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Kristen K. Reynolds, PhD Associate Medical Director, VP Laboratory Operations Copyright 2010 PGXL Laboratories LLC, Louisville KY All materials herein are the exclusive property of PGXL Laboratories Enabling Personalized Medicine Intuitive Medicine Precision Medicine ~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 and psychotropic receptor variants alter drug dose and/or selection SSRI TCA SNRI PD Response 5-HTT 5-HTR2A DRD2 FGA SGA Dependent on drug concentration, receptor expression and affinity PK PMs Metabolism CYP2D6 EMs X Clearance UMs 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. Genetics of Warfarin metabolism and response • 40% of population have deficient CYP2C9 • > 70% of population have decreased VKOR and are more sensitive to warfarin r a f r a 4 0 C Y P 2 C 9 Accumulation 0 0 C Y P 2 C 9 C Y P 2 C 9 S 2 Steady-State - 8 0 W 0 CYP2C9 status increases magnitude of accumulation/unit dose as well as time to achieve steady-state 6 0 0 0 0 3 6 91 12 T Linder et al. J Thrombosis & Thrombolysis 2002;14:227-232 15 28 i 21 m 24 37 e 0 ( d VKORC1 -1639 G>A genotype dictates S-warfarin therapeutic concentration All within INR 2-3 Dose 2.7 ± 1.2 mg Zhu Y et al. Clin Chem 2007;53(7):1199-1205. Dose 4.2 ± 2.2 mg Dose 6.7 ± 3.3 mg PerMIT:Warfarin © Powered by PGXL Laboratories • Calculation of estimated maintenance dose • Modeling of individualized response to dose changes • Guidance for: Monitoring strategy Dosing modifications Transition: induction to maintenance therapy All; 66 y/o, female, 130 lbs No Loading Dose PerMIT-guided Loading Dose Concentration/Response Time Profile Genotype: CYP2C9*1*2 // VKORC1 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 . . . . . . 6 mg/d. . . . . . . 10, 10, 8, 6 mg/d CONFIDENTIAL Linder MW et al. 2011 (unpublished results) 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 Incidence of Adverse events in patients prescribed standard dosages of Clopidogrel by CYP2C19 Phenotype. PHENOTYPE Stent Thrombosis EM CV death, MI, Ischemic Stroke 8% (BASELINE) 8.9% 1.4% IM 10% 2.4% PM 12.7% 5.7% Mega et.al., JAMA. 2010;304(16);1821-1830. 0.9% New Draft Report THERAPEUTIC IMPLICATIONS Gene X CYP2C19 *2/*2 Phenotype Poor Metabolizer Avoid Clopidogrel* 1 Alternative Consideration Prasugrel Adjust Dosage † Imipramine † Sertraline Adjustment 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. CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012 Application of Pharmacogenetics to Pain Management CYP2D6 - Opioids • • • • Hydrocodone Oxycodone Methadone Others… • Propoxyphene • Tramadol • Codeine CODEINE CYP2D6 PM: inadequate morphine CYP2D6 UM: morphine toxicity CYP3A4 CYP2D6 Morphine Norcodeine Morphine-6-glucuronide Morphine3-glucuronide Renal Excretion Reynolds KR et al. Clin Lab Med 2008;28:581–598. Active opioid effects Effects of CYP2D6 • 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 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 CASE: Depression/ADHD • 51 y/o male • Problematic Polypharmacy (Atomoxetine, Topiramate, Oxcarbazapine, Aripaprazole,Valproic acid) • Genotyping results Locus CYP2D6 CYP2C9 CYP2C19 28 Genotype CYP2D6*4/*6 CYP2C9*2/*3 CYP2C19*1/*1 Phenotype PM PM EM Relevance to case (drugs affected) Medication atomoxetine aripiprazole 29 PGx Gene PM Effect CYP2D6 Reduced clearance. Half life ~ 5 times longer CYP2D6 80% increase in exposure, half-life twice as long How to apply PGx to atomoxetine therapy? • • • • Adjust dosage based on PK Goal to achieve normalized exposure and ADR risk Adjust monitoring expectations for SS delay Allow for adequate “washout” period Pl asma at omoxet i ne ( ng/ mL) 1500 P M2 0mg q 1 2 h 1200 900 600 P M1 0mg q 1 2 h 300 EM 0 0 24 48 72 96 120 144 168 192 216 240 264 Ti me ( hrs) S S ;E M S S ;P M Medications to avoid by CYP2D6 phenotype UM CODEINE AMITRIPTYLINE CLOMIPRAMINE OXYCODONE RISPERIDONE ZUCLOPENTHIXOL IM PROPAFENONE RISPERIDONE VENLAFAXINE PM CODEINE AMITRYPTYLINE OXYCODONE RISPERIDONE TAMOXIFEN TRAMADOL VENLAFAXINE New Draft Report RESULTS Gene X CYP2D6 *4/*4 THERAPEUTIC IMPLICATIONS Phenotype Poor Metabolizer Avoid Codeine* Hydrocodone* Oxycodone* Tramadol* 1 Alternative Consideration Morphine, non-opioid Hydromorphone, non-opioid Oxymorphone, non-opioid Consider active drug, nonopioid Citalopram, sertraline Citalopram, sertraline Quetiapine, olanzapine, clozapine Anastrozole, exemestane, letrozole Adjust Dosage † Aripiprazole † Clomipramine † Doxepin † Flecainide † Haloperidol † Imipramine † Nortriptyline † Propaphenone † Metoprolol Adjustment 10 mg/day maximum 50% 60% 50% 50% † Amitriptyline 70% † Venlafaxine 60% † Risperidone 70% 75%, or atenolol, Tamoxifen* bisoprolol, carvedilol Zuclopenthixol 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. 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 Medications and metabolic pathways CYP2C9 CYP2C19 CELECOXIB IBUPROFEN NAPROXEN GLYBURIDE GLIPIZIDE TOLBUTAMIDE GLIMEPIRIDE PHENYTOIN FLUVASTATIN LOSARTAN CELEBREX ADVIL, MOTRIN ALEVE DIABETA GLUCOTROL ORINASE AMARYL DILANTIN LESCOL COZAAR CYP2C9/VKORC1 WARFARIN COUMADIN CLOPIDOGREL CITALOPRAM ESCITALOPRAM IMIPRAMINE SERTRALINE OMEPRAZOLE ESOMEPRAZOLE PANTOPRAZOLE RABEPRAZOLE LANSOPRAZOLE DIAZEPAM NELFINAVIR PLAVIX CELEXA VARIOUS BRANDS TOFRANIL ZOLOFT PRILOSEC NEXIUM PROTONIX ACIPHEX PREVACID VALIUM VIRACEPT Medications and CYP2D6 pathway Pain Management Psychiatry Codeine Oxycodone Hydrocodone Dextromethorphan Tramadol Various brands Oxycontin, various Various brands Various brands Ultram, various Cardiology Carvedilol Metoprolol Propanolol Propafenone Flecainide Coreg Toprol-XL Inderal, various Rythmol Tambocor Other Loratadine Donepezil Tamoxifen Claritin Aricept Various brands Amitriptyline Clomipramine Desipramine Doxepin Imipramine Nortriptyline Fluoxetine Paroxetine Venlafaxine Risperidone Aripiprazole Zuclopenthixol Maprotoline Duloxetine Various brands Ananfranil Norpramin Sinequan Tofranil Pamelor, Aventyl Prozac Paxil Effexor Risperidol Abilify Various brands Ludiomil Cymbalta