Kristen K. Reynolds, PhD VP Laboratory Operations Pharmacogenetics and Personalized Medicine: Reaping the Benefits for Your Patients Kristen K. Reynolds, PhD VP Laboratory Operations Copyright 2012-2013PGXL Laboratories, Louisville KY All materials herein are the exclusive property of PGXL Laboratories

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 Panel Metabolism of >85% of medications CYP2D6 CYP2C9 CYP2C19 CYP3A4 CYP3A5 CYP1A2

Panels* Core: CYP2D6 CYP2C9 CYP2C19 CYP3A4 CYP3A5 CYP1A2 Panel Add-Ons: VKORC1 (warfarin) SLC6A4 (SSRIs) SULT4A1 (STA2R, Olanzapine) SLCO1B1 (statins) OPRM1 (opioids) Thrombophilia: FVL FII MTHFR Warfarin: CYP2C9 VKORC1 *All genes always orderable individually

Pain Management

Common pain medications with PGXL tests 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 Hydrocodone** Lortab, Vicodin Hydromorphone Dilaudid UGT2B7+ (OPRM1) Ibuprofen Advil, Motrin Lidocaine CYP1A2 Methadone CYP2C19, CYP2B6+ Morphine UGT2B7+ (OPRM1) Naproxen Aleve Oxycodone** Oxycontin, Percocet CYP2D6, CYP3A4/5 Oxymorphone Opana Ropivicaine Tizanidine Zanaflex Tramadol** Ultram, various Zolmipitran Zomig **prodrug; + test not yet available

Pharmacokinetic Gene Metabolism Pharmacodynamic Gene Clinical Effect

CODEINE Active opioid effects Morphine CYP3A4 CYP2D6 CYP2D6 PM: inadequate morphine CYP2D6 UM: morphine toxicity CYP3A4 CYP2D6 Active opioid effects Morphine Norcodeine Morphine-6-glucuronide Morphine-3-glucuronide Renal Excretion Reynolds KR et al. Clin Lab Med 2008;28:581–598.

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 Clomipramine decrease 50% Oxycodone** Oxymorphone, non Doxepin 60% Tramadol** Consider active drug, non Flecainide Tamoxifen** Anastrozole, exemestane, letrozole Haloperidol Amitriptyline Citalopram, sertraline Imipramine 70% Venlafaxine Citalopram, sertraline Nortriptyline Risperidone Quetiapine, olanzapine, clozapine Propafenone Metoprolol 75%, or atenolol, bisoprolol Zuclopenthixol 50%, or flupenthixol, quetiapine, olanzapine, clozapine decrease 50% **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

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 relief 2C19 EXTENSIVE METABOLIZER : Pt now taking low dose methadone and pain is controlled

8-15-12 and 2-20-13 FDA Drug Safety Advisories Morphine Overdose from Codeine 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

Application of PGx to Cardiology

Cardiology Med List **indicates prodrug

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

Gene-Dose dependency of therapeutic platelet inhibition Mega et al. JAMA 2011;23/30; 306(20)

Cost-effectiveness Cost model based on event occurrence in TRITON-TIMI 38 Treatment CV Events Bleed Events ICER Genotype guided 813 340 Clopidogrel 1210 380 $ 6,790 Prasugrel 990 500 $ 11,710 $2.9M $3.9M Genotype-guided therapy selection may be more cost effective and lead to fewer adverse outcomes Reese, E.S. et. al., Pharmacotherapy 2012;32(4):323–332

2C19 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. 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.   CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012

Anticoagulation Therapy

>70% VKOR sensitivity variant 40% 2C9 deficient >70% VKOR sensitivity variant Reynolds et al. Pers Med 2007;4(1):11-31.

Warfarin Genotyping CYP2C9 sets the rate, affects time to SS (accumulation and elimination) Avoid misinterpretation of INR and premature dose changes 6.7 ± 3.3 mg VKORC1 sets the target concentration (predicts warfarin sensitivity) 4.2 ± 2.2 mg 2.7 ± 1.2 mg Linder et al. 2002 Thrombosis Thrombolysis; Zhu et al 2007 Clin Chem; Reynolds et al Pers Med 2007

CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012 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. CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012

Application of PGx to behavioral health

Psychiatry Medications – Metabolic Routes   Antidepressants Antipsychotics, Mood Stabilizers Generic Brand Metabolic Route Amitriptyline Various brands CYP2D6 Alprazolam Xanax CYP3A4/CYP3A5 Bupropion Wellbutrin CYP1A2, (CYP2B6) Amphetamine Adderall Citalopram Celexa CYP2C19 Aripiprazole Abilify Clomipramine Ananfranil CYP2D6, CYP1A2 Asenapine Saphris CYP1A2 Atomoxetine Strattera Desipramine Norpramin Buspirone Buspar Desvenlafaxine Pristiq Carbamazepine Doxepin Sinequan Chlorpromazine Thorazine Duloxetine Cymbalta Clozapine Clozaril Escitalopram Lexapro, various Diazepam Valium Fluoxetine Prozac Haloperidol Haldol Fluvoxamine Luvox Iloperidine Fanapt Imipramine Tofranil CYP2D6, CYP2C19, CYP1A2 Lurasidone Latuda Maprotiline Ludiomil Midazolam Versed Mianserin Olanzapine Zyprexa Mirtazapine Remeron Perphenazine Trilafon Nefazadone Serzone Promazine Sparine Nortriptyline Pamelor, Aventyl CYP2D6, CYP3A4/CYP3A5 Quetiapine Seroquel Paroxetine Paxil Risperidone Risperidol Reboxetine Edronax Thioridazine Mellaril Sertraline Zoloft Triazolam Halcion Trazadone Desyrel Ziprasidone Geodon Trimipramine Surmontil Zuclopenthixol Venlafaxine Effexor Vilazodone Viibryd

SLC6A4 X CYP2D6 and serotonin transporter variants alter drug dose and/or selection SSRI Antidepressants PD Response SLC6A4 Dependent on drug concentration, receptor expression and affinity PK Metabolism PMs X EMs Clearance CYP2D6 UMs 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) Medication PGx Gene PM Effect atomoxetine CYP2D6 Reduced clearance Half life ~ 5x longer aripiprazole 80% increase in exposure half-life 2x longer

2D6 Atomoxetine PMs 4x longer to SS 4x higher drug levels 20 mg q12h PMs 4x longer to SS 4x higher drug levels 4x longer to wash-out More likely to have AE

How to apply PGx to atomoxetine therapy Adjust dosage based on PK: decrease by 50% Goal to normalize exposure and ADR risk Adjust monitoring and wash-out expectations

50% dose reduction for 2D6 PMs Abilify monograph: 50% dose reduction for 2D6 PMs 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

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 failure Increased 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

SULT4A1 Brain enzyme that interacts with neurochemicals Efficacy advantage with olanzapine Efficacy Hospitalization Liu et al. Prim Care Comp 2012; Ramsey et al. Pharmacogenomics 2011

STA2R Panel Report

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