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Laboratory Reports and Services Kristen K. Reynolds, PhD VP Laboratory Operations Copyright 2010 PGXL Laboratories, Louisville KY All materials herein are the exclusive property of PGXL Laboratories Overview • Test menu and clinical applications • Report formats • Consultation and support services Current Test Menu PHARMACOGENETICS - CYP2D6 - CYP2C19 - CYP2C9/VKORC1 - CYP2C9 - CYP1A2 - CYP3A4 - CYP3A5 - NAT2 - HLA-B*5701 Abacavir - SLC6A4 Serotonin Transporter - SLCO1B1 Statins - SULT4A1 Olanzapine - MTHFR - Factor II (Prothrombin 20210 G>A) - Factor V Leiden - Hepatitis-B Virus DNA Quantitative MOLECULAR ONCOLOGY - CYP2D6 tamoxifen KRAS BRAF BCR/ABL (quantitative) FUTURE OPRM1 (opioid sensitivity/resistance) PGXL Core Panel Metabolism of >85% of medications CYP2D6 CYP2C9 CYP2C19 CYP3A4 CYP3A5 CYP1A2 Panels* Panel 1: Panel 2: CYP2D6 CYP2C9 CYP2C19 CYP3A4 CYP3A5 CYP1A2 Panel 1 + thrombophilia (FVL, FII, MTHFR) *All genes always orderable a la carte Panel Add-Ons (build specialtyspecific): VKORC1 (warfarin) SLC6A4 (SSRIs) SLCO1B1 (statins) OPRM1 (opioids) Genotype Frequency % Gene EM IM PM UM 2D6 53 35 10 2 2C19 36 32 4 28 2C9 57 40 3 NA 3A4 87 12 1 NA 3A5 1 18 81 NA Genotype Interpretations Regulations require Summary of variants and methods Clinical interpretation • Including limitations, clinical implications • Implications can be based on the patient-specific scenario CLIA; Mol 36000, 36125; MOLPATH Checklist, CAP 2010; NACB PGx LMPG 2010 Should the result be linked to a specific drug usage? – Associating genotype to clinical metabolizer status • Genotype AND substrate dependent • Prodrug versus active drug – Providing patient-specific drug-gene interaction information • Inducers, inhibitors NACB PGx LMPG 2010 Application of PGx to Cardiology Cardiology Med List CARDIOLOGY Anti-Arrhythmics, Anti-Hypertensives Amlodipine Norvasc Carvedilol Coreg Diltiazem Cardizem Felodipine Plendil Flecainide Tambocor Lercanidipine Zanidip Losartan Cozaar Metoprolol Toprol-XL Nifedipine Adalat Nisoldipine Sular Nitrendipine Various brands Propafenone Rythmol Propanolol Inderal, various Quinidine Various brands Timolol Blocadren Verapamil Various brands CYP3A4/CYP3A5 CYP2D6 CYP3A4/CYP3A5 CYP3A4/CYP3A5 CYP2D6 CYP3A4/CYP3A5 CYP2C9 CYP2D6 CYP3A4/CYP3A5 CYP3A4/CYP3A5 CYP3A4/CYP3A5 CYP2D6 CYP2D6 CYP3A4/CYP3A5 CYP2D6 CYP3A4/CYP3A5 Antithrombotics Clopidogrel** Rivaroxaban Ticareglor Warfarin Plavix Xarelto Brilinta Coumadin CYP2C19 CYP3A4/CYP3A5 CYP3A4/CYP3A5 CYP2C9 Statins Atorvastatin Fluvastatin Lovastatin Mevastatin Rosuvastatin Simvastatin Lipitor Lescol Mevacor, Advicor Compactin Crestor Zocor, Vytorin, Caduet, Simcor CYP3A4/CYP3A5 CYP2C9 CYP3A4/CYP3A5 CYP3A4/CYP3A5 CYP2C9 CYP3A4/CYP3A5 **indicates prodrug n i r a r f Warfarin Genotyping . 0 0 2 . 4 1 . 8 1 . 2 0 . 6 0 0 . 0 0 a 3 W 0 - 0 C Y P 2 C 9 C Y P 2 C 9 * C Y P 2 C 9 * S CYP2C9 sets the rate, affects time to SS 0 (accumulation and elimination) 0 3 6 9 1 21 T 51 i 82 m 0.8 (predicts warfarin sensitivity) 0.6 42 e 73 ( 6.7 ± 3.3 mg 0.7 S-warfarin VKORC1 sets the target concentration 12 4.2 ± 2.2 mg 2.7 ± 1.2 mg 0.5 0.4 0.3 A/A A/G VKORC1 G/G 0 d a y Warfarin Genotyping Guides dose selection –Estimates Maintenance Dose Requirement Guides optimal INR interpretation –Estimates Time to Reach Steady-State CYP2C9 *2/*3 CYP2C9 Phenotype Poor Metabolizer THERAPEUTIC IMPLICATIONS (adapted from published resources) Decreased metabolic clearance expected. Adjust Dosage Adjustment Phenytoin† decrease 50% Adjust based on multiple factors Warfarin† VKORC1 GA VKORC1 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) Intermediate Average VKORC1 enzyme expression and average warfarin dose requirement expected. warfarin sensitivity WARFARIN DOSE INFORMATION Estimated time to steady-state: Delayed, 16-22 days Estimated warfarin maintenance dose requirement: 3.9 mg/day‡ _ 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 CYP2C9 Celecoxib Celebrex Ibuprofen Advil, Motrin Naproxen Aleve Glyburide Diabeta Glipizide Glucotrol Tolbutamide Orinase Glimepiride Amaryl Phenytoin Dilantin Fluvastatin Lescol Rosuvastatin Crestor Losartan Cozaar CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012 Anti-platelet therapy 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 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% 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 $2.9M Prasugrel 990 500 $ 11,710 $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 CYP2C19 *2/*2 CYP2C19 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) Poor Metabolizer Avoid Clopidogrel** Alternative Consideration Adjust Dosage Adjustment Prasugrel Imipramine† Sertraline† decrease 30% decrease 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 2C19 all RESULTS Gene THERAPEUTIC IMPLICATIONS (adapted from published resources) Phenotype Avoid Alternative Consideration Adjust Dosage Adjustment † Caution, consider 30% Caution, consider 50% † 30% 50% ! CYP2C19 *1/*2 Intermediate Metabolizer Clopidogrel* Prasugrel Imipramine † Sertraline X CYP2C19 *2/*2 Poor Metabolizer Clopidogrel* Prasugrel Imipramine † Sertraline X CYP2C19 *17/*17 Ultra-Rapid Metabolizer Increased metabolic clearance expected. Possible increased risk of bleeding events with clopidogrel. CYP2C19 *1/*1 Extensive Metabolizer Normal metabolic clearance expected. up to 150% Citalopram † up to 150% Escitalopram † 100-200% Omeprazole † 50-100% Esomeprazole † 200% Lansoprazole † 400% Pantoprazole Common CYP2C19 medications next page ! CYP2C19 *2/*17 Or *3/*17 Intermediate ∫ Metabolizer Decreased metabolic clearance expected based on presence of the inactive allele. Imipramine † Sertraline † † Caution, consider 30% Caution, consider 50% CYP2C19 Clopidogrel Citalopram Escitalopram Imipramine Sertraline Diazepam Omeprazole Esomeprazole Pantoprazole Rabeprazole Lansoprazole Nelfinavir Plavix Celexa Lexapro, various Tofranil Zoloft Valium Prilosec Nexium Protonix Aciphex Prevacid Viracept CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012 Statin Therapy Statin therapy reduces risk of CV events Statin therapy can lead to muscle weakness – Myalgia – Myopathy – Rhabdomyolysis Genotyping can guide statin choice and dose CYP3A4 and 3A5 Together metabolize 50% of all medications 80% redundancy of function Genetic variants in each – decrease enzyme function (clearance) – Increased risk of dose-dependent adverse events CYP3A4/5 master drug list CYP3A4/CYP3A5 Substrates PSYCHIATRY Benzodiazepines Alprazolam Xanax Midazolam Versed Triazolam Halcion Antipsychotics Quetiapine Seroquel Ziprasidone Geodon Buspirone Buspar Lurasidone Latuda Carbamazepine Various brands Antidepressants Desvenlafaxine Pristiq Vilazodone Viibryd Trazadone Desyrel Nefazadone Serzone Reboxetine Edronax Nortriptyline Pamelor, Aventyl CARDIOLOGY Quinidine Ticareglor Rivaroxaban Statins Atorvastatin Lovastatin Mevastatin Simvastatin Ca Channel Blockers Amlodipine Diltiazem Felodipine Lercanidipine Nifedipine Nisoldipine Nitrendipine Verapamil Various brands Brilinta Xarelto Lipitor Mevacor, Advicor Compactin Zocor, Vytorin, Caduet, Simcor Norvasc Cardizem Plendil Zanidip Adalat Sular Various brands Various brands OTHER Antimicrobials/antivirals Clarithromycin Erythromycin Telithromycin Indinavir Nelfinavir Ritonavir Saquinavir Biaxin E-Mycin Ketek Crixivan Viracept Norvir Fortovase Steroids Estradiol Hydrocortisone Progesterone Testosterone Various brands Various brands Various brands Various brands Chemotherapeutics Vincristine Docetaxel Oncovin Taxotere Pain Management Cyclobenzaprine Fentanyl Alfentanil Flexaril Actiq, Duragesic Alfenta Immunosuppressants Cyclosporine Tacrolimus Gengraf Prograf CYP3A4/5 significant variants CYP3A4*22 – Decreased dose requirements for tacrolimus, cyclosporin, simvastatin, atorvastatin, lovastatin, midazolam – 4-8% frequency CYP3A5*3 – Decreased dose requirements vincristine, tacrolimus, cyclosporin – 90% freq Cauc, 50% AA, 60% Asians 3A4 Interpretation CYP3A4 Phenotype Extensive Metabolizer CYP3A4 Phenotype Partially Decreased Metabolizer CYP3A4 Phenotype Decreased Metabolizer CYP3A4 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) Normal metabolic clearance expected. Common CYP3A4 medications below. THERAPEUTIC IMPLICATIONS (adapted from published resources) Decreased metabolic clearance expected with increased risk of dose-dependent side effects. Common CYP3A4 medications below. THERAPEUTIC IMPLICATIONS (adapted from published resources) Decreased metabolic clearance expected with increased risk of dose-dependent side effects. Common CYP3A4 medications below. THERAPEUTIC IMPLICATIONS (adapted from published resources) Adjust Dosage *22 Decreased metabolic clearance expected Simvastatin Decreased with increased risk of dose-dependent side Atorvastatin Metabolizer effects. Lovastatin Tacrolimus Adjustment max 10-20 mg, or consider alternative statin if also SLCO1B1 *5/*5 genotype max 10-20 mg max 10-20 mg decrease by up to 40% 3A5 Interpretation CYP3A5 Phenotype Extensive Metabolizer CYP3A5 Phenotype Partially Decreased Metabolizer CYP3A5 Phenotype Decreased Metabolizer THERAPEUTIC IMPLICATIONS (adapted from published resources) Genotype consistent with the highest baseline enzymatic activity for CYP3A5. Patients with this genotype represent only 1% of the population. Maintenance dosages for most CYP3A5 drugs may be at the higher end of the typical dose range. Common CYP3A5 medications below. THERAPEUTIC IMPLICATIONS (adapted from published resources) Genotype consistent with intermediate CYP3A5 enzymatic activity and represents approximately 20% of the population. For PDMs, maintenance dosages for most CYP3A5 drugs are lower than extensive metabolizers and are higher than decreased metabolizers. THERAPEUTIC IMPLICATIONS (adapted from published resources) Genotype consistent with reduced CYP3A5 enzymatic activity and represents the majority (60-80%) of the population. For DMs, maintenance dosages for most CYP3A drugs are lower than extensive metabolizers. Common CYP3A5 medications below. N Engl J Med 2008;359:789-99. SLC01B1 OATP1B1 ~35% of population are carriers of the SLC01B1*5 allele – Myalgia/muscle cramps – CK> 3x ULN Myopathy: – SLCO1B1 *1/*5; OR = 4.5 (95% CI, 2.6 to 7.7) – SLCO1B1 *5/*5; OR 16.9 (95% CI, 4.7 to 61.1) Most frequently associated with simvastatin > atorvastatin > pravastatin Vanderbilt Algorithm Wilke et al. Clin Pharmaco Ther 2012;92(1). Statin Combo Interpretation CYP3A4 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) Adjust Dosage *22 Decreased Decreased metabolic clearance expected with Metabolizer increased risk of dose-dependent side effects. SLCO1B1 Phenotype Simvastatin Atorvastatin Lovastatin Tacrolimus Adjustment max 10-20 mg, or consider alternative statin if also SLCO1B1 *5/*5 genotype max 10-20 mg max 10-20 mg decrease by up to 40% THERAPEUTIC IMPLICATIONS (adapted from published resources) Avoid >5 Fold Increased Simvastatin Myopathy Risk Alternative Consideration pravastatin, lovastatin, fluvastatin, rosuvastatin, mevastatin Adjust Dosage Adjustment Atorvastatin max 10-20 mg Anti-arrhythmics and Anti-hypertensives 3A4: Ca++ Channel Blockers Amlodipine Diltiazem Felodipine Lercanidipine Nifedipine Nisoldipine Nitrendipine Verapamil CYP3A4 Phenotype Extensive Metabolizer CYP3A4 Phenotype Partially Decreased Metabolizer CYP3A4 Phenotype Decreased Metabolizer Norvasc Cardizem Plendil Zanidip Adalat Sular Various brands Various brands THERAPEUTIC IMPLICATIONS (adapted from published resources) Normal metabolic clearance expected. Common CYP3A4 medications below. THERAPEUTIC IMPLICATIONS (adapted from published resources) Decreased metabolic clearance expected with increased risk of dose-dependent side effects. Common CYP3A4 medications below. THERAPEUTIC IMPLICATIONS (adapted from published resources) Decreased metabolic clearance expected with increased risk of dose-dependent side effects. Common CYP3A4 medications below. CYP2D6 CYP2D6 *4/*4 CYP2D6 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) Poor Metabolizer Avoid Codeine** Hydrocodone** Oxycodone** Tramadol** Tamoxifen** Amitriptyline † Venlafaxine † Risperidone † Alternative Consideration Adjust Dosage Adjustment Morphine, non-opioid Hydromorphone, non-opioid Oxymorphone, non-opioid Consider active drug, non-opioid Anastrozole, exemestane, letrozole Citalopram, sertraline Citalopram, sertraline Quetiapine, olanzapine, clozapine Aripiprazole † 10 mg/day maximum decrease 50% decrease 60% decrease 50% decrease 50% decrease 70% decrease 60% decrease 70% decrease 75%, or atenolol, bisoprolol, carvedilol decrease 50%, or flupenthixol, quetiapine, olanzapine, clozapine Clomipramine † Doxepin † Flecainide † Haloperidol † Imipramine† Nortriptyline † Propafenone † Metoprolol † Zuclopenthixol † **Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to diminished drug clearance. CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012 Application of PGx to Pain Management Pain Meds Generic Brand Alfentanil Alfenta Carisoprodol** Soma Celecoxib Celebrex Codeine** Various brands Cyclobenzaprine Flexaril Fentanyl Actiq, Duragesic Hydrocodone** Various brands Ibuprofen Advil, Motrin Lidocaine Various brands Methadone Various brands Naproxen Aleve Oxycodone** Oxycontin, various Ropivicaine Various brands Tizanidine Zanaflex Tramadol** Ultram, various Zolmipitran Zomig **Indicates prodrug Metabolic Route CYP3A4/CYP3A5 CYP1A2 CYP2C9 CYP2D6 CYP1A2, CYP3A4/CYP3A5 CYP3A4/CYP3A5 CYP2D6 CYP2C9 CYP1A2 CYP2C19 CYP2C9 CYP2D6 CYP1A2 CYP1A2 CYP2D6 CYP1A2 CYP2D6 - Opioids Hydrocodone Oxycodone Codeine Propoxyphene Tramadol Others… CODEINE CYP2D6 PM: inadequate morphine CYP2D6 UM: morphine toxicity CYP3A4 CYP2D6 Morphine Norcodeine Morphine-6-glucuronide Morphine-3-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 Morphine Overdose Case Report #1: Nursing neonate overdose • Healthy male infant difficulty breastfeeding and lethargy starting on day 7, found deceased day 13 • Toxicology: – Blood morphine = 70 ng/mL (normal 0-2.2) – Day 10 breast milk morphine = 87 ng/mL (normal 2-20 ng/mL after repeated 60mg every 6hr ) • Mother Rx 2 wks codeine 30mg+APA 500 mg (Tylenol #3) – 4 tabs first day, only 2 tabs daily thereafter because of maternal somnolence and constipation Koren et al. Lancet 2006;368:704. Maternal CYP2D6 Genotype Results CYP2D6 *1/*2xN = (gene duplication) Ultra-rapid Metabolizer (UM) Leads to increased formation of morphine from codeine Infant was an EM Koren et al. Lancet 2006;368:704. Clinical Case Conclusions CNS depressant effects of codeine due to morphine by CYP2D6 Inherited differences in CYP2D6 can be life-threatening for some breastfed babies “Codeine cannot be considered as a safe drug for all infants during breastfeeding” FDA issued Public Health Advisory August 17, 2007 “Anyone can be an Ultra-rapid Metabolizer without knowing it. The only way to find out is with a genetic test… Among pain relievers, ultra-rapid metabolism has only been reported as a problem with codeine, although it has the potential to affect other narcotics” Koren et al. Lancet 2006;368:704. 8-15-12 FDA Drug Safety Case Report #2: Post-tonsillectomy overdose Codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare, but life-threatening adverse events or death • 3 deaths and 1 case of severe respiratory depression were reported in children (25yo) who received codeine after undergoing tonsillectomy and/or adenoidectomy for obstructive sleep apnea • 3 deaths in children who were CYP2D6 UMs; 1 life-threatening case in an EM • All children received typical codeine doses • Morphine toxicity signs developed within 1-2 days after starting codeine • Supratherpeutic post-mortem morphine concentrations in the 3 death cases FDA recommendations for Physicians: • • Use the lowest effective codeine dose for the shortest period of time on an as-needed basis (i.e., not scheduled around the clock) Counsel parents: – how to recognize the signs of morphine toxicity – Advise them to stop giving the child codeine – Seek medical attention immediately if child exhibits these signs • • FDA-cleared tests are available for determining a patient’s CYP2D6 genotype Consider prescribing alternative analgesics for children Application of PGx to behavioral health Psychiatry Medications – Metabolic Routes PSYCHIATRY Antidepressants Antipsychotics, Mood Stabilizers Generic Amitriptyline Bupropion Citalopram Clomipramine Brand Various brands Wellbutrin Celexa Ananfranil Metabolic Route CYP2D6 CYP1A2, (CYP2B6) CYP2C19 CYP2D6, CYP1A2 Desipramine Desvenlafaxine Doxepin Duloxetine Escitalopram Fluoxetine Fluvoxamine Imipramine Norpramin Pristiq Sinequan Cymbalta Lexapro, various Prozac Luvox Tofranil Maprotiline Mianserin Mirtazapine Nefazadone Nortriptyline Ludiomil Various brands Remeron Serzone Pamelor, Aventyl Paroxetine Reboxetine Sertraline Trazadone Trimipramine Venlafaxine Vilazodone Paxil Edronax Zoloft Desyrel Surmontil Effexor Viibryd CYP2D6 CYP3A4/CYP3A5 CYP2D6 CYP2D6, CYP1A2 CYP2C19 CYP2D6 CYP2D6 CYP2D6, CYP2C19, CYP1A2 CYP2D6 CYP2D6, CYP1A2 CYP2D6, CYP1A2 CYP3A4/CYP3A5 CYP2D6, CYP3A4/CYP3A5 CYP2D6 CYP3A4/CYP3A5 CYP2C19 CYP3A4/CYP3A5 CYP2D6 CYP2D6 CYP3A4/CYP3A5 Generic Alprazolam Amphetamine Aripiprazole Asenapine Atomoxetine Buspirone Carbamazepine Chlorpromazine Clozapine Diazepam Haloperidol Iloperidine Lurasidone Brand Xanax Adderall Abilify Saphris Strattera Buspar Various brands Thorazine Clozaril Valium Haldol Fanapt Latuda Metabolic Route CYP3A4/CYP3A5 CYP2D6 CYP2D6 CYP1A2 CYP2D6 CYP3A4/CYP3A5 CYP3A4/CYP3A5 CYP2D6 CYP1A2 CYP2C19 CYP2D6 CYP2D6 CYP3A4/CYP3A5 Midazolam Olanzapine Perphenazine Promazine Quetiapine Versed Zyprexa Trilafon Sparine Seroquel CYP3A4/CYP3A5 CYP1A2 CYP2D6 CYP1A2 CYP3A4/CYP3A5 Risperidone Thioridazine Triazolam Ziprasidone Zuclopenthixol Risperidol Mellaril Halcion Geodon Various brands CYP2D6 CYP2D6 CYP3A4/CYP3A5 CYP3A4/CYP3A5 CYP2D6 CASE: Depression/ADHD •51 y/o male •Problematic Polypharmacy (Atomoxetine, Topiramate, Oxcarbazapine, Aripaprazole,Valproic acid) •Genotyping results Locus CYP2D6 CYP2C9 CYP2C19 Genotype CYP2D6*4/*6 CYP2C9*2/*3 CYP2C19*1/*1 Phenotype PM PM EM Relevance to case (drugs affected) Medication atomoxetine aripiprazole PGx Gene PM Effect CYP2D6 Reduced clearance Half life ~ 5x longer CYP2D6 80% increase in exposure half-life 2x longer 2D6 Atomoxetine PMs • 4x longer to SS • 4x higher drug levels • 4x longer to wash-out • More likely to have AE Plasma atomoxetine (ng/mL) 2600 20 mg q12h PM 2080 7 2 h rs 1560 1040 EM 520 0 0 24 48 72 96 120 144 168 192 216 240 264 Time (hrs) S S ;E M S S ;P M Strattera and Abilify Monographs 1. Higher blood levels in PMs may lead to higher rate of ADRs 2. PM blood levels ≈ blood levels in EMs taking strong 2D6 inhibitors 3. Dosage adjustment for Strattera or Abilify with CYP2D6 inhibitors: – Initiate at 50% of the usual target dose 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 Plasma atomoxetine (ng/mL) 1500 P M 2 0 mg q12 h 1200 900 600 P M 10 mg q12 h 300 EM 0 0 24 48 72 96 120 144 168 192 216 240 264 Time (hrs) S S ;E M S S ;P M CYP2D6 genotyping may be useful in predicting which patients are at increased risk of atomoxetine and aripiprazole–induced ADRs. Aripiprazole Accumulation Aripirazole blood concentrations (ng/mL) According to CYP2D6 Genotype EM 10 mg/d PM 10 mg/d PM 5 mg/d 400 300 200 100 0 0 200 400 600 Time (hrs) 800 1000 1200 Dosing guidelines for inhibitors may be considered for PM dose adjustments Surja, Reynolds, Linder, El-Mallakh. Pers Med 2008;5(4):361-365 2D6 Paroxetine P aroxetine A ccumulation (20 mg q 24 hr) Plasma paroxetine (ng/mL) 70 PM 56 144 hr 42 28 EM 14 0 0 92 184 276 S S ;P M S S ;E M Tim e (hr s) 368 460 CYP2D6 *4/*4 CYP2D6 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) Poor Metabolizer Avoid Alternative Consideration Adjust Dosage Adjustment Codeine** Hydrocodone** Oxycodone** Tramadol** Tamoxifen** Amitriptyline † Venlafaxine † Risperidone † Morphine, non-opioid Hydromorphone, non-opioid Oxymorphone, non-opioid Consider active drug, non-opioid Anastrozole, exemestane, letrozole Citalopram, sertraline Citalopram, sertraline Quetiapine, olanzapine, clozapine Aripiprazole † Clomipramine † Doxepin † Flecainide † Haloperidol † Imipramine† Nortriptyline † Propafenone † Metoprolol † 10 mg/day maximum decrease 50% decrease 60% decrease 50% decrease 50% decrease 70% decrease 60% decrease 70% decrease 75%, or atenolol, bisoprolol, carvedilol decrease 50%, or flupenthixol, quetiapine, olanzapine, clozapine Zuclopenthixol † **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 RESULTS Gene X CYP2D6 *4/*4 THERAPEUTIC IMPLICATIONS (adapted from published resources) Phenotype Poor Metabolizer Avoid Codeine* Hydrocodone* Oxycodone* Tramadol* Normal metabolic clearance expected. Adjustment 10 mg/day maximum 50% 60% 50% 50% 70% 60% 70% 75%, or atenolol, bisoprolol, carvedilol † Zuclopenthixol 50%, or flupenthixol, quetiapine, olanzapine, clozapine Common CYP2D6 medications next page Oxycodone* Hydrocodone* † Propafenone Oxymorphone, non-opioid Hydromorphone, non-opioid Sotalol, disopyramide, quinidine, amiodarone Quetiapine, olanzapine, clozapine Citalopram, sertraline Codeine* Tramadol* Tamoxifen* Morphine, non-opioid Hydromorphone, non-opioid Oxymorphone, non-opioid Citalopram, sertraline Citalopram, sertraline Citalopram, sertraline Methylphenidate Quetiapine, olanzapine, clozapine Flupenthixol, quetiapine, olanzapine, clozapine Sotalol, disopyramide, quinidine, amiodarone Tramadol* † Imipramine † Nortriptyline † Venlafaxine Tamoxifen* Amitriptyline † Venlafaxine † Risperidone CYP2D6 *1/*1 ! CYP2D6 *1/*4 Extensive Metabolizer Intermediate Metabolizer Risperidone † † † Velafaxine X CYP2D6 *1/*1xN Ultra-Rapid Metabolizer Codeine* Hydrocodone* Oxycodone* † Amitriptyline † Clomipramine † Paroxetine † Atomoxetine † Risperidone Zuclopenthixol Propafenone † † Alternative Consideration Morphine, non-opioid Hydromorphone, non-opioid Oxymorphone, non-opioid Consider active drug, nonopioid Anastrozole, exemestane, letrozole Citalopram, sertraline Citalopram, sertraline Quetiapine, olanzapine, clozapine Adjust Dosage † Aripiprazole † Clomipramine † Doxepin † Flecainide † Haloperidol † Imipramine † Nortriptyline † Propafenone † Metoprolol † Amitriptyline † Imipramine † Nortriptyline † Zuclopenthixol † Doxepin † Flecainide † Metoprolol Haloperidol † † Doxepin † Metoprolol 15-60 mg/hr titrate to pain relief Avoid CYP2D6 inhibitors, e.g. paroxetine, or consider aromatase inhibitor in postmenopausal women 25% 30% 40% 25% 20% 25% 50%, or atenolol, bisoprolol, carvedilol 30% 70% 60% 150%, or citalopram, sertraline based on plasma measurement, or pimozide, flupenthixol, fluphenazine, quetiapine, olanzapine, clozapine 100% up to 250%, or atenolol, bisoprolol, carvedilol CYP2D6 Pain Management Codeine** Oxycodone** Hydrocodone** Tramadol** Various brands Oxycontin, various Various brands Ultram, various Cardiology Carvedilol Metoprolol Propanolol Timolol Propafenone Flecainide Coreg Toprol-XL Inderal, various Blocadren Rythmol Tambocor Other Loratadine Donepezil Dextromethorphan Tamoxifen** Claritin Aricept Various brands Various brands Psychiatry Antidepressants Fluoxetine Fluvoxamine Paroxetine Venlafaxine Duloxetine Maprotiline Mirtazapine Amitriptyline Clomipramine Desipramine Doxepin Imipramine Nortriptyline Trimipramine Prozac Luvox Paxil Effexor Cymbalta Ludiomil Remeron Various brands Ananfranil Norpramin Sinequan Tofranil Pamelor, Aventyl Surmontil CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012 Antipsychotics Haloperidol Risperidone Aripiprazole Zuclopenthixol Perphenazine Thioridazine Iloperidine Chlorpromazine Atomoxetine Amphetamine Haldol Risperidol Abilify Various brands Trilafon Mellaril Fanapt Thorazine Strattera Adderall PGXL Psych Panels* PGXL Depression Panel STA2R Panel = Psychosis 2D6 2C19 2C9 1A2 3A4 3A5 Add on: SLC6A4 SULT4A1:olanzapine 2D6 2C19 2C9 1A2 3A4 3A5 SLC6A4 *updated as of 11-20-12 Serotonin Transporter (SLC6A4) add-on SLC6A4 • 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 • S/S, S/LG, or LG/LG should be considered for non-SSRI therapies SLC6A4 interpretations SLC6A4 Phenotype Normal Responder SLC6A4 Phenotype Intermediate Responder SLC6A4 Phenotype Poor Responder THERAPEUTIC IMPLICATIONS (adapted from published resources) Normal serotonin transporter expression expected. Patients with the LA/LA genotype are more likely to respond within the first 4 weeks of therapy, achieve remission, and are less likely to have adverse effects when treated with SSRIs. THERAPEUTIC IMPLICATIONS (adapted from published resources) Carriers of S or LG alleles may have decreased serotonin transporter expression compared to LA/LA subjects. Possible risk of decreased or slower response to SSRIs or increased risk of adverse events. THERAPEUTIC IMPLICATIONS (adapted from published resources) Decreased serotonin transporter expression expected. Risk of decreased response to SSRI-based therapies and increased risk of adverse events. Consider non-SSRI antidepressant therapies, such as SNRIs or tricyclic antidepressants alternatives. Antidepressants 2C19 2C19 2D6 2D6,1A2 2D6 2C19 3A4/5 SSRIs citalopram escitalopram fluoxetine fluvoxamine paroxetine sertraline vilazodone Celexa Lexapro Prozac Luvox Paxil Zoloft Viibryd 2D6,1A2,3A4/5 2D6,1A2 2D6,2C19 2D6 2D6 2D6,3A4/5 2D6,3A4/5,2C19 TCAs amitriptyline clomipramine desipramine doxepin imipramine nortriptyline trimipramine Elavil Anafranil Norpramin Sinequan Tofranil Pamelor, Aventyl Surmontil 2C19 MAOIs phenelzine tranylcyromine isocarboxazid moclobemide Black, major pathway; gray, minor pathway Nardil Parnate Marplan 2D6,1A2 2D6 3A4/5 renal 2D6,1A2,3A4/5 SNRIs duloxetine venlafaxine desvenlafaxine milnacipran mirtazapine 2B6,1A2 3A4/5 3A4/5 2D6 2D6,1A2 3A4/5 Atypicals (NRIs, NDRIs) bupropion Wellbutrin trazadone Desyrel nefazadone Serzone maprotiline Ludiomil mianserin reboxetine Edronax Cymbalta Effexor Pristiq Savella Remeron PGXL Depression Panel (Panel + SLC6A4 add-on) DRAFT SLC6A4 S/S SLC6A4 THERAPEUTIC IMPLICATIONS (adapted from published resources) Phenotype Poor Responder Decreased serotonin transporter expression expected. Risk of decreased response to SSRIbased therapies and increased risk of adverse events. Consider non-SSRI antidepressant therapies, such as SNRIs or tricyclic antidepressant alternatives. CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012 PGXL exclusive provider of SULT4A1 marker (schizophrenia, bipolar disorder) – Enhanced efficacy on olanzapine – Reduced risk of hospitalization – Reduced hospitalization costs SULT4A1 Brain enzyme that interacts with neurochemicals Efficacy advantage with olanzapine Efficacy Hospitalization SULT4A1 Interpretations Gene THERAPEUTIC IMPLICATIONS (adapted from published resources) SULT4A1-1 Consider olanzapine. SULT4A1-1 positive patients have been shown to demonstrate POSITIVE enhanced treatment efficacy and reduced hospitalization risk when treated with olanzapine compared to both SULT4A1-1 negative patients treated with olanzapine and SULT4A1-1 positive patients treated with risperidone. SULT4A1-1 SULT4A1-1 negative patients treated with olanzapine do not display the expected efficacy NEGATIVE advantage compared to other atypical antipsychotics. Is olanzapine likely to have increased efficacy? Yes See SULT4A1 Does consensus data suggest alternatives to risperidone? Yes See CYP2D6 Are SSRIs likely to have decreased efficacy and increased Yes risk of side effects? See SLC6A4 See below for possible dosage considerations. STA2R Panel Report SULT4A1 rs763120 CC rs5764010 TT SULT4A1-1 THERAPEUTIC IMPLICATIONS (adapted from published resources) Phenotype POSITIVE Consider olanzapine. SULT4A1-1 positive patients have been shown to demonstrate enhanced treatment efficacy and reduced hospitalization risk when treated with olanzapine compared to both SULT4A1-1 negative patients treated with olanzapine and SULT4A1-1 positive patients treated with risperidone. CYP2D6 *4/*4 CYP2D6 Phenotype Poor Metabolizer THERAPEUTIC IMPLICATIONS (adapted from published resources) Avoid Alternative Consideration Adjust Dosage Adjustment Risperidone† Venlafaxine† Amitriptyline† Quetiapine, olanzapine, clozapine Citalopram, sertraline Citalopram, sertraline Aripiprazole† Clomipramine† Doxepin† Haloperidol† Imipramine† Nortriptyline† Zuclopenthixol† 10 mg/day maximum Decrease 50% Decrease 60% Decrease 50% Decrease 70% Decrease 60% Decrease 50%, or flupenthixol, quetiapine, olanzapine, clozapine SLC6A4 S/S SLC6A4 THERAPEUTIC IMPLICATIONS (adapted from published resources) Phenotype Poor Responder Decreased serotonin transporter expression expected. Risk of decreased response to SSRIbased therapies and increased risk of adverse events. Consider non-SSRI antidepressant therapies, such as SNRIs or tricyclic antidepressant alternatives. CYP2C19 *2/*2 CYP2C19 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) Poor Metabolizer Decreased metabolic clearance expected. Adjust Dosage Adjustment Imipramine† Sertraline† Decrease 30% Decrease 50% CYP1A2 *1F/*1F CYP1A2 THERAPEUTIC IMPLICATIONS (adapted from published resources) SLC6A4 S/S Phenotype SLC6A4 THERAPEUTIC IMPLICATIONS (adapted from published resources) HYPERINDUCER Rapid metabolism expected, especially in smokers. Consider dose increases for Phenotype medications inactivated by CYP1A2 particularly in smokers, or decreased alternative medications. Poor Responder Decreased serotonin transporter expression expected. Risk of response to SSRICommon CYP1A2 next based therapies andmedications increased risk ofpage. adverse events. Consider non-SSRI antidepressant *Lack of efficacy duetherapies, to failure tosuch produce active metabolite; risk of adverse events due to as SNRIs or tricyclic†Increased antidepressant alternatives. diminished drug clearance. CYP3A4 Phenotype Partially Decreased Metabolizer CYP3A5 Phenotype Decreased Metabolizer CYP1A2 Phenotype Hyperinducer THERAPEUTIC IMPLICATIONS (adapted from published resources) Decreased metabolic clearance expected with increased risk of dose-dependent side effects. Common CYP3A4 medications below. THERAPEUTIC IMPLICATIONS (adapted from published resources) Genotype consistent with reduced CYP3A5 enzymatic activity and represents the majority (60-80%) of the population. For DMs, maintenance dosages for most CYP3A drugs are lower than extensive metabolizers. Common CYP3A5 medications below. THERAPEUTIC IMPLICATIONS (adapted from published resources) Rapid metabolism expected, especially in smokers. Consider dose increases for medications inactivated by CYP1A2 particularly in smokers, or alternative medications not metabolized by CYP1A2. Common CYP1A2 medications below. Thrombophilia panel Thrombophilia Panel • Factor V Leiden • Factor II (prothrombin) • MTHFR X Factor V Leiden AA >9 fold Increased Thrombosis Risk Female, Positive family history of thrombotic events: avoid estrogen-containing oral contraceptives and consider alternative contraceptive (e.g., IUD or progestin-only contraceptive). ! Factor II GA 2-3 fold Increased Thrombosis Risk X MTHFR 677 TT 1298 AA Increased Risk Negative family history of thrombotic events: avoid additional risk factors (e.g., obesity, smoking). Increased risk of hyperhomocysteinemia, coronary artery disease, and thrombosis when folate deficiency is present. Consider folate supplementation. Factor V Leiden High Thrombosis Risk: This genotype result revealed that the patient is homozygous for (has two copies of) the Factor V Leiden (1691 G>A) variant, which has been associated with an increased risk of thromboembolic events. This variant is found in approximately 4% of individuals in the U.S. Presence of the Factor V Leiden variant increases the risk of venous thromboembolism (VTE) by 3-8 fold in heterozygous carriers and >9 fold in homozygous carriers. Factor II Moderate Thrombosis Risk: This genotype result revealed that the patient is heterozygous for (has one copy of) the Factor II (Prothrombin) 20210 G>A variant, which has been associated with an increased risk of thromboembolic events. This variant is found in approximately 2% of individuals in the U.S. Presence of the Factor II 20210G>A variant increases the risk of venous thromboembolism (VTE) by 2-3 fold in heterozygous carriers and >3 fold in homozygous carriers. MTHFR Increased Risk: Presence of the 677 C>T polymorphism of MTHFR leads to decreased MTHFR enzymatic activity and elevated homocysteine. This patient’s genotype is consistent with an increased risk of hyperhomocysteinemia, atherosclerotic heart disease, myocardial infarction, cerebrovascular disease, and venous thrombosis. Additionally, associations between the 677 C>T polymorphism and increased risk for methotrexate toxicity, increased 5-fluorouracil chemosensitivity, and increased risk of fetal neural tube defects in pregnant women have also been reported in states of folate deficiency. Consultation Services PGXL provides state-of-the-art interpretive reports with actionable guidance PGXL medical directors are available for clinical consultation with ordering practitioners before and after testing Ongoing VIP review consultation after 50-100 patients tested Educational lecture series and/or CME events as needed Thank You! [email protected]
