copyright 2010 pgxl laboratories, louisville ky all materials herein are the exclusive property of...

Copyright 2010 PGXL Laboratories, Louisville KYAll materials herein are the exclusive property of PGXL Laboratories

Laboratory Reports and Services

Kristen K. Reynolds, PhDVP Laboratory Operations

Overview

• Test menu and clinical applications• Report formats• Consultation and support services

Current Test Menu

- CYP2D6- CYP2C19- CYP2C9/VKORC1 - CYP2C9- CYP1A2- CYP3A4- CYP3A5- NAT2- HLA-B*5701 Abacavir FUTURE- SLC6A4 Serotonin Transporter OPRM1 (opioid sensitivity/resistance)- SLCO1B1 Statins- SULT4A1 Olanzapine- MTHFR- Factor II (Prothrombin 20210 G>A)- Factor V Leiden- Hepatitis-B Virus DNA Quantitative

- CYP2D6 tamoxifen - KRAS- BRAF- BCR/ABL (quantitative)

MOLECULAR ONCOLOGYPHARMACOGENETICS

PGXL Core PanelMetabolism of >85% of medications

CYP2D6CYP2C9CYP2C19CYP3A4CYP3A5CYP1A2

Panels*Panel 1:

CYP2D6CYP2C9CYP2C19CYP3A4CYP3A5CYP1A2

Panel 2:

Panel 1 + thrombophilia(FVL, FII, MTHFR)

Panel Add-Ons (build specialty-specific):

VKORC1 (warfarin)SLC6A4 (SSRIs)SLCO1B1 (statins)OPRM1 (opioids)

*All genes always orderable a la carte

Genotype Frequency %

Gene EM IM PM UM

2D6 53 35 10 2

2C19 36 32 4 28

2C9 57 40 3 NA

3A4 87 12 1 NA

3A5 1 18 81 NA

Genotype InterpretationsRegulations require

Summary of variants and methodsClinical interpretation

• Including limitations, clinical implications• Implications can be based on the patient-specific scenario

CLIA; Mol 36000, 36125; MOLPATH Checklist, CAP 2010; NACB PGx LMPG 2010

– Associating genotype to clinical metabolizer status• Genotype AND substrate dependent• Prodrug versus active drug

– Providing patient-specific drug-gene interaction information

• Inducers, inhibitors

Should the result belinked to a specific drug usage?

NACB PGx LMPG 2010

Application of PGx to

Cardiology

Cardiology Med List

**indicates prodrug

CARDIOLOGY Anti-Arrhythmics, Anti-Hypertensives Amlodipine Norvasc CYP3A4/CYP3A5 Carvedilol Coreg CYP2D6 Diltiazem Cardizem CYP3A4/CYP3A5 Felodipine Plendil CYP3A4/CYP3A5 Flecainide Tambocor CYP2D6 Lercanidipine Zanidip CYP3A4/CYP3A5 Losartan Cozaar CYP2C9 Metoprolol Toprol-XL CYP2D6 Nifedipine Adalat CYP3A4/CYP3A5 Nisoldipine Sular CYP3A4/CYP3A5 Nitrendipine Various brands CYP3A4/CYP3A5 Propafenone Rythmol CYP2D6 Propanolol Inderal, various CYP2D6 Quinidine Various brands CYP3A4/CYP3A5 Timolol Blocadren CYP2D6 Verapamil Various brands CYP3A4/CYP3A5 Antithrombotics Clopidogrel** Plavix CYP2C19 Rivaroxaban Xarelto CYP3A4/CYP3A5 Ticareglor Brilinta CYP3A4/CYP3A5 Warfarin Coumadin CYP2C9 Statins Atorvastatin Lipitor CYP3A4/CYP3A5 Fluvastatin Lescol CYP2C9 Lovastatin Mevacor, Advicor CYP3A4/CYP3A5 Mevastatin Compactin CYP3A4/CYP3A5 Rosuvastatin Crestor CYP2C9 Simvastatin Zocor, Vytorin, Caduet, Simcor CYP3A4/CYP3A5

Warfarin Genotyping

CYP2C9 sets the rate, affects time to SS(accumulation and elimination)

0 3 6 9 12 15 18 21 24 27 30

Ti me (days)

0. 00

0. 60

1. 20

1. 80

2. 40

3. 00

S-W

arfa

rin

(mg/

L)

CYP2C9*1/*3

CYP2C9*1/*1

CYP2C9*1/*2

0.3

0.4

0.5

0.6

0.7

0.8

S-w

arfa

rin

A/A A/G G/G

VKORC1

2.7 ± 1.2 mg

4.2 ± 2.2 mg

6.7 ± 3.3 mg

VKORC1 sets the target concentration(predicts warfarin sensitivity)

Warfarin Genotyping

Guides dose selection–Estimates Maintenance Dose Requirement

Guides optimal INR interpretation–Estimates Time to Reach Steady-State

CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012

CYP2C9 *2/*3 CYP2C9 Phenotype

THERAPEUTIC IMPLICATIONS (adapted from published resources)

Poor Metabolizer Decreased metabolic clearance expected. Adjust Dosage Adjustment Phenytoin† decrease 50%

Warfarin† Adjust based on multiple factors

VKORC1 GA VKORC1 Phenotype


Intermediate warfarin sensitivity

Average VKORC1 enzyme expression and average warfarin dose requirement expected.

WARFARIN DOSE INFORMATION Estimated time to steady-state: Delayed, 16-22 days

Estimated warfarin maintenance dose requirement: 3.9 mg/day‡ _

CYP2C9 Poor Metabolizer (PM): This patient’s genotype is consistent with significantly 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 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.

CYP2C9

Celecoxib Celebrex

Ibuprofen Advil, Motrin

Naproxen Aleve

Glyburide Diabeta

Glipizide Glucotrol

Tolbutamide Orinase

Glimepiride Amaryl

Phenytoin Dilantin

Fluvastatin Lescol

Rosuvastatin Crestor

Losartan Cozaar


Anti-platelet therapy

CYP2C19 - Plavix

Clopidogrel (Plavix) is a PRODRUG

Active metabolite elicits the desired antiplatelet response

~ 30% of patients have deficiency in CYP2C19

– Decreased amount of active metabolite

– High on-treatment platelet reactivity

Influence of CYP2C19 on Clopidogrel Response

Mega et al. JAMA 2011;23/30; 306(20)

Gene-Dose dependency of therapeutic platelet inhibition

Treatment CV Events Bleed Events ICER

Genotype guided 813 340

Clopidogrel 1210 380 $ 6,790

Prasugrel 990 500 $ 11,710

Cost-effectiveness

Reese, E.S. et. al., Pharmacotherapy 2012;32(4):323–332

$2.9M

$3.9M

• Cost model based on event occurrence in TRITON-TIMI 38

• Genotype-guided therapy selection may be more cost effective and lead to fewer adverse outcomes


**Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to diminished drug clearance.

2C19CYP2C19 *2/*2 CYP2C19 Phenotype


Poor Metabolizer Avoid Alternative Consideration Adjust Dosage Adjustment Clopidogrel** Prasugrel Imipramine† decrease 30% Sertraline† decrease 50%

CYP2C19 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.

2C19 all

! CYP2C19 *1/*2

Intermediate Metabolizer

Clopidogrel* Prasugrel Imipramine† Sertraline†

Caution, consider 30% Caution, consider 50%

X CYP2C19 *2/*2

Poor Metabolizer

Clopidogrel*

Prasugrel Imipramine† Sertraline†

30% 50%

X CYP2C19 *17/*17

Ultra-Rapid Metabolizer

Increased metabolic clearance expected. Possible increased risk of bleeding events with clopidogrel.

Citalopram† Escitalopram† Omeprazole† Esomeprazole† Lansoprazole† Pantoprazole†

up to 150% up to 150% 100-200% 50-100% 200% 400%

CYP2C19 *1/*1

Extensive Metabolizer

Normal metabolic clearance expected. 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%

RESULTS THERAPEUTIC IMPLICATIONS (adapted from published resources)

Gene Phenotype Avoid Alternative Consideration Adjust Dosage Adjustment


CYP2C19Clopidogrel PlavixCitalopram CelexaEscitalopram Lexapro, variousImipramine TofranilSertraline ZoloftDiazepam ValiumOmeprazole PrilosecEsomeprazole NexiumPantoprazole ProtonixRabeprazole AciphexLansoprazole PrevacidNelfinavir Viracept

Statin Therapy

Statin therapy reduces risk of CV events

Statin therapy can lead to muscle weakness – Myalgia – Myopathy– Rhabdomyolysis

Genotyping can guide statin choice and dose

CYP3A4 and 3A5Together metabolize 50% of all medications80% redundancy of functionGenetic variants in each

– decrease enzyme function (clearance)– Increased risk of dose-dependent adverse events

CYP3A4/5 master drug list

CYP3A4/CYP3A5 Substrates PSYCHIATRY OTHER Benzodiazepines Antimicrobials/antivirals Alprazolam Xanax Clarithromycin Biaxin Midazolam Versed Erythromycin E-Mycin Triazolam Halcion Telithromycin Ketek Antipsychotics Indinavir Crixivan Quetiapine Seroquel Nelfinavir Viracept Ziprasidone Geodon Ritonavir Norvir Buspirone Buspar Saquinavir Fortovase Lurasidone Latuda Carbamazepine Various brands Steroids Antidepressants Estradiol Various brands Desvenlafaxine Pristiq Hydrocortisone Various brands Vilazodone Viibryd Progesterone Various brands Trazadone Desyrel Testosterone Various brands Nefazadone Serzone Reboxetine Edronax Chemotherapeutics Nortriptyline Pamelor, Aventyl Vincristine Oncovin Docetaxel Taxotere CARDIOLOGY Quinidine Various brands Pain Management Ticareglor Brilinta Cyclobenzaprine Flexaril Rivaroxaban Xarelto Fentanyl Actiq, Duragesic Statins Alfentanil Alfenta Atorvastatin Lipitor Lovastatin Mevacor, Advicor Immunosuppressants Mevastatin Compactin Cyclosporine Gengraf Simvastatin Zocor, Vytorin, Caduet, Simcor Tacrolimus Prograf Ca Channel Blockers Amlodipine Norvasc Diltiazem Cardizem Felodipine Plendil Lercanidipine Zanidip Nifedipine Adalat Nisoldipine Sular Nitrendipine Various brands Verapamil Various brands

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 InterpretationCYP3A4 Phenotype



Normal metabolic clearance expected. Common CYP3A4 medications below.

CYP3A4 Phenotype


Partially Decreased Metabolizer

Decreased metabolic clearance expected with increased risk of dose-dependent side effects. Common CYP3A4 medications below.

CYP3A4 Phenotype


Decreased Metabolizer


CYP3A4 Phenotype


*22 Decreased Metabolizer

Decreased metabolic clearance expected with increased risk of dose-dependent side effects.

Adjust Dosage Adjustment

Simvastatinmax 10-20 mg, or consider alternative statin if also SLCO1B1 *5/*5 genotype

Atorvastatin max 10-20 mgLovastatin max 10-20 mgTacrolimus decrease by up to 40%

3A5 InterpretationCYP3A5 Phenotype



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.

CYP3A5 Phenotype



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.

CYP3A5 Phenotype



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.

N Engl J Med 2008;359:789-99.

SLC01B1 OATP1B1

~35% of population are carriers of the SLC01B1*5 allele– Myalgia/muscle cramps– CK> 3x ULN

Myopathy: – SLCO1B1 *1/*5; OR = 4.5 (95% CI, 2.6 to 7.7) – SLCO1B1 *5/*5; OR 16.9 (95% CI, 4.7 to 61.1)

Most frequently associated with simvastatin > atorvastatin > pravastatin

Vanderbilt Algorithm

Wilke et al. Clin Pharmaco Ther 2012;92(1).

Statin Combo Interpretation

SLCO1B1 Phenotype


>5 Fold Increased Myopathy Risk

Avoid Alternative Consideration Adjust Dosage Adjustment

Simvastatinpravastatin, lovastatin, fluvastatin, rosuvastatin, mevastatin

Atorvastatin max 10-20 mg

CYP3A4 Phenotype


*22 Decreased Metabolizer

Decreased metabolic clearance expected with increased risk of dose-dependent side effects.

Adjust Dosage Adjustment

Simvastatinmax 10-20 mg, or consider alternative statin if also SLCO1B1 *5/*5 genotype

Atorvastatin max 10-20 mgLovastatin max 10-20 mgTacrolimus decrease by up to 40%

Anti-arrhythmics and Anti-hypertensives

3A4: Ca++ Channel Blockers

CYP3A4 Phenotype



Normal metabolic clearance expected. Common CYP3A4 medications below.

CYP3A4 Phenotype




CYP3A4 Phenotype




Amlodipine Norvasc Diltiazem Cardizem Felodipine Plendil Lercanidipine Zanidip Nifedipine Adalat Nisoldipine Sular Nitrendipine Various brands Verapamil Various brands



CYP2D6 *4/*4 CYP2D6 Phenotype


Poor Metabolizer Avoid Alternative Consideration Adjust Dosage Adjustment Codeine** Morphine, non-opioid Aripiprazole† 10 mg/day maximum 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, carvedilol

Zuclopenthixol† decrease 50%, or flupenthixol, quetiapine, olanzapine, clozapine

CYP2D6

Application of PGx to

Pain Management

Pain MedsGeneric Brand Metabolic RouteAlfentanil Alfenta CYP3A4/CYP3A5Carisoprodol** Soma CYP1A2Celecoxib Celebrex CYP2C9Codeine** Various brands CYP2D6Cyclobenzaprine Flexaril CYP1A2, CYP3A4/CYP3A5Fentanyl Actiq, Duragesic CYP3A4/CYP3A5Hydrocodone** Various brands CYP2D6Ibuprofen Advil, Motrin CYP2C9Lidocaine Various brands CYP1A2Methadone Various brands CYP2C19Naproxen Aleve CYP2C9Oxycodone** Oxycontin, various CYP2D6Ropivicaine Various brands CYP1A2Tizanidine Zanaflex CYP1A2Tramadol** Ultram, various CYP2D6Zolmipitran Zomig CYP1A2

**Indicates prodrug

CYP2D6 - OpioidsHydrocodoneOxycodoneCodeine

PropoxypheneTramadolOthers…

CODEINE

CYP3A4 CYP2D6

Norcodeine

Morphine

Morphine-6-glucuronide Morphine-3-glucuronide

Active opioid effects

Renal Excretion

Reynolds KR et al. Clin Lab Med 2008;28:581–598.

CYP2D6 PM: inadequate morphine

CYP2D6 UM: morphine toxicity

Decreased drug metabolism = lack of efficacy– Poor pain control– Mis-interpretation of drug seeking behavior

Ultra-rapid drug metabolism = possible side effects– Over-production of active compound– Mis-interpretation of over-compliance– Possible lower doses required

Effects of CYP2D6

CYP2D6 Variants

Extensive Metabolizers (EM) 55 – 60 % of population

Intermediate Metabolizers (IM) 25 – 30% of population

Poor Metabolizers (PM) 7 – 10 % of population

Ultra-rapid Metabolizers (UM) 1 – 3 % of population

Morphine Overdose

Case Report #1: Nursing neonate overdose

• Healthy male infant difficulty breastfeeding and lethargy starting on day 7, found deceased day 13

• Toxicology:– Blood morphine = 70 ng/mL (normal 0-2.2)– Day 10 breast milk morphine = 87 ng/mL (normal 2-20 ng/mL after

repeated 60mg every 6hr )

• Mother Rx 2 wks codeine 30mg+APA 500 mg (Tylenol #3) – 4 tabs first day, only 2 tabs daily thereafter because of maternal

somnolence and constipation

Koren et al. Lancet 2006;368:704.

Maternal CYP2D6 Genotype Results

CYP2D6 *1/*2xN = Ultra-rapid Metabolizer(gene duplication) (UM)

Leads to increased formation of morphine from codeineInfant was an EM


CNS depressant effects of codeine due to morphine by CYP2D6

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”

FDA issued Public Health Advisory August 17, 2007 “Anyone can be an Ultra-rapid Metabolizer without knowing it. The only way to find out is with a genetic test…Among pain relievers, ultra-rapid metabolism has only been reported as a problem with codeine, although it has the potential to affect other narcotics”


Clinical Case Conclusions

8-15-12 FDA Drug SafetyCase Report #2: Post-tonsillectomy overdose

Codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare, but life-threatening adverse events or death

• 3 deaths and 1 case of severe respiratory depression were reported in children (2-5yo) who received codeine after undergoing tonsillectomy and/or adenoidectomy for obstructive sleep apnea

• 3 deaths in children who were CYP2D6 UMs; 1 life-threatening case in an EM• All children received typical codeine doses• Morphine toxicity signs developed within 1-2 days after starting codeine• Supratherpeutic post-mortem morphine concentrations in the 3 death cases

FDA recommendations for Physicians:

• Use the lowest effective codeine dose for the shortest period of time on an as-needed basis (i.e., not scheduled around the clock)

• Counsel parents:– how to recognize the signs of morphine toxicity– Advise them to stop giving the child codeine– Seek medical attention immediately if child exhibits these signs

• FDA-cleared tests are available for determining a patient’s CYP2D6 genotype

• Consider prescribing alternative analgesics for children

Application of PGx to behavioral health

Psychiatry Medications – Metabolic RoutesPSYCHIATRY Antidepressants Antipsychotics, Mood Stabilizers

Generic Brand Metabolic Route Generic Brand Metabolic RouteAmitriptyline Various brands CYP2D6 Alprazolam Xanax CYP3A4/CYP3A5 Bupropion Wellbutrin CYP1A2, (CYP2B6) Amphetamine Adderall CYP2D6Citalopram Celexa CYP2C19 Aripiprazole Abilify CYP2D6Clomipramine Ananfranil CYP2D6, CYP1A2 Asenapine Saphris CYP1A2 Atomoxetine Strattera CYP2D6Desipramine Norpramin CYP2D6 Buspirone Buspar CYP3A4/CYP3A5 Desvenlafaxine Pristiq CYP3A4/CYP3A5 Carbamazepine Various brands CYP3A4/CYP3A5 Doxepin Sinequan CYP2D6 Chlorpromazine Thorazine CYP2D6Duloxetine Cymbalta CYP2D6, CYP1A2 Clozapine Clozaril CYP1A2Escitalopram Lexapro, various CYP2C19 Diazepam Valium CYP2C19Fluoxetine Prozac CYP2D6 Haloperidol Haldol CYP2D6Fluvoxamine Luvox CYP2D6 Iloperidine Fanapt CYP2D6Imipramine Tofranil CYP2D6, CYP2C19,

CYP1A2 Lurasidone Latuda CYP3A4/CYP3A5

Maprotiline Ludiomil CYP2D6 Midazolam Versed CYP3A4/CYP3A5 Mianserin Various brands CYP2D6, CYP1A2 Olanzapine Zyprexa CYP1A2Mirtazapine Remeron CYP2D6, CYP1A2 Perphenazine Trilafon CYP2D6Nefazadone Serzone CYP3A4/CYP3A5 Promazine Sparine CYP1A2Nortriptyline Pamelor, Aventyl CYP2D6,

CYP3A4/CYP3A5 Quetiapine Seroquel CYP3A4/CYP3A5

Paroxetine Paxil CYP2D6 Risperidone Risperidol CYP2D6Reboxetine Edronax CYP3A4/CYP3A5 Thioridazine Mellaril CYP2D6Sertraline Zoloft CYP2C19 Triazolam Halcion CYP3A4/CYP3A5 Trazadone Desyrel CYP3A4/CYP3A5 Ziprasidone Geodon CYP3A4/CYP3A5 Trimipramine Surmontil CYP2D6 Zuclopenthixol Various brands CYP2D6Venlafaxine Effexor CYP2D6 Vilazodone Viibryd CYP3A4/CYP3A5

CASE: Depression/ADHD

•51 y/o male•Problematic Polypharmacy (Atomoxetine, Topiramate, Oxcarbazapine, Aripaprazole,Valproic acid)•Genotyping results

Relevance to case (drugs affected)

MedicationPGx Gene PM Effect

atomoxetine CYP2D6Reduced clearance Half life ~ 5x longer

aripiprazole CYP2D680% increase in exposurehalf-life 2x longer

2D6 Atomoxetine

0 24 48 72 96 120 144 168 192 216 240 264

Time (hrs)

0

520

1040

1560

2080

2600

Pla

sm

a a

tom

oxetine (ng/m

L)

SS; EM SS ; P M

72 hrs

PMPM

EM

20 mg q12hPMs

• 4x longer to SS

• 4x higher drug levels

• 4x longer to wash-out

• More likely to have AE

Strattera and Abilify Monographs

1. Higher blood levels in PMs may lead to higher rate of ADRs

2. PM blood levels ≈ blood levels in EMs taking strong 2D6 inhibitors

3. Dosage adjustment for Strattera or Abilify with CYP2D6 inhibitors:– Initiate at 50% of the usual target dose

Adjust dosage based on PK: decrease by 50%

Goal to normalize exposure and ADR risk

Adjust monitoring and wash-out expectations

How to apply PGx to atomoxetine therapy

0 24 48 72 96 120 144 168 192 216 240 264

Time (hrs)

0

300

600

900

1200

1500

Pla

sm

a a

tom

oxetine (ng/m

L)

SS; EM SS ; P M

PM 2 0 mg q 1 2 h

EM

PM 1 0 mg q 1 2 h

CYP2D6 genotyping may be useful in predicting which patients are at increased risk of atomoxetine and aripiprazole–induced ADRs.

Dosing guidelines for inhibitors may be considered for PM dose adjustments

Surja, Reynolds, Linder, El-Mallakh. Pers Med 2008;5(4):361-365

0 200 400 600 800 1000 1200

Time (hrs)

0

100

200

300

400

Arip

irazo

le b

lood

con

cent

ratio

ns (n

g/m

L)

Aripiprazole AccumulationAccording to CYP2D6 Genotype

EM10 mg/d

PM10 mg/d

PM5 mg/d

0 92 184 276 368 460

Time (hrs)

0

14

28

42

56

70

Pla

sma p

arox

etin

e (

ng

/mL

)

Paroxetine Accumulation (20 mg q 24 hr)

SS; EM SS ; P M

PM

EM

144 hr

2D6 Paroxetine


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.


CYP2D6 *4/*4 CYP2D6 Phenotype


Poor Metabolizer Avoid Alternative Consideration Adjust Dosage Adjustment Codeine** Morphine, non-opioid Aripiprazole† 10 mg/day maximum 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, carvedilol

Zuclopenthixol† decrease 50%, or flupenthixol, quetiapine, olanzapine, clozapine

RESULTS THERAPEUTIC IMPLICATIONS (adapted from published resources) Gene Phenotype Avoid Alternative Consideration Adjust Dosage Adjustment X CYP2D6 *4/*4

Poor Metabolizer

Codeine* Hydrocodone* Oxycodone* Tramadol* Tamoxifen* Amitriptyline† Venlafaxine† Risperidone†

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† Clomipramine† Doxepin† Flecainide† Haloperidol† Imipramine† Nortriptyline† Propafenone† Metoprolol† Zuclopenthixol†

10 mg/day maximum 50% 60% 50% 50% 70% 60% 70% 75%, or atenolol, bisoprolol, carvedilol 50%, or flupenthixol, quetiapine, olanzapine, clozapine

CYP2D6 *1/*1


Normal metabolic clearance expected. Common CYP2D6 medications next page

! CYP2D6 *1/*4

Intermediate Metabolizer

Oxycodone* Hydrocodone* Propafenone† Risperidone† Velafaxine†

Oxymorphone, non-opioid Hydromorphone, non-opioid Sotalol, disopyramide, quinidine, amiodarone Quetiapine, olanzapine, clozapine Citalopram, sertraline

Codeine* Tramadol* Tamoxifen* Amitriptyline† Imipramine† Nortriptyline† Zuclopenthixol† Doxepin† Flecainide† Metoprolol†

15-60 mg/hr titrate to pain relief Avoid CYP2D6 inhibitors, e.g. paroxetine, or consider aromatase inhibitor in post-menopausal women 25% 30% 40% 25% 20% 25% 50%, or atenolol, bisoprolol, carvedilol

X CYP2D6 *1/*1xN

Ultra-Rapid Metabolizer

Codeine* Hydrocodone* Oxycodone* Amitriptyline† Clomipramine†

Paroxetine† Atomoxetine†

Risperidone† Zuclopenthixol† Propafenone†

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†

Haloperidol† Doxepin†

Metoprolol†

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


CYP2D6 Pain Management PsychiatryCodeine** Various brands Antidepressants Antipsychotics Oxycodone** Oxycontin, various Fluoxetine Prozac Haloperidol HaldolHydrocodone** Various brands Fluvoxamine Luvox Risperidone RisperidolTramadol** Ultram, various Paroxetine Paxil Aripiprazole Abilify Venlafaxine Effexor Zuclopenthixol Various brandsCardiology Duloxetine Cymbalta Perphenazine TrilafonCarvedilol Coreg Maprotiline Ludiomil Thioridazine MellarilMetoprolol Toprol-XL Mirtazapine Remeron Iloperidine FanaptPropanolol Inderal, various Amitriptyline Various brands Chlorpromazine ThorazineTimolol Blocadren Clomipramine Ananfranil Atomoxetine StratteraPropafenone Rythmol Desipramine Norpramin Amphetamine AdderallFlecainide Tambocor Doxepin Sinequan Imipramine Tofranil Other

Nortriptyline Pamelor, Aventyl

Loratadine Claritin Trimipramine Surmontil Donepezil Aricept Dextromethorphan Various brands Tamoxifen** Various brands

PGXL Psych Panels*STA2R Panel = Psychosis

SULT4A1:olanzapine2D62C192C91A23A43A5SLC6A4

PGXL Depression Panel

2D62C192C91A23A43A5Add on: SLC6A4

*updated as of 11-20-12

Serotonin Transporter (SLC6A4) add-on

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

SLC6A4 interpretationsSLC6A4 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources)

Normal ResponderNormal 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.

SLC6A4 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources)

Intermediate ResponderCarriers 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.

SLC6A4 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources)

Poor ResponderDecreased 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.

AntidepressantsSSRIs SNRIs

2C19 citalopram Celexa 2D6,1A2 duloxetine Cymbalta2C19 escitalopram Lexapro 2D6 venlafaxine Effexor2D6 fluoxetine Prozac 3A4/5 desvenlafaxine Pristiq2D6,1A2 fluvoxamine Luvox renal milnacipran Savella2D6 paroxetine Paxil 2D6,1A2,3A4/5 mirtazapine Remeron2C19 sertraline Zoloft3A4/5 vilazodone Viibryd

TCAs2D6,1A2,3A4/5 amitriptyline Elavil Atypicals (NRIs, NDRIs)2D6,1A2 clomipramine Anafranil 2B6,1A2 bupropion Wellbutrin2D6,2C19 desipramine Norpramin 3A4/5 trazadone Desyrel2D6 doxepin Sinequan 3A4/5 nefazadone Serzone2D6 imipramine Tofranil 2D6 maprotiline Ludiomil2D6,3A4/5 nortriptyline Pamelor, Aventyl 2D6,1A2 mianserin2D6,3A4/5,2C19 trimipramine Surmontil 3A4/5 reboxetine Edronax

MAOIsphenelzine Nardiltranylcyromine Parnateisocarboxazid Marplan

2C19 moclobemide

Black, major pathway; gray, minor pathway

PGXL Depression Panel

(Panel + SLC6A4 add-on)DRAFT

SLC6A4 S/S 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 antidepressant alternatives.


PGXL exclusive provider of SULT4A1 marker (schizophrenia, bipolar disorder)

– Enhanced efficacy on olanzapine– Reduced risk of hospitalization– Reduced hospitalization costs

SULT4A1Brain enzyme that interacts with neurochemicalsEfficacy advantage with olanzapine

Efficacy Hospitalization

SULT4A1 Interpretations

Gene THERAPEUTIC IMPLICATIONS (adapted from published resources)

SULT4A1-1POSITIVE

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.

SULT4A1-1NEGATIVE

SULT4A1-1 negative patients treated with olanzapine do not display the expected efficacy advantage compared to other atypical antipsychotics.

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 risk of side effects?

Yes See SLC6A4

See below for possible dosage considerations.

SULT4A1 rs763120 CC rs5764010 TT SULT4A1-1 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

SLC6A4 S/S

CYP2C19 *2/*2

CYP1A2 *1F/*1F

*Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to diminished drug clearance.

STA2R Panel Report

SLC6A4 S/S 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 antidepressant alternatives.

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.

CYP3A4 Phenotype




CYP3A5 Phenotype



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.

Thrombophilia panel

Thrombophilia Panel

• Factor V Leiden• Factor II (prothrombin)• MTHFR

X Factor V Leiden AA

>9 fold Increased Thrombosis Risk

Female, 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).

! Factor II GA

2-3 fold Increased Thrombosis Risk

X MTHFR 677 TT 1298 AA

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.

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Ongoing VIP review consultation after 50-100 patients tested

Educational lecture series and/or CME events as needed

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cyp2c9 cyp1a2

reduced cyp2c9 activity