Vicodin, Norco
Oxycontin, Percocet
Tramal, Ultram
Cardiology
Carvedilol
Flecainide
Metoprolol
Nebivolol
Propafenone
Propranolol
Timolol
Coreg
Tambocor
Toprol-XL
Bystolic
Rythmol
Inderal, InnoPran
Blocadren
Urology
Darifenacin
Fesoterodine
Tamsulosin
Tolterodine
Enablex
Toviaz
Flomax
Detrol
Other
Dextromethorphan
Diphenhydramine
Donepezil
Doxorubicin
Gefitinib
Loratadine
Meclizine
Promethazine
Tamoxifen**
Robitussin D, Delsym
Benadryl
Aricept
Adriamycin
Iressa
Claritin
Antivert
Phenergan
Soltamox
(**indicates prodrug)
CYP2C19 common medications
Amitriptyline
Elavil, Levate
Lansoprazole
Prevacid
Carisoprodol**
Soma
Methadone (active portion)
Various Brands
Citalopram
Celexa
Nelfinavir
Viracept
Clopidogrel**
Plavix
Omeprazole
Prilosec
Dexlansoprazole
Dexilant
Pantoprazole
Protonix
Diazepam
Valium
Rabeprazole
Aciphex
Escitalopram
Lexapro
Sertraline
Zoloft
Esomeprazole
Nexium
Voriconazole
Vfend
Imipramine
(**indicates prodrug)
Tofranil
CYP2C9 common medications
Celecoxib
Celebrex
Losartan
Cozaar
Diclofenac
Cataflam, Voltaren XR
Meloxicam
Mobic
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Fluvastatin
Lescol
Naproxen
Aleve
Glimepiride
Amaryl
Phenytoin
Dilantin
Glipizide
Glucotrol
Rosuvastatin
Crestor
Glyburide
Diabeta
Tolbutamide
Orinase
Ibuprofen
Advil, Motrin
Warfarin
Coumadin
CYP3A4/CYP3A5 common medications
PSYCHIATRY
Benzodiazepines
Alprazolam
Xanax
Midazolam
Versed
Triazolam
Halcion
Antipsychotics
Buspirone
Carbamazepine
Lurasidone
Quetiapine
Ziprasidone
Buspar
Tegretol
Latuda
Seroquel
Geodon
Antidepressants
Desvenlafaxine
Levomilnacipran
Nefazodone
Reboxetine
Trazodone
Vilazodone
Pristiq
Fetzima
Serzone
Edronax
Desyrel
Viibryd
CARDIOLOGY
Amiodarone
Cilostazol
Dronedarone
Quinidine
Ranolazine
Rivaroxaban
Ticagrelor
Cordarone
Pletal
Multaq
Quinaglute, Quinidex
Ranexa
Xarelto
Brilinta
Statins
Atorvastatin
Lovastatin
Mevastatin
Simvastatin
Lipitor, Caduet
Mevacor, Advicor
Compactin
Zocor, Vytorin, Simcor
Ca Channel Blockers
Amlodipine
Diltiazem
Felodipine
Lercanidipine
Nifedipine
Nisoldipine
Nitrendipine
Verapamil
Norvasc
Cardizem
Plendil
Zanidip
Adalat
Sular
Various brands
Calan, Isoptin, Verelan
ONCOLOGY
Docetaxel
Doxorubicin
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Taxotere
Adriamycin
PAIN MANAGEMENT
Alfentanil
Buprenorphine
Cyclobenzaprine
Fentanyl
Alfenta
Subutex, Suboxone
Flexeril
Actiq, Duragesic
UROLOGY
Alfuzosin
Avanafil
Darifenacin
Doxazosin
Dutasteride
Finasteride
Oxybutynin
Sildenafil
Silodosin
Solifenacin
Tamsulosin
Tadalafil
Vardenafil
Uroxatral
Stendra
Enablex
Cardura
Avodart
Proscar
Ditropan
Viagra
Rapaflo
Vesicare
Flomax
Cialis
Levitra
OTHER
Antimicrobials
Clarithromycin
Erythromycin
Indinavir
Nelfinavir
Ritonavir
Saquinavir
Telithromycin
Biaxin
E-Mycin
Crixivan
Viracept
Norvir
Fortovase
Ketek
Steroids
Beclomethasone
Budesonide
Estradiol
Hydrocortisone
Progesterone
Testosterone
QVAR
Symbicort, Uceris
Various brands
Various brands
Various brands
Various brands
Immunosuppressants
Cyclosporine
Sirolimus
Tacrolimus
Gengraf
Rapamune
Prograf
Other
Bromocriptine
Colchicine
Eletriptan
Guanfacine
Parlodel
Colcrys
Relpax
Intuniv
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ent name: Test, Patient
Erlotinib
Gefitinib
Imatinib
Pazopanib
Regorafenib
Vincristine
CYP1A2 common medications
Other
Cyclobenzaprine
Flutamide
Frovatriptan
Lidocaine
Rasagiline
Ropinirole
Ropivacaine
Tacrine
Theophylline
Tizanidine
Triamterene
Zolmipitran
Caffeine
17-beta estradiol
PG-14-01698
Tarceva
Iressa
Gleevec
Votrient
Stivarga
Loperamide
Saxagliptin
Zolpidem
Flexeril
Eulexin
Frova
Xylocaine
Azilect
Requip
Naropin, Polyamp
Cognex
Aerolate
Zanaflex
Dyrenium
Zomig
Various
Various
Psychiatry
Asenapine
Clozapine
Duloxetine
Olanzapine
Promazine
Imodium
Onglyza
Saphris
Clozaril
Cymbalta
Zyprexa
Sparine
Methods:
Laboratory specimens were analyzed by a real-time PCR method (TaqMan SNP Genotyping, Life Technologies) developed by PGXL
Laboratories. Alleles tested may include up to all of the following, depending on the clinical order, as reported above: CYP2D6: active
*1,*2; partially active *9,*10,*17,*29,*41; inactive *3,*4,*5 (deletion),*6,*7,*11,*12; gene duplication *1,*2,*4 (inactive),*6 (inactive),
*9,*10,*17,*29 or *41; CYP2C19: active *1; inactive *2,*3,*4,*6,*8,*9,*10; hyperactive *17; CYP2C9: active *1; decreased function alleles
*2,*3,*4,*5,*6,*8,*11,*12; CYP3A4: active: *1; decreased activity *3,*17,*22; CYP3A5: active *1; decreased activity: *2,*3,*6,*7; CYP1A2
normal *1A,*1E; decreased inducer *1C,*1K; hyperinducer based on presence of -163 C>A variant *1F,*1J,*1L; VKORC1 high sensitivity
variant -1639 G>A; SLCO1B1 normal *1, variant *5; OPRM1 118A>G poor responder variant; COMT 472G>A (158 Val>Met) low activity
variant; Factor V Leiden 1691 G>A; Factor II (prothrombin) 20210 G>A; MTHFR 677C>T and 1298A>C; SULT4A1 rs763120 T>C and
rs5764010 C>T. SULT4A1-1 positive haplotype is defined by presence of rs76210 C and rs5764010 T, as these variants are in linkage
disequilibrium with the complete SULT4A1-1 haplotype previously described. As applicable, testing for SLC6A4 was performed by
PCRRFLP analysis, including normal transporter expression allele LA, decreased expression alleles S, LG. Performance characteristics
were validated by PGXL Laboratories with analytical specificity and sensitivity of >99% for detection of the above variants. Other known
variants that are not listed are not detected. These methods have not been cleared or approved by the U.S. FDA, however the FDA has
determined that such clearance or approval is not necessary. This test is used for clinical purposes and should not be regarded as
investigational or for research. This laboratory is certified under the Clinical Laboratory Improvement Amendments (CLIA) as qualified to
perform high complexity clinical laboratory testing. All testing was performed at PGXL Laboratories, CLIA No. 18D0983143, KY State
License No.
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Copyright 2012-2014 Pharmacogenetics Diagnostic Laboratory, LLC
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Patient name: Test, Patient
PG-14-01698
200251, 201 E. Jefferson Street, Suite 309, Louisville, KY 40202, (502)569-1584.
References available upon request
Electronically Signed on 11/17/2014 at 5:09 PM by Mark Borgman, PhD
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Patient name: Test, Patient
PG-14-01698
END OF REPORT (Final)
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