Mark W Linder, Ph.D., DABCC, FACB Medical 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 PGXL Laboratories LLC, Louisville KY All materials herein are the exclusive property of PGXL laboratories

Enabling Personalized Medicine Intuitive Medicine Precision Medicine 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

4 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

6 Clopidogrel (Plavix) activation. PharmGKB.org

7 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

TreatmentCV EventsBleed EventsICER Genotype guided Clopidogrel $ 6,790 Prasugrel990500$ 11,710 Cost-effectiveness comparisons Reese, E.S. et. al., Pharmacotherapy 2012;32(4):323–332

Application of Pharmacogenomics to warfarin therapy

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

12 40% of population have deficient CYP2C9 > 70% of population have decreased VKOR and are more sensitive to warfarin Genetics of Warfarin metabolism and response

Accumulation Steady-State Linder et al. J Thrombosis & Thrombolysis 2002;14: CYP2C9 status increases magnitude of accumulation/unit dose as well as time to achieve steady-state CONFIDENTIAL

VKORC G>A genotype dictates S-warfarin therapeutic concentration Dose 2.7 ± 1.2 mg Dose 4.2 ± 2.2 mg Dose 6.7 ± 3.3 mg All within INR 2-3 Zhu Y et al. Clin Chem 2007;53(7): CONFIDENTIAL

Calculation of estimated maintenance dose Modeling of individualized response to dose changes Guidance for:  Monitoring strategy  Dosing modifications  Transition: induction to maintenance therapy 16 PerMIT:Warfarin © Powered by PG XL Laboratories CONFIDENTIAL

All; 66 y/o, female, 130 lbs

18 Concentration/Response Time Profile Genotype: CYP2C9*1*2 // VKOR C1 GG Estimated Maintenance dose: 6.3 mg/d (5.7 – 7.0) Time to Steady-State; 11 to 15 days Target therapeutic concentration: 0.8 mg/L mg/d , 10, 8, 6 mg/d Linder MW et al (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

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