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The Next Generation: New Genes and Panels at PGXL Kristen K. Reynolds, PhD VP Laboratory Operations Copyright 2012 PGXL Laboratories, Louisville KY All materials herein are the exclusive property of PGXL Laboratories 2012 Q4 New Genes CYP3A4/3A5: Statins, benzodiazepines, Ca++ channel blockers CYP1A2: Antidepressants, antipsychotics SLCO1B1: Statin-induced myopathy risk SLC6A4 (Serotonin transporter): SSRI antidepressant sensitivity/resistance SULT4A1: Olanzapine OPRM1: Opioid sensitivity/resistance (expected December 2012) CYP3A4 and CYP3A5 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. SLCO1B1 statin myopathy risk • Statin therapy reduces risk of CV events • Statin therapy can lead to muscle weakness and ultimately muscle breakdown with rhabdomyolysis • GWAS studies revealed a single genetic determinant of statin induced myopathy N Engl J Med 2008;359:789-99. SLC01B1 OATP1B1 • ~35% of population are carriers of the SLC01B1*5 allele – Myalgia/muscle cramps • Myopathy on 40mg/day: – SLCO1B1 *1/*5, OR = 2.6 – SLCO1B1 *5/*5, OR = 5.2 • Most frequently associated with simvastatin > atorvastatin > pravastatin Vanderbilt Algorithm Wilke et al. Clin Pharmaco Ther 2012;92(1). SLCO1B1 Interpretation SLCO1B1 THERAPEUTIC IMPLICATIONS (adapted from published resources) Phenotype No Increased RiskNormal OATP1B1 transporter function. No increased risk of statin-induced myopathy expected at low to moderate doses (10-40 mg). Consider 10-20 mg dose if also CYP3A4*22 carrier. SLCO1B1 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) Adjust Dosage 2.6 Fold Increased Myopathy Risk Reduced OATP1B1 transporter function. Increased risk of statin-induced myopathy. Simvastatin Atorvastatin SLCO1B1 Phenotype Adjustment max 10-20 mg and consider monitoring CK levels, or consider alternative statin if also taking verapamil or diltiazem. Consider low 10-20 mg dose of alternative statin if patient also CYP3A4*22 carrier. max 10-20 mg 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 SLC6A4 serotonin transporter SLC6A4 Serotonin Transporter 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 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 Nardil Parnate Marplan Black indicates major pathway; Gray indicates minor pathway SNRIs 2D6,1A2 duloxetine 2D6 venlafaxine 3A4/5 desvenlafaxine renal milnacipran 2D6,1A2,3A4/5 mirtazapine 2B6,1A2 3A4/5 3A4/5 2D6 2D6,1A2 3A4/5 Cymbalta Effexor Pristiq Savella Remeron Atypicals (NRIs, NDRIs) bupropion Wellbutrin trazadone Desyrel nefazadone Serzone maprotiline Ludiomil mianserin reboxetine Edronax 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. CYP1A2 CYP1A2 • Metabolizes many antidepressants and antipsychotics • Inducible by several medications and smoking • Variants cause altered enzymatic activity, particularly in the presence of an inducer • Increased risk of having adverse drug reactions or therapeutic failure to standard dosages of CYP1A2 medications CYP1A2 master drug list CYP1A2 Other Psychiatry Ropivicaine Various brands Olanzapine Zyprexa Lidocaine Various brands Clozapine Clozaril Theophylline Aerolate Imipramine Tofranil Zolmipitran Zomig Clomipramine Anafranil Triamterene Dyrenium Mirtazapine Remeron Flutamide Eulexin Bupropion Wellbutrin Tizanidine Zanaflex Duloxetine Cymbalta Tacrine Cognex Promazine Sparine Cyclobenzaprine Flexaril Asenapine Saphris Caffeine 17-beta estradiol 1A2 Interpretation CYP1A2 Phenotype Normal Inducer THERAPEUTIC IMPLICATIONS (adapted from published resources) Normal metabolic clearance expected. Common CYP1A2 medications below. This patient’s genotype is consistent with normal CYP1A2 enzymatic activity and normal induction in the presence of an inducer, such as tobacco smoke. CYP1A2*1A/*1A patients with inducers have 30% lower plasma concentrations of CYP1A2 substrates such as olanzapine. CYP1A2*1A*1A patients without inducers have a 30% increased plasma concentration over those who have inducers present. CYP1A2 Phenotype Hyperinducer 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. CYP1A2 Hyperinducer: Presence of the CYP1A2*1F allele results in the hyperinduction phenotype. Hyperinduction may yield 20-40% higher CYP1A2 activity compared to the normal *1A allele in the presence of an inducer, such as tobacco smoke. Patients who are homozygous for the CYP1A2*1F/*1F genotype may exhibit even higher rates of CYP1A2 enzymatic activity and have been described as ultra-rapid metabolizers for olanzapine. As an example, carriers of CY1A2*1F with the hyperinduction phenotype may exhibit as much as 50% lower than expected plasma levels of olanzapine, clozapine, and haloperidol, which could lead to sub-therapeutic response. Hyperinducers may require increased dosages of CYP1A2 substrates due to higher than normal rates of drug metabolism in the presence of an inducer. CYP1A2 Phenotype Non-Inducer THERAPEUTIC IMPLICATIONS (adapted from published resources) Normal metabolic clearance not affected by inducers. Consider dose decreases for medications inactivated by CYP1A2 or alternative medications not metabolized by CYP1A2. Common CYP1A2 medications below. SULT4A1 psychosis • PGXL exclusive provider of SULT4A1 marker (schizophrenia, bipolar disorder) 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. How do we implement these new genes? Panels and specialty-specific focus Panels* PGXL Core Panel: Thrombophilia Panel: CYP2D6 CYP2C9 CYP2C19 CYP3A4 CYP3A5 CYP1A2 Factor V Leiden Factor II MTHFR *All genes always orderable a la carte Panel Add-Ons (build specialtyspecific uses): VKORC1 (warfarin) SLC6A4 (SSRIs) SLCO1B1 (statins) OPRM1 (opioids) Specialty Requisition Forms General Practice - DRAFT Cardiology - DRAFT Pain Management - DRAFT OB/GYN - DRAFT Psychiatry - DRAFT Psychosis Depression PGXL Depression Panel DRAFT (Panel + SLC6A4 add-on) 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 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) Phenotype HYPERINDUCER Rapid metabolism expected, especially in smokers. Consider dose increases for medications inactivated by CYP1A2 particularly in smokers, or alternative medications. Common CYP1A2 medications next page. *Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to diminished drug clearance. 2D6 master drug List CYP2D6 Pain Management Codeine** Oxycodone** Hydrocodone** Tramadol** Various brands Oxycontin, various Various brands Ultram, various Cardiology Carvedilol Metoprolol Propanolol Coreg Toprol-XL Inderal, various Timolol Propafenone Flecainide Blocadren Rythmol Tambocor Clomipramine Desipramine Doxepin Imipramine Nortriptyline Claritin Aricept Various brands Various brands Trimipramine Other Loratadine Donepezil Dextromethorphan Tamoxifen** ** indicates prodrug Psychiatry Antidepressants Fluoxetine Fluvoxamine Paroxetine Venlafaxine Duloxetine Maprotiline Mirtazapine Amitriptyline Prozac Luvox Paxil Effexor Cymbalta Ludiomil Remeron Various brands Ananfranil Norpramin Sinequan Tofranil Pamelor, Aventyl Surmontil Antipsychotics Haloperidol Risperidone Aripiprazole Zuclopenthixol Perphenazine Thioridazine Iloperidine Chlorpromazine Haldol Risperidol Abilify Various brands Trilafon Mellaril Fanapt Thorazine Atomoxetine Amphetamine Strattera Adderall 2C19 and 2C9 master drug lists CYP2C19 Clopidogrel** Citalopram Escitalopram Imipramine Sertraline Diazepam Omeprazole Esomeprazole Pantoprazole Rabeprazole Lansoprazole Nelfinavir Methadone Carisoprodol** Voriconazole Plavix Celexa Lexapro, various Tofranil Zoloft Valium Prilosec Nexium Protonix Aciphex Prevacid Viracept Various brands Soma Vfend CYP2C9 Warfarin Celecoxib Ibuprofen Naproxen Glyburide Glipizide Tolbutamide Glimepiride Phenytoin Fluvastatin Rosuvastatin Losartan Coumadin Celebrex Advil, Motrin Aleve Diabeta Glucotrol Orinase Amaryl Dilantin Lescol Crestor Cozaar Cliff Notes on the Portal CYP3A4 CYP3A4 is a liver enzyme that, in concert with CYP3A5, metabolizes approximately 50% of medications, including many of the statins, benzodiazepines, antibiotics, and antipsychotics. Detecting variants of the CYP3A4 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions while taking standard dosages of 3A4 substrates. Roughly 4-10% of the general population possesses inherited differences in 3A4 that cause decreased metabolism. These Decreased Metabolizers may be at increased risk for dose-dependent side effects to drugs normally inactivated by 3A4. SLCO1B1 SLCO1B1 is the gene that makes a liver enzyme called OATP1B1, which helps transport statins medications into the liver more effectively. Roughly 15% of the population possesses the *5 variant, an inherited form of SLOC1B1 which increases risk of statin-induced muscle damage, or myopathy, by 3 to 5 fold. Risk of myopathy with the *5 variant is most closely associated with simvastatin and to a lesser extent, atorvastatin. Patients with the *5 variant may need the lowest doses of simvastatin or an alternative statin to reduce risk of myopathy. SLC6A4 SLC6A4 is the gene that makes the serotonin transporter in the brain. The role of the serotonin transporter is to shuttle the potent brain chemical serotonin from one neuron to another. Inhibiting serotonin transport is associated with improved mood; thus the effectiveness of many antidepressant drugs (namely selective serotonin reuptake inhibitors, SSRIs) is thought to be due to their inhibition of the serotonin transporter. Nearly 75% of people have an inherited form of the SLC6A4 gene that can lead to decreased response to SSRI therapy. The Short (S) and Long G (LG) forms of the transporter are associated with delayed response to SSRI antidepressants and increased risk of adverse drug reactions (ADRs) during antidepressant therapy. Patients who possess two copies of the S or LG forms may be more likely to benefit from non-SSRI therapies. Questions? Thank You! [email protected] 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. 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. 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 Amitriptyline † Venlafaxine † Risperidone CYP2D6 *1/*1 ! CYP2D6 *1/*4 Extensive Metabolizer Intermediate Metabolizer Risperidone † † † Velafaxine X CYP2D6 *1/*1xN Ultra-Rapid Metabolizer ) 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 Tamoxifen* 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 1,4,6 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 2C19 CYP2C19 *1/*2 CYP2C19 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) Intermediate Metabolizer Avoid Alternative Consideration Adjust Dosage Adjustment Clopidogrel** Prasugrel Imipramine† Sertraline† Caution, consider decrease 30% Caution, consider decrease 30% *Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to diminished drug clearance. CYP2C19 Intermediate Metabolizer (IM): This patient’s genotype is consistent with reduced CYP2C19 enzymatic activity. IMs are at slightly increased risk of drug-induced side effects due to diminished drug elimination of active drugs. Patients with reduced CYP2C19 function (IMs) taking clopidogrel may exhibit suboptimal drug activation and may have increased risk for cardiovascular events compared to CYP2C19 extensive metabolizers. CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012 2C19 all † 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 7 increased risk of bleeding events with clopidogrel . CYP2C19 *1/*1 Extensive Metabolizer Normal metabolic clearance expected. Citalopram up to 150% † Escitalopram up to 150% † Omeprazole 100-200% † Esomeprazole 50-100% † Lansoprazole 200% † Pantoprazole 400% 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% CYP2C9 *1/*2 CYP2C9 Phenotype Intermediate Metabolizer VKORC1 GG VKORC1 Phenotype Low warfarin sensitivity THERAPEUTIC IMPLICATIONS (adapted from published resources) Decreased metabolic clearance expected. Adjust Dosage Adjustment Phenytoin† Warfarin† decrease 25% See below THERAPEUTIC IMPLICATIONS (adapted from published resources) Estimated warfarin maintenance dose requirement: 6.20 mg/day‡ Estimated time to steady-state: Delayed, 8-11 days INRs measured before steady state blood concentrations have been achieved should be interpreted with caution as they may not be indicative of stable therapy. **Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to diminished drug clearance. CYP2C9 Intermediate Metabolizer (IM): This patient’s genotype is consistent with reduced CYP2C9 enzymatic activity. Reduced CYP2C9 activity leads to lower warfarin dose requirement due to decreased clearance, increased elimination half-life, and increased time to reach steady-state blood concentrations. The time to reach steady-state affects the timing of INR measurement for optimal interpretation. Time to reach steady-state is the time period required for the dosage to consistently yield reproducible blood concentrations of warfarin. INR measurements are most reliable when measured after steady-state has been achieved. INR measurements before steady-state blood concentrations have been achieved should be interpreted with caution, as they may not be indicative of stable therapy. VKORC1 Low Warfarin Sensitivity: This patient’s genotype is consistent with higher VKORC1 enzyme expression and higher warfarin dose requirement. ‡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 All warf possible CYP2C9 *1/*1 Extensive Metabolizer Normal metabolic clearance expected. Common CYP2C9 medications next page. For warfarin see below. ! CYP2C9 *1/*3 Intermediate Metabolizer Decreased metabolic clearance expected. Phenytoin † Warfarin † 25% See below X CYP2C9 *3/*3 Poor Metabolizer Decreased metabolic clearance expected. Phenytoin † Warfarin † 50% See below High warfarin sensitivity Estimated warfarin maintenance dose requirement: 4.1 mg/day Estimated warfarin time to steady-state: Average, 6-9 days (flex CYP2C9-specific times) INRs measured before steady state blood concentrations have been achieved should be interpreted with caution as they may not be indicative of stable therapy. ‡ Estimated warfarin maintenance dose requirement: 4.6 mg/day Estimated time to steady-state: Delayed, 8-11 days (flex CYP2C9-specific times) INRs measured before steady state blood concentrations have been achieved should be interpreted with caution as they may not be indicative of stable therapy. ‡ Estimated warfarin maintenance dose requirement: 5.6 mg/day Estimated time to steady-state: Delayed, 12-15 days (flex CYP2C9-specific times) INRs measured before steady state blood concentrations have been achieved should be interpreted with caution as they may not be indicative of stable therapy. X VKORC1 AA VKORC1 AG ! VKORC1 GG Intermediate warfarin sensitivity Low warfarin sensitivity ‡ X Factor V Leiden AA ! Factor II GA X MTHFR 677 TT 1298 AA >9 fold Increased Thrombosis Risk Positive family history of thrombotic events: avoid estrogen-containing oral contraceptives and consider alternative contraceptive (e.g., IUD or progestin-only contraceptive). Negative family history of thrombotic events: avoid additional risk factors (e.g., obesity, smoking). 2-3 fold Increased Thrombosis Risk Increased Risk 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. Factor V Leiden GG ! Factor V Leiden GA X Factor V Leiden AA Factor II GG No Increased Thrombosis Risk 3-8 fold Female, Positive family history of thrombotic events: Increased avoid estrogen-containing oral contraceptives and Thrombosis consider alternative contraceptive (e.g., IUD or Risk progestin-only contraceptive). >9 fold Positive family history of thrombotic events: avoid Increased estrogen-containing oral contraceptives and consider Thrombosis alternative contraceptive (e.g., IUD or progestin-only Risk contraceptive). No Increased Thrombosis Risk Female, Negative family history of thrombotic events: avoid additional risk factors (e.g., obesity, smoking). Negative family history of thrombotic events: avoid additional risk factors (e.g., obesity, smoking). ! Factor II GA 2-3 fold Increased Thrombosis Risk X Factor II AA >3 fold Increased Thrombosis Risk MTHFR 677 CC 1298 AA MTHFR 677 CC 1298 AC MTHFR 677 CC 1298 CC MTHFR 677 CT 1298 AA MTHFR 677 CT 1298 AC MTHFR 677 CT 1298 CC X MTHFR 677 TT 1298 CC X MTHFR 677 TT 1298 AC X MTHFR 677 TT 1298 AA No Increased Risk of hyperhomocysteinemia, coronary artery disease, or thrombosis No Increased Risk of hyperhomocysteinemia, coronary artery disease, or thrombosis No Increased Risk of hyperhomocysteinemia, coronary artery disease, or thrombosis No Increased Risk of hyperhomocysteinemia, coronary artery disease, or thrombosis No Increased Risk of hyperhomocysteinemia, coronary artery disease, or thrombosis No Increased Risk of hyperhomocysteinemia, coronary artery disease, or thrombosis Increased Risk Increased risk of hyperhomocysteinemia, coronary artery disease, and thrombosis when folate deficiency is present. Consider folate supplementation. Increased Risk Increased risk of hyperhomocysteinemia, coronary artery disease, and thrombosis when folate deficiency is present. Consider folate supplementation. Increased Risk Increased risk of hyperhomocysteinemia, coronary artery disease, and thrombosis when folate deficiency is present. Consider folate supplementation.
