Pharmacogenomics Dosing Drugs Based on Your Genes

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Presentation transcript:

Pharmacogenomics Dosing Drugs Based on Your Genes Emily Holm, PharmD, BCACP MN Academy of Physician Assistants May 11th, 2018 Talk about why I am giving this talk.

Objectives: Define Pharmacogenomics (PGx) Review Pharmacokinetics/Pharmacodynamics Review Prodrugs vs Active Drugs Learn Basic PGx Concepts Review most common gene/drug interactions Learn how PGx can be used in practice Learn where to find additional PGx resources Review simple and complex patient cases

THE BASICS!

Basic Concepts to Remember Pharmaco: genomics kinetics dynamics

genomics Pharmaco: Basic Concepts Is the study of how a persons genes affect the body’s response to drugs Definition is from Mayo Clinic Center for Individualized Medicine

What the body does to the drug (ADME) Basic Concepts Pharmaco: kinetics What the body does to the drug (ADME) Absorption Distribution Metabolism Elimination

Pharmaco: dynamics Basic Concepts The effect the drug has on the body Genetic variant could make this have a “lack of effect” or toxicity

Types of Metabolizers (phenotypes) Cytochrome P450 System Family of enzymes in the liver responsible for the metabolism of most drugs CYPs of Interest CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4 CYP3A5 Types of Metabolizers (phenotypes) Ultra Rapid Rapid Normal Intermediate Poor The RIGHT study from Mayo looked at 1000 patients PGx and found that 99% of the patients had a least one variant that would effect how certain drugs would be metabolized.

Prodrugs Prodrug Compound that has little or no activity on a desired pharmacological target, but is converted to an active, or more active form by metabolism Few Examples: Venlafaxine Codeine Tramadol Clopidogrel Tamoxifen

Drug Response Active Drug Prodrug Type of Metabolizer (Phenotype) Ultra Rapid Rapid Normal Intermediate Poor Lack of Drug Effect Drug Accumulates Drug Accumulates Lack of Drug Effect

Case E.B. is 45 year old female that presents to clinic for depression Failed or had intolerance (GI upset) the following antidepressants: Fluoxetine Paroxetine Bupropion Nortriptyline Provider starts Venlafaxine ER 37.5mg daily Two weeks later, patient reports symptoms have not improved so the provider increases the dose to 75mg daily. Two weeks, patient returns to clinic with no improvement

Case What is the cost? Provider decides to order PGx How is it collected? Buccal swab Blood sample Saliva sample What is the cost? Historically, $2000-$3000 Starting at the beginning of April 2017 prices dropped $250 Dropped

Case- PGx Results Gene (Metabolizing Enzyme) Genotype Phenotype CYP2D6 *4/*4 Poor SLCO1B1 *1/*5 Increased Risk HLA-B*5801 Negative Normal Risk CYP1A2 Multiple Variations Normal CYP2C9 *1/*1 CYP2C19 *1/*2 Intermediate VKORC1 -1639 GA Intermediate Sensitivity CYP3A4 CYP3A5 *3/*3 Genotype = variant Phenotype is the trait

PGx Results Patient is poor CYP2D6 metabolizer Venlafaxine is a prodrug Drug Accumulates Patient not be able to metabolize venlafaxine into the active form, therefore the drug will not be effective. Talk about the other intolerances to paroxetine, fluoxetine, nortriptyline, bupropion.

Desvenlafaxine (Active metabolite of venlafaxine) Plan Switch venlafaxine to an antidepressant that is not metabolized by CYP2D6 Escitalopram (CYP2C19) Citalopram (CYP2C19) Sertraline (CYP2C19) Desvenlafaxine (Active metabolite of venlafaxine) If you want to do a PA.

How is PGx useful? Eliminates Medication Trial and Error Avoids Therapeutic Failure Decreases Medication Adverse Effects Decreases Cost Individualizes Patient Care

Pertain To All Medications Explain Drug Allergies PGx DOES NOT Pertain To All Medications Explain Drug Allergies Explain Drug-Drug Interactions Explain Drug-Food Interactions Still have to look at the patient as a whole. Still need to look at renal function/hepatic function Drug Pharmacology/Drug-Drug interactions/then PGx. Ask yourself.. Does this make sense?

Important Drug-Gene Pairs allopurinol HLA-B*5801 warfarin CYP2C9/ VKORC1 clopidogrel, citalopram, escitalopram, sertraline CYP2C19 codeine, tramadol, tamoxifen, venlafaxine, fluoxetine, paroxetine CYP2D6 simvastatin SLCO1B1 This list is not all inclusive

HLA-B*5801 and Allopurinol HLA-B*5801 is linked to life-threatening cutaneous adverse reactions (SCAR) in some populations (Stevens-Johnson Syndrome) American College of Rheumatology published updated guidelines in 2012 for the management of gout, including consideration of HLA-B*5801 testing prior to the initiation of allopurinol in select populations (Asian descent). If patient is found to carry the HLA-B*5801 allele, the use of allopurinol is considered contraindicated Frequency in Asian populations is 6%-12%. Universal HLA-B*58:01 screening prior to prescribing allopurinol is not recommended, based on current evidence that Caucasians (HLA-B*58:01 allele frequency of ~2%) are at much lower risk than Asian populations (HLA-B*58:01 allele frequency of ~6 to 12%), in part due to differences in allele frequency AME https://askmayoexpert.mayoclinic.org/topic/clinical-answers/gnt-20137278/sec-20137275 Accessed 03/28/17

HLA-B*5801 and Allopurinol Recommendations: Alternative options if allopurinol is contraindicated: Treatment of gout Probenecid Uloric® (febuxostat)

CYP2C9/VKORC1 and Warfarin Warfarin metabolism is influenced by variants in the CYP2C9 and VKORC1 genes Patients with non-wild type CYP2C9 alleles may have altered metabolism Warfarin decreases vitamin K-dependent clotting factors by inhibiting the VKOR enzyme Dosage requirements 25% lower in the GA genotype 50% lower in the AA genotype

CYP2C9/VKORC1 and Warfarin Recommendations: Dosing Table for starting warfarin (Adapted from Ask Mayo Expert) CYP2C9 VKORC1 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5 to 7mg 3 to 4mg 0.5 to 2mg GA AA https://askmayoexpert.mayoclinic.org/topic/clinical-answers/gnt-20143449/sec-20143470

Case- PGx Results

Case CYP2C9 is normal - *1/*1 VKORC1 is GA: Intermediate sensitivity Routine genotyping prior to initiation of warfarin therapy is not currently recommended. This is in keeping with the most recent Chest 2012 guidelines on anticoagulant management. However, if genotype test results are available, they may assist in guiding warfarin initiation.

CYP2C19 and Clopidogrel Clopidogrel is a prodrug Effectiveness is dependent on metabolism to active metabolite by CYP2C19 Poor metabolizers with acute coronary syndrome or those undergoing percutaneous coronary intervention display higher cardiovascular event rates when treated with clopidogrel at normal doses than patients who are normal metabolizer CYP2C19 loss-of-function alleles appear to be associated with higher rates of recurrent cardiovascular events in patients receiving clopidogrel. https://askmayoexpert.mayoclinic.org/topic/clinical-answers/gnt-20136538/sec-20136547

CYP2C19 and Clopidogrel Recommendations: Alternative medications should be considered for patient who are intermediate to poor metabolizers Brilinta® (ticagrelor) Effient® (prasugrel) Preemptive PGx is not currently recommended by the ACCF/AHA TAILOR-PCI trial Studying if CYP2C19 preemptive genotyping in patients undergoing PCI improves outcomes http://mayoresearch.mayo.edu/center-for-individualized-medicine/cardiovascular-disease-study.asp Tye – KA- grel- or Finding 30% of patients have genetic variation that interferes with CYP2C19 metabolism. I am one of these people.

CYP2C19 and Citalopram/Escitalopram/Sertraline Citalopram, escitalopram, sertraline are active drugs Primarily metabolized via CYP2C19 Intermediate to Poor metabolizers have an increased risk of adverse drug events due to drug accumulation https://askmayoexpert.mayoclinic.org/topic/clinical-answers/gnt-20148873/sec-20148896

CYP2C19 and Citalopram/Escitalopram/Sertraline Recommendations Alternative medications include: Fluoxetine Venlafaxine Duloxetine Bupropion Paroxetine Fluvoxamine Nortriptyline Mirtazapine * Consultation with a pharmacist or psychiatrist is warranted for patients who are poor or poor to intermediate metabolizers for both CYP2D6 and CYP2C19

CYP2D6 and Antidepressants Intermediate to Poor Metabolizers Increase risk of side effects with Fluoxetine Fluvoxamine (can decrease dose by 25%-50% if needed) Paroxetine (can decrease dose by 50% if needed) Increase risk of treatment failure Venlafaxine Recommendations Choose antidepressant not metabolized by 2D6 Citalopram, escitalopram, sertraline CYP2D6 is reasonable for the metabolism of about 25% of all drugs. Side effects – GI upset, serotonin syndrome or QTc prolongation.. Consultation with a pharmacist or psychiatrist is warranted for patients who are poor or poor to intermediate metabolizers for both CYP2D6 and CYP2C19

CYP2D6 and Analgesics Both Tramadol and Codeine are prodrugs Metabolized into active forms by CYP2D6 Tramadol to O-desmethyltramadol Codeine to morphine Types of metabolizers at risk Ultra Rapid (risk of toxicity) Rapid (risk of toxicity) Poor (reduced efficacy)

CYP2D6 and Analgesics Recommendations Alternatives Hydrocodone/APAP Oxycodone Both are also substrates of CYP2D6, but it’s a minor pathway Morphine Hydromorphone Fentanyl If appropriate https://askmayoexpert.mayoclinic.org/topic/clinical-answers/gnt-20137159/sec-20137178

CYP2D6 and Tamoxifen Tamoxifen SERM used for the prevention and treatment of ER+ breast cancer Tamoxifen is a prodrug and is metabolized to active form (endoxifen) by CYP2D6 Types of Metabolizers at risk Intermediate – Avoid medications that inhibit CYP2D6 Poor to Intermediate (limited therapeutic response) Poor (possible therapeutic failure) Tamoxifen is a selective estrogen receptor modulator approved by the U.S. Food and Drug Administration for the prevention and treatment of estrogen receptor-positive breast cancer. Tamoxifen is a prodrug. Patients who have decreased activity of the liver enzyme CYP2D6 are less effective at converting tamoxifen into the active metabolite endoxifen. Women who have a poor, poor to intermediate, or intermediate ability to metabolize tamoxifen via CYP2D6 may have a limited therapeutic response, depending on the setting in which tamoxifen is administered.

CYP2D6 and Tamoxifen Recommendations Intermediate metabolizer Usual tamoxifen dosing, however AVOID medications that inhibit CYP2D6 Diphenhydramine, hydroxyzine, chlorpheniramine Celecoxib Bupropion*, duloxetine, fluoxetine*, paroxetine*, sertraline Poor to intermediate OR Poor Should be switched to Aromatase Inhibitor Anastrozole Exemestane Letrozole Ex –e- MES- tane Patients who are unable to tolerate an aromatase inhibitor or have other contraindications for an aromatase inhibitor should still be treated with tamoxifen. However, these patients may have a limited therapeutic response, depending on the setting and duration of tamoxifen administration. Other measures considered investigational include increasing tamoxifen dosage from 20 mg/day to 40 mg/day in women who are poor CYP2D6 metabolizers, which has been shown to increase endoxifen concentrations https://askmayoexpert.mayoclinic.org/topic/clinical-answers/gnt-20137241/sec-20137254 * Denotes Strong Inhibitors

SLCO1B1 and Simvastatin Statin-induced myopathies are difficult to predict Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine discovered that the SLCO1B1 CC and TC genotypes were linked with a higher risk of statin-induced myopathy when compared with the TT (normal) genotype in patients taking simvastatin (Zocor) 40 or 80 mg daily. The SLCO1B1 gene influences the extent of the drug's hepatic uptake by its transporter (OATP1B1) and its serum concentration. https://askmayoexpert.mayoclinic.org/topic/clinical-answers/gnt-20136569/sec-20136573 https://askmayoexpert.mayoclinic.org/topic/clinical-answers/gnt-20136569/sec-20136573

SLCO1B1 and Simvastatin Recommendations Genotypes at increase risk of myopathy CC TC Alternative statin options Atorvastatin Pravastatin Rosuvastatin If simvastatin must used, the max dose recommended is 20mg/day https://askmayoexpert.mayoclinic.org/topic/clinical-answers/gnt-20136569/sec-20136581

Complex Case F.H. is a 55 year old female who presents to clinic with chief complaint of musculoskeletal pain. She has been taking APAP 1000mg 4xday and IBU 600mg TID with no relief

Complex Case Type 2 DM STEMI (10/2016) Hypertension Hyperlipidemia Metformin 1000mg 2xday Type 2 DM Clopidogrel 75mg daily STEMI (10/2016) Lisinopril 20mg daily Metoprolol XL 100mg daily Hypertension Simvastatin 40mg Hyperlipidemia Acetaminophen 1000mg 4xday Ibuprofen 600mg 3xday Pain Pantoprazole 40mg daily Acid Reflux

Complex Case Vitals BP: 118/85 mmHg HR: 46 bpm A1c: 6.8% Scr: 0.8 AST: 13 ALT: 20

Complex Case Tramadol 50mg Q6H is prescribed Patient returns after one week with continuing pain and no response to tramadol Patient has preemptive PGx in her chart Discuss recommendations based on patients presentation, medications, and PGx results

Complex Case- Questions to ask yourself Look at the PGx report and ask yourself….. Are the drug(s) in question an active drugs or a prodrugs? What are the metabolic pathway(s) of the drug(s)? Does this make sense?

Complex Case- PGx Results Gene (Metabolizing Enzyme) Genotype Phenotype CYP2D6 *4/*4 Poor SLCO1B1 *1/*5 Increased Risk HLA-B*5801 Negative Normal Risk CYP1A2 Multiple Variations Normal CYP2C9 *1/*1 CYP2C19 *1/*2 Intermediate VKORC1 -1639 AA High Warfarin Sensitivity CYP3A4 CYP3A5 *3/*3 Extensive = normal

Complex Case Discussion Poor CYP2D6 Metabolizer Tramadol is a prodrug, therefore lack of efficacy Metoprolol is metabolized by CYP2D6, possible drug accumulation (HR is 46 bpm SLCO1B1 increased risk of myopathy with simvastatin Intermediate CYP2C19 Metabolizer Clopidogrel is a prodrug, therefore lack of efficacy Bonus: Pantoprazole inhibits CYP2C19, therefore this may additionally decrease clopidogrel activity*

Complex Case Plan D/C Tramadol due to ineffectiveness Consider Oxycodone or Hydrocodone/APAP for pain Decrease metoprolol XL to 50mg due to bradycardia Switch simvastatin to atorvastatin/pravastatin/rosuvastatin Consult Cardiology to switch clopidogrel to Effient® (prasugrel) or Brilinta® (ticagrelor) Could lower the dose of simvastatin if needed

Patient Video http://mayoresearch.mayo.edu/center-for-individualized-medicine/video-center.asp

Where to find additional resources CPIC Guidelines PharmGKB https://www.pharmgkb.org/view/dosing-guidelines.do?source=CPIC OneOme CYP Inducers and Inhibitors Table https://oneome.com/cyp-info

Summary PGx can help eliminate medication trial and error PGx can help avoid therapeutic failures PGx can decrease medication side effects PGx can help decrease healthcare costs PGx individualizes patient care

Summary

Questions? Thank you!

Bibliography http://www.mayomedicallaboratories.com/it-mmfiles/Pharmacogenomic_Associations_Tables.pdf https://oneome.com/cyp-info https://www.pharmgkb.org/view/dosing-guidelines.do?source=CPIC Li XQ, Andersson TB, Ahlstrom M, et al, “Comparison of Inhibitory Effects of the Proton Pump-Inhibiting Drugs Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole, and Rabeprazole on Human Cytochrome P450 Activities,” Drug Metab Dispos, 2004, 32:821-7.  “HLA-B*5801 and Allopurinol (pharmacogenomics)." AskMayoExpert. Mayo Clinic, 19 Sept. 2016. Web. 30 Mar. 2017. “Warfarin and CYP2C9 and VKORC1(pharmacogenomics).” AskMayoExpert. Mayo Clinic, 19 Sept. 2016. Web. 30 Mar. 2017 “CYP2C19 and clopidogrel (pharmacogenomics).” AskMayoExpert. Mayo Clinic, 19 Sept. 2016. Web. 30 Mar. 2017 “Antidepressant Medication and Pharmacogenomics.” AskMayoExpert. Mayo Clinic, 19 Sept. 2016. Web. 30 Mar. 2017 “Tramadol and CYP2D6 (pharmacogenomics).” AskMayoExpert. Mayo Clinic, 19 Sept. 2016. Web. 30 Mar. 2017 “Codeine and CYP2D6 (pharmacogenomics).” AskMayoExpert. Mayo Clinic, 19 Sept. 2016. Web. 30 Mar. 2017 “ Tamoxifen and CYP2D6 (pharmacogenomics).” AskMayoExpert. Mayo Clinic, 19 Sept. 2016. Web. 30 Mar. 2017 “Simvastatin and SLCO1B1 (pharmacogenomics).” AskMayoExpert. Mayo Clinic, 19 Sept. 2016. Web. 30 Mar. 2107 Huttunen, Kristiina M., Hannu Raunio, and Jarkko Rautio. "Prodrugs-from Serendipity to Rational Design." Pharmacological Reviews 63.3 (2011): 750-71. Print