Mark W Linder, Ph.D., DABCC, FACBMedical Director, EVP Operations

Kristen K. Reynolds Ph.D.Associate Medical Director, VP Laboratory Operations

Mark P. Borgman, Ph.D.Assistant Medical Director, Director of Laboratories

Copyright 2010-12 PGXL Laboratories LLC, Louisville KYAll materials herein are the exclusive property of PGXL laboratories

Enabling Personalized Medicine

IntuitiveMedicine

PrecisionMedicine

Indicators Suggest: Diagnostic services will trump therapeutics(Clayton M Christenson in: The Innovator’s Prescription, MaCGraw Hill, 2009)

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

122 drugs have FDA box warnings related to genetics

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Clinical Applications of Pharmacogenetic Information

• Anti-coagulation– Warfarin– Plavix (clopidogrel)

• Psychiatry– Anti-depressants

• Oncology– Thiopurines– Tamoxifen– EGFRi’s

• Pain management– Codeine– Methadone

• Epilepsy– Phenytoin– Carbamazepine

• Diabetes– Glipizide

Application of Pharmacogenomics to Anti-platelet therapy

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• Clopidogrel (Plavix) activation.

PharmGKB.org

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Antiplatelet Response

• ~ 30% of patients have deficiency in CYP2C19

– CYP2C19 *1/*2 (28%)

– CYP2C19 *2/*2 (2%)

• Decreased activation of clopidogrel – Decreased amount of active metabolite

– High on-treatment platelet reactivity

Influence of CYP2C19 on Clopidogrel Response

Treatment CV Events Bleed Events ICER

Genotype guided 813 340

Clopidogrel 1210 380 $ 6,790

Prasugrel 990 500 $ 11,710

Cost-effectiveness comparisons

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

Application of Pharmacogenomics to warfarin therapy

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The Problem

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

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• 40% of population have deficient CYP2C9

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

Genetics of Warfarin metabolism and response

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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

CONFIDENTIAL

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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.

CONFIDENTIAL

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• 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

CONFIDENTIAL

All; 66 y/o, female, 130 lbs

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Concentration/Response Time Profile

Genotype: CYP2C9*1*2 // VKOR C1 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

• State-of-the-art estimation of optimal warfarin doses, from induction to transitional, maintenance, and INR-adjustment dosing

• Dynamic and interactive tools that respond physician decisions

• Ongoing application of PGx results

• Minimized risk of out-of-range INRs

Randomized Control Pilot Trial • In collaboration with the University of Utah• Standard of care vs PerMIT:warfarin• Target enrollment of 15 subjects per arm• Outcomes• Time to first therapeutic INR• Time to stable therapy• Overall time in range• Incidence of above range INR’s

Outcomes

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

Clinical Implementation– Identify conflicts– Assess impact on care– Manage conflicts• Avoid pro-drugs in PM’s• Increase or decrease dosing• Alert/inform patient of potential side-effects

Thank You