Pharmacogenetics in: Primary Care. Bradley T. Wajda D.O.

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1 Pharmacogenetics in: Primary Care Bradley T. Wajda D.O.

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3 Pharmacogenomics Defined Pharmacogenomics uses information about a person s genetic makeup, or genome, to choose the drugs and drug doses that are likely to work best for that particular person. National Institutes of Health National Human Genome Research Institute

4 Pharmacokinetics and Pharmacodynamics Polymorphisms in pharmacodynamic (PD) genes can affect drug action at its target (e.g. receptor binding). Systemic Circulation Polymorphisms in pharmacokinetic (PK) genes (e.g. CYP450) can affect drug blood levels. Excretion

5 Key Pharmacogenomic Genes Pharmacodynamic (PD) OPRM1 (μ-opioid receptor) SLC6A4 (serotonin transporter) 5HTR2A (serotonin 2A receptor) ADRA2A (α-2a adrenergic receptor) COMT (catechol-o-methyltransferase) Pharmacokinetic (PK) CYP2D6 CYP2C19 CYP2C9 CYP1A2 CYP2B6 CYP3A4 MTHFR (methyltetrahydrofolate reductase)

6 THE CYP450 System The CYP450 system is a family of about 57 enzymes responsible for drug metabolism, primarily in the liver. Multiple enzymes may be involved in the metabolism of a given drug

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11 CYP450 Metabolizer Phenotypes Ultrarapid (UM) : Rapid rate of metabolism Extensive (EM) : Normal metabolism 13% 6% Intermediate (IM) : Reduced rate of metabolism 35% 46% Poor (PM) : Slow rate of metabolism CYP2D6 Phenotype Frequency

12 CYP2D6 and Nortriptyline Plasma concentration/ 25 mg dose (nmol/l) Number of functional CYP2D6 genes Hours Dalén P, Dahl ML, Bernal Ruiz ML, Nordin J, Bertilsson L. Clin Pharmacol Ther Apr;63(4):444-52

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18 FDA s Table of Pharmacogenomic Biomarkers in Drug Labeling An extensive list of medications that the FDA has included pharmacogenetic references within the package inserts. These medications are categorized by Therapeutic Area(s), including: Anesthesiology Gynecology Oncology Cardiology Hematology Psychiatry Dental Infectious Diseases Pulmonology Gastroenterology Neurology Rheumatology Urology The FDA also maintains Drug Interactions and Labeling giving an extensive list of sensitive substrates, strong to weak inhibitors, and strong to weak inducers arranged according to cytochrome P450 isoenzymes.

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20 The FDA and Pharmacogenomics The Food and Drug Administration (FDA) includes pharmacogenomic language in the package inserts: Aripiprazole The aripiprazole dose in PM patients should initially be reduced to one-half (50%) of the usual dose. CYP2D6 PM Citalopram The maximum dose should be limited to 20 mg/day in patients who are CYP2C19 poor metabolizers. CYP2C19 PM Thioridazine The use of thioridazine in patients known to have reduced activity of P450 2D6 are contraindicated. CYP2D6 IM or PM Vortioxetine The maximum recommended dose of BRINTELLIX is 10 mg/day in known CYP2D6 poor metabolizers. CYP2D6 PM The contents of this page have not been endorsed by the FDA and are the sole responsibility of Assurex Health

21 Pharmacodynamics: OPRM1 and Response OPRM1 encodes the mu opioid receptor, the main target for many medications analgesic Patients who are carriers of the G allele for the A118G SNP show a reduced analgesic response with opioid medications such as morphine, codeine, and oxycodone. endogenous opioids OPRM1 Phenotype Frequency 2% Mu-opioid receptor 21% 77% Normal Activity (A/A) Intermediate Activity (A/G) Reduced Activity (G/G) 1. Reyes-Gibby, et al. Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain 130(1-2)25-30.

22 OPRM1 and Naltrexone In contrast to full μ-opioid agonist therapy (e.g. methadone), OPRM1 G-carriers show improved response to naltrexone in dependent patients compared to wild type. These findings support the use of OPRM1 to select patients for naltrexone therapy. 1. Anton RF, et al. An evaluation of μ-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence. Arch Gen Psychiatry 2008;65(2): Kranzler HR, et al. Variation in OPRM1 moderates the effect of desire to drink on subsequent drinking and its attenuation by naltrexone treatment. Addiction Biology 2013;18: Oslin DW, et al. A functional polymorphism of the μ-opioid receptor gene is associated with naltrexone response in alcohol dependent patients. Neuropsychopharmacology 2003;28:

23 OPRM1 and Adverse Events Despite showing reduced analgesic response, OPRM1 G-carriers have not been shown to be protected against respiratory depression. 1 One study showed that, among patients with an acute drug overdose, G-carriers were 5.3 times more likely to experience cardiac or respiratory arrest. 2 Other data has shown associations with OPRM1 G carriers and likelihood to become addicted to opiates Romberg RR, et al. Polymorphism of μ-opioid receptor gene does not protect against opioid-induced respiratory depression despite reduced analgesic response. Anesthesiology 2005;102: Manini AF, et al. Opioid receptor polymorphism A118G associated with clinical severity in a drug overdose population. J. Med. Toxicol 2013;9: Nagaya D, et al. A118G mu opioid receptor polymorphism among drug addicts in Malaysia. J Integrative Neuroscience 2012;11(1):

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28 The FDA and Codeine Some people have genetic variations that make [CYP2D6] overactive, causing codeine to be converted to morphine faster and more completely than in other people. These ultra-rapid metabolizers are more likely to have higher than normal amounts of morphine in their blood after taking codeine. High levels of morphine can result in breathing difficulty, which may be fatal. The only way to know if someone is an ultra-rapid metabolizer is to do a genetic test.

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30 Pharmacodynamic Pharmacogenomics Serotonin Transporter (SLC6A4) The serotonin transporter is encoded by the SLC6A4 gene. It is responsible for reuptake of serotonin into the presynaptic neuron. Selective serotonin reuptake inhibitors (SSRIs) inhibit this process, allowing for more serotonin in the synaptic cleft.

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33 Catechol-O-methyl Transferase Catechol-O-methyltransferase (COMT) breaks down both norepinephrine and dopamine in the synapse COMT gene has a polymorphism (Val158Met) that results in an amino acid change methionine (met) for valine (val) at codon 158 Met/Met homozygotes have 4-5x less COMT activity 1 Met/Met carriers showed a reduced rate of response to stimulant medications 2 22% 50% 28% Normal Activity (Val/Val) Intermediate Activity (Val/Met) Reduced Activity (Met/Met) 1. Lachman HM, et al. Human catechol- O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics (3): Cheon KA, et al. Association of the catechol-o-methyltransferase polymorphism with methylphenidate response in a classroom setting in children with attention-deficit hyperactivity disorder. International Clinical Psychopharmacology. 2008;23:

34 ADHD Pharmacogenomics: ADRA2A The alpha 2A adrenergic receptor is a receptor in the norepinephrine system A SNP in the promoter region (-1291G>C) of this gene has been shown to have an effect on response to methylphenidate and the alpha-2a agonists. The Noradrenergic Neuron norepinephrine 11% 48% 41% Typical Response (G/G) Typical Response (C/G) Reduced Response (C/C) adrenergic receptor

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36 MTHFR The C677T SNP in the MTHFR gene confers reduced enzymatic activity. 1 Normal Activity (C/C) 52% Multiple studies have confirmed lower serum folate levels and higher homocysteine levels in individuals with the T/T or T/C genotype relative to the Intermediate Activity (C/T) 39% C/C genotype. 2-4 Reduced Activity (T/T) 9% 0% 1. Nelson JC. The evolving story of folate in depression and the therapeutic potential of l-methylfolate. Am J Psychiatry 2012;169(12): Nazki F, et al. Folate: metabolism, genes, polymorphisms, and the associated diseases. Gene 2014; Molloy AM, et al. Thermolabile variant of 5,10 methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet 1997;349: Anderson CAM, et al. Response of serum and red blood cell folate concentrations to folic acid supplementation depends on methylenetetrahydrofolate reductase C677T genotype: results from a crossover trial. Mol Nutr Food Res 2013;67:

37 MTHFR Folate Intermediates Folate Intermediates Folate Intermediates MTHFR 677 C/C MTHFR 677 T/C MTHFR 677 T/T NORMAL methylfolate levels INTERMEDIATE methylfolate levels Reduced methylfolate levels

38 Clinical Implications of MTHFR Folate deficiency is treatable, with multiple options for folate supplementation: Supplementation with l-methylfolate (5-MTHF), the active form of folate. Several recent studies have shown that increasing the intake of folic acid to try and overcome the effect of reduced MTHFR activity has the potential to mask a Vitamin B12 deficiency Qin et al. Effect of folic acid intervention on the change of serum folate level in hypertensive Chinese adults: do methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms affect therapeutic responses? Pharmacogenetics and Genomics (2012);22: Anderson CAM, et al. Response of serum and red blood cell folate concentrations to folic acid supplementation depends on methylenetetrahydrofolate reductase C677T: results from a crossover trial. Mol Nutr. Food Res. 2013;57: Ashfield-Watt PAL, et al. Methylenetetrahydrofolate reductase 677C>T genotype modulates homocysteine responses to a folate rich diet or a low dose folic acid supplement: a randomized controlled trial. Am J Clin Nutr (2002);76:

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