Copyright 2012-2013PGXL Laboratories, Louisville KYAll materials herein are the exclusive property of PGXL Laboratories

Pharmacogenetics and Personalized Medicine:

Reaping the Benefits for Your Patients

Kristen K. Reynolds, PhDVP Laboratory Operations

Overview• Scope of PGx utility• Application examples

• Hydrocodone• Plavix• Warfarin• SSRIs and antipsychotics

• PGXL interpretive report

~60% of meds in top 20 list causing ADRs are linked to a genetic variation

122 drugs have FDA box warnings related to genetics

Clinical Applications of Pharmacogenetic Information

Cardiology– Warfarin– Clopidogrel– Statins

Psychiatry– Anti-depressants– Anti-psychotics

Oncology– Thiopurines– Tamoxifen– EGFRi’s

Pain management– Codeine– Hydrocodone– Oxycodone– NSAIDs

Neurology– Phenytoin– Carbamazepine

Diabetes– Glipizide– Glyburide

PGXL Core PanelMetabolism of >85% of medications

CYP2D6CYP2C9CYP2C19CYP3A4CYP3A5CYP1A2

Panels*Core:

CYP2D6CYP2C9CYP2C19CYP3A4CYP3A5CYP1A2

Thrombophilia:

FVLFIIMTHFR

Warfarin:

CYP2C9VKORC1

Panel Add-Ons:

VKORC1 (warfarin)SLC6A4 (SSRIs)SULT4A1 (STA2R, Olanzapine)SLCO1B1 (statins)OPRM1 (opioids)

*All genes always orderable individually

Pain Management

Generic Brand Metabolic Route

Alfentanil Alfenta CYP3A4/CYP3A5

Carisoprodol** Soma CYP2C19

Celecoxib Celebrex CYP2C9

Codeine** Various brands CYP2D6

Cyclobenzaprine Flexeril CYP1A2, CYP3A4/CYP3A5

Fentanyl Actiq, Duragesic CYP3A4/CYP3A5

Hydrocodone** Lortab, Vicodin CYP2D6

Hydromorphone Dilaudid UGT2B7+ (OPRM1)

Ibuprofen Advil, Motrin CYP2C9

Lidocaine Various brands CYP1A2

Methadone Various brands CYP2C19, CYP2B6+

Morphine Various brands UGT2B7+ (OPRM1)

Naproxen Aleve CYP2C9

Oxycodone** Oxycontin, Percocet CYP2D6, CYP3A4/5

Oxymorphone Opana UGT2B7+ (OPRM1)

Ropivicaine Various brands CYP1A2

Tizanidine Zanaflex CYP1A2

Tramadol** Ultram, various CYP2D6

Zolmipitran Zomig CYP1A2

**prodrug; + test not yet available

Common pain medications with PGXL tests

Pharmacokinetic GeneMetabolism

Pharmacodynamic GeneClinical Effect

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

**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

CYP2D6 *4/*4 CYP2D6 Phenotype

THERAPEUTIC IMPLICATIONS (adapted from published resources)

Poor Metabolizer Avoid Alternative Consideration Adjust Dosage Adjustment Codeine** Morphine, non- opioid Aripiprazole† 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

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

decrease 50%

Case study

• Middle-aged male, chronic pain patient• 2 pain clinics released him due to negative UDT when

prescribed hydrocodone• 3rd pain clinic ordered PGXL testing:

2D6 POOR METABOLIZER:Pt does not produce hydromorphone = negative UDT and lack of pain relief2C19 EXTENSIVE METABOLIZER :Pt now taking low dose methadone and pain is controlled

8-15-12 and 2-20-13 FDA Drug Safety Advisories

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

• 3 deaths in children (2-5yo) taking codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea

• 3 deaths in children who were CYP2D6 UMs• All children received typical codeine doses, developed toxic levels

Morphine Overdose from Codeine

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, Caduet CYP3A4/CYP3A5 Fluvastatin Lescol CYP2C9 Lovastatin Mevacor, Advicor CYP3A4/CYP3A5 Mevastatin Compactin CYP3A4/CYP3A5 Rosuvastatin Crestor CYP2C9 Simvastatin Zocor, Vytorin, Simcor CYP3A4/CYP3A5

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

Clopidogrel

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

CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012

**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

THERAPEUTIC IMPLICATIONS (adapted from published resources)

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. 

Anticoagulation Therapy

Reynolds et al. Pers Med 2007;4(1):11-31.

40% 2C9 deficient

>70% VKOR sensitivity variant

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)

Linder et al. 2002 Thrombosis Thrombolysis; Zhu et al 2007 Clin Chem; Reynolds et al Pers Med 2007

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

THERAPEUTIC IMPLICATIONS (adapted from published resources)

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.

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      

CYP2D6

SLC6A4

SSRIAntidepressants

Clearance

PDResponse

PKMetabolism

UMs

EMs

PMs X

Dependent on drug concentration, receptor expression and affinity

CYP2D6 and serotonin transporter variantsalter drug dose and/or selection

Ramey-Hartung, El-Mallakh, Reynolds. Clin Lab Med 2008;28:627-43.

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

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.

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

Abilify monograph:50% dose reduction for 2D6 PMs

Serotonin Transporter and Antidepressants• 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 version of SLC6A4

Risk of SSRI failureIncreased ADR risk

Greatest SSRI efficacy

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

– Rule-in for olanzapine– Reduced risk of hospitalization– Reduced hospitalization costs

SULT4A1Brain enzyme that interacts with neurochemicalsEfficacy advantage with olanzapine

Efficacy Hospitalization

Liu et al. Prim Care Comp 2012; Ramsey et al. Pharmacogenomics 2011

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

THERAPEUTIC IMPLICATIONS (adapted from published resources)

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

THERAPEUTIC IMPLICATIONS (adapted from published resources)

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.

Applications of pharmacogenomics

• Individualize drug therapy selection

• Predict adverse reactions, dosing, response

• Identify increased sensitivity to drug interactions

Stay tuned for future webinars!

• Pain Management

• Cardiology

• Behavioral Health

• Personalized medicine “program” implementation

Thank You!

kreynolds@pgxlab.com

Key Service Lines

Pain Management– opioid resistance and opioid toxicity

Behavioral Health– Drug selection to manage treatment resistant depression and psychosis– Dosing information to minimize adverse drug reactions

Statin therapy – Minimum effective statin dose and myopathy risk

Anti-platelet therapy– Clopidogrel resistance and increased bleeding risk

Anti-coagulant therapy– warfarin dose estimation and optimal INR interpretation guidance

Thrombotic risk assessment