Kristen K. Reynolds, PhD Associate Medical Director, VP Laboratory Operations Copyright 2010 PGXL Laboratories LLC, Louisville KY All materials herein.

Kristen K. Reynolds, PhDAssociate Medical Director, VP Laboratory Operations

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

Enabling Personalized Medicine

IntuitiveMedicine

PrecisionMedicine

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

~122 drugs have FDA box warnings related to genetics

Applications of pharmacogenomics• Individualizing drug therapy selection

• Predicting adverse reactions, dosing, response

• Identify increased sensitivity to drug interactions

CYP2D6

DRD2

5-HTT

5-HTR2A

SSRI

SNRI

TCA

FGA

SGA

MetabolismClearance

PDResponse

PK

UMs

EMs

PMs X

Dependent on drug concentration, receptor expression and affinity

CYP2D6 and psychotropic receptor variantsalter drug dose and/or selection

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

Clinical Applications of Pharmacogenetic Information

• Anti-coagulation– Warfarin– Clopidogrel

• Psychiatry– Anti-depressants

• Oncology– Thiopurines– Tamoxifen– EGFRi’s

• Pain management– Codeine– Methadone

• Epilepsy– Phenytoin– Carbamazepine

• Diabetes– Glipizide

Application of Pharmacogenomics to warfarin therapy

The Problem

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

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

• 40% of population have deficient CYP2C9

• > 70% of population have decreased VKOR and are more sensitive to warfarin

Genetics of Warfarin metabolism and response

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

Accumulation

Steady-State

Linder et al. J Thrombosis & Thrombolysis 2002;14:227-232

CYP2C9 status increases magnitude of accumulation/unit dose as well as time to achieve steady-state

VKORC1 -1639 G>A genotype dictates S-warfarin therapeutic concentration

Dose2.7 ± 1.2 mg

Dose4.2 ± 2.2 mg

Dose6.7 ± 3.3 mg

All within INR 2-3

Zhu Y et al. Clin Chem 2007;53(7):1199-1205.

• Calculation of estimated maintenance dose• Modeling of individualized response to dose changes• Guidance for:

Monitoring strategy Dosing modifications Transition: induction to maintenance therapy

PerMIT:Warfarin©

Powered by PGXL Laboratories

All; 66 y/o, female, 130 lbs

No Loading Dose

PerMIT-guided Loading Dose

Concentration/Response Time Profile

Genotype: CYP2C9*1*2 // VKORC1 GGEstimated Maintenance dose: 6.3 mg/d (5.7 – 7.0)Time to Steady-State: 11 to 15 daysTarget therapeutic concentration: 0.8 mg/L

. . . . . . 6 mg/d. . . . . . . 10, 10, 8, 6 mg/d

Linder MW et al. 2011 (unpublished results)

CONFIDENTIAL

Application of Pharmacogenomics to Anti-platelet therapy

CYP2C19 - Plavix

• Clopidogrel (Plavix) is a pro-drug which is converted to an active metabolite by CYP2C19

• Active metabolite is what elicits the desired antiplatelet response

• ~ 30% of patients have deficiency in CYP2C19

Influence of CYP2C19 on Clopidogrel Response

New Draft Report

CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012

THERAPEUTIC IMPLICATIONS1 Gene Phenotype Avoid Alternative Consideration Adjust Dosage Adjustment X CYP2C19 *2/*2

Poor Metabolizer

Clopidogrel*

Prasugrel Imipramine† Sertraline†

30% 50%

*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.

Application of Pharmacogenetics to Pain Management

CYP2D6 - Opioids

• Hydrocodone• Oxycodone• Methadone• Others…

• Propoxyphene• Tramadol• Codeine

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

Application of Pharmacogenomics to behavioral health

28

CASE: Depression/ADHD• 51 y/o male• Problematic Polypharmacy (Atomoxetine, Topiramate,

Oxcarbazapine, Aripaprazole,Valproic acid)• Genotyping results

29

Relevance to case (drugs affected)

MedicationPGx Gene PM Effect

atomoxetine CYP2D6Reduced clearance. Half life ~ 5 times longer

aripiprazole CYP2D680% increase in exposure, half-life twice as long

• Adjust dosage based on PK• Goal to achieve

normalized exposure and ADR risk

• Adjust monitoring expectations for SS delay

• Allow for adequate “wash-out” period

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

UM IM PMCODEINEAMITRIPTYLINECLOMIPRAMINEOXYCODONERISPERIDONEZUCLOPENTHIXOL

PROPAFENONERISPERIDONEVENLAFAXINE

CODEINEAMITRYPTYLINEOXYCODONERISPERIDONETAMOXIFENTRAMADOLVENLAFAXINE

Medications to avoid by CYP2D6 phenotype

RESULTS THERAPEUTIC IMPLICATIONS1 Gene Phenotype Avoid Alternative Consideration Adjust Dosage Adjustment X CYP2D6 *4/*4

Poor Metabolizer

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

Morphine, non-opioid Hydromorphone, non-opioid Oxymorphone, non-opioid Consider active drug, non-opioid Citalopram, sertraline Citalopram, sertraline Quetiapine, olanzapine, clozapine Anastrozole, exemestane, letrozole

Aripiprazole† Clomipramine† Doxepin† Flecainide† Haloperidol† Imipramine† Nortriptyline† Propaphenone† Metoprolol† Zuclopenthixol

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

*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.

New Draft Report

CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012

Fundamental Principles• Genetic variability in drug metabolism significantly increases risk of

ADRs and non-response• Genetic variation can be managed:

• Poor Metabolizers• Decreased maintenance dosing (20 – 70% )• Increased pro-drug dosing• Allow longer time to reach Steady-State• Allow longer time between medication changes• Increased observation • Choose alternative medication

• Rapid metabolizers• Increased dosages (50 – 200%)• Decreased pro-drug dosages

CYP2C9 CELECOXIB CELEBREXIBUPROFEN ADVIL, MOTRINNAPROXEN ALEVEGLYBURIDE DIABETAGLIPIZIDE GLUCOTROLTOLBUTAMIDE ORINASEGLIMEPIRIDE AMARYLPHENYTOIN DILANTINFLUVASTATIN LESCOLLOSARTAN COZAAR CYP2C9/VKORC1WARFARIN COUMADIN

CYP2C19

CLOPIDOGREL PLAVIXCITALOPRAM CELEXAESCITALOPRAM VARIOUS BRANDSIMIPRAMINE TOFRANILSERTRALINE ZOLOFTOMEPRAZOLE PRILOSECESOMEPRAZOLE NEXIUMPANTOPRAZOLE PROTONIXRABEPRAZOLE ACIPHEXLANSOPRAZOLE PREVACIDDIAZEPAM VALIUMNELFINAVIR VIRACEPT

Medications and metabolic pathways

Medications and CYP2D6 pathwayPain Management Psychiatry

Codeine Various brands Amitriptyline Various brandsOxycodone Oxycontin, various Clomipramine AnanfranilHydrocodone Various brands Desipramine NorpraminDextromethorphan Various brands Doxepin SinequanTramadol Ultram, various Imipramine Tofranil Nortriptyline Pamelor, AventylCardiology Fluoxetine ProzacCarvedilol Coreg Paroxetine PaxilMetoprolol Toprol-XL Venlafaxine EffexorPropanolol Inderal, various Risperidone RisperidolPropafenone Rythmol Aripiprazole AbilifyFlecainide Tambocor Zuclopenthixol Various brands Maprotoline LudiomilOther Duloxetine CymbaltaLoratadine Claritin Donepezil Aricept Tamoxifen Various brands