CORE DME PANEL Highlands Parkway, Suite 100 Smyrna, GA 30082

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1 CORE DME PANEL Castle's CORE DME panel predicts the activity levels of key - drug metabolizing enzymes in the cytochrome P450 superfamily: CYP2D6, CYP2C9, CYP2C19, CYP2B6, CYP3A4, and - CYP3A5. Apart from CYP genes, this panel also tests other - genes which contribute to drug response and clearance. OPRM1 controls production of the µ-opioid receptor, which is the primary site of action for opioid drugs. SLCO1B1 translates into a protein that spans the cell membrane and transports drugs from blood into liver cells assisting in their clearance. COMT encodes an enzyme that is involved in the inactivation of catecholamine neurotransmitters and is hence associated with many psychotropic disorders. A total of 60 allelic variants of these enzymes are tested and analyzed to predict an individual s drug metabolizing potential. Appropriate positive and negative internal controls are included in each reac- - tion in order to ensure precision and data quality. Based on the patient s genotype, Castle relays the CPIC's dosage recommendations for select drugs. Specimen OraCollect (OC-100) swab. Please provide a separate swab for each panel ordered. Storage Room temperature, out of intense light. Do not freeze or refrigerate specimens. Instructions Please follow the instructions provided with the saliva collection kit. Cause of Rejection Insufficient/Contaminated DNA recovery Purpose Variation in drug-metabolizing enzymes, transporter proteins, and receptors can influence patients responses to drugs. This variation is usually caused by genetic polymorphisms. Clinical effects of these polymorphisms depend on the drug and the specific genetic changes involved. Genotyping helps in predicting the right dosage regimen for drugs, reducing the chance of drug-induced adverse reactions and possible therapeutic failure of prodrugs. - Who should take this test? Patients who are currently using, or planning to use, a medication whose dosage or efficacy is affected by variation in the above-listed genes. Methodology and Limitations TaqMan fluorescent probe based assays assessed by real-time polymerase chain reaction (qpcr). This is not a sequencing test and will only detect the variations listed in these documents; other, rare variations may also be present. Additional information Apart from patient s genotype, the activity of CYP enzymes is also influenced by a patient s physiological state, diet, and other concomitant medications.

2 C YP2D6 Genetic Variants and their s *1X2 Duplication in *1 Increased *3 rs Inactive *4 rs , rs Inactive *4X2 Duplication in *4 Unpredictable *5 CYP2D6 is entirely absent Inactive in this allele. *6 rs Inactive *7 rs Inactive *8 rs (A) Inactive *10 rs Decreased *11 rs Inactive *12 rs Inactive *14 rs (T) Inactive *41 rs Inactive rs rs Inactive rs rs Decreased rs rs Inactive rs rs Inactive *4-like X2 Duplication in *4-like Cannot define *1 X2 Duplication in *1 Increased rs X2 Duplication in rs Increased CYP2D6 CYP2D6 metabolizes a significant number of clinically-used medications, including select opioids, antidepressants, anti-psychotics, beta blockers, and antiarrhythmics. Based on CYP2D6 genotype, the following phenotype categories can - be predicted: or close-to-normal CYP2D6 enzyme activity. Patients with this phenotype have two normal alleles, one normal and one decreased activity allele, one normal and one inactive allele, or two decreased function alleles. Somewhat reduced CYP2D6 enzyme activity. Patients in this category have one decreased activity and one inactive allele. This phenotype is associated with two inactive alleles. Poor metabolizers have diminished capacity to eliminate drugs and so are at increased risk of drug-induced side effects. Also, poor metabolizers have reduced potential to activate prodrugs, which might result in therapeutic failure in some cases. Ultrarapid metabolizer This category indicates the presence of an extra copy of CYP2D6, which results in higher-than-normal enzyme activity. The patient's increased ability to eliminate drugs might result in diminished or no therapeutic activity. At the same time, these patients will rapidly activate prodrugs, putting them at increased risk of adverse drug reaction.

3 C YP2C19 Genetic Variants and their s *2 rs Inactive *2B rs , rs Inactive *3 rs Inactive *4 rs Inactive *5 *6 *8 *9 *10 *17 rs (insg) rs Inactive rs Inactive rs Inactive rs Decreased rs rs rs (insg) Decreased Increased Decreased CYP2C19 This enzyme metabolizes 10-15% of all clinically relevant drugs including diazepam, carisoprodol, and some anticonvulsants, tricyclic antidepressants, antiplatelet agents, and proton pump inhibitors. Based on CYP2C19 genotype, the following phenotype categories can be predicted: CYP2C19 enzyme activity. Patients with this pheno-type have two normal alleles. Partially reduced CYP2C19 enzyme activity. Patients in this category have one normal and one inactive allele. This phenotype is associated with two inactive alleles. Poor metabolizers have diminished capacity to eliminate drugs, which increases the risk of drug-induced side effects due to slow elimination of drugs from the body. These patients are also prone to therapeutic failure of prodrug medications due to slow activation of the drugs. Rapid/Ultrarapid metabolizer The CYP2C19*17 variant causes an increase in the rate of CYP2C19 enzyme formation, which results in higher-than-normal enzyme activity. The patient's increased ability to eliminate drugs might result in diminished or no therapeutic activity. At the same time, these patients will rapidly activate prodrugs, putting them at increased risk of adverse drug reaction.

4 C YP2C9 Genetic Variants and their s *2 rs Inactive *3 rs Inactive *5 rs Inactive *7 rs Inactive *8(A) rs (a) *8(T) rs (t) Inactive *10 rs Decreased *11 rs Decreased *13 rs Decreased *15 rs Inactive CYP2C9 CYP2C9 plays a major role in metabolizing drugs with narrow therapeutic indices such as warfarin and phenytoin. Most nonsteroidal anti-inflammatory drugs (NSAIDs) are also metabolized by CYP2C9. Based on CYP2C9 genotype, the following phenotype categories can be predicted: CYP2C9 enzyme activity. Patients in this category have two normal alleles. Partially reduced CYP2C9 enzyme activity. Patients in this category have one normal and one inactive allele. This phenotype is associated with two inactive alleles. Poor metabolizers have reduced enzymatic activity, leading to reduced activation of prodrugs and slowed clearance of other drugs.

5 C YP3A4 Genetic Variants and their s *2 rs Decreased *3 rs Decreased *4 rs Decreased *5 rs Decreased *6 rs Decreased *11 rs Decreased *12 rs Decreased *13 rs Decreased *15 rs Decreased *16 rs Decreased *17 rs Decreased rs rs Decreased CYP3A4 CYP3A4 is responsible for the metabolism of approximately 50-60% of all currently-used clinical drugs, including buprenorphine, citalopram, escitalopram, levomilnacipran, buspirone, mirtazapine, cyclophosphamide, isophosphamide, tamoxifen, haloperidol, aripiprazole, iloperidone, lurasidone, quetiapine, ziprasidone, guanfacine, modafinil, and cyclobenzaprine, as well as several benzodiazepines, mood stabilizers, opioids, and proton pump inhibitors. Based on CYP3A4 genotype, the following phenotype categories can be predicted: CYP3A4 enzyme activity. This phenotype includes patients with two normal alleles. Partially reduced CYP3A4 enzyme activity. Patients in this category have one normal and one decreased-function allele. This phenotype is associated with two decreased-function alleles. s have reduced enzymatic activity, leading to reduced activation of prodrugs and slowed clearance of other drugs.

6 C YP3A5 Genetic Variants and their s *1A - Full function *2 rs Decreased *2, *3C rs776746, rs Inactive *3B rs776746, rs Inactive *3C rs Inactive *3D rs776746, rs Inactive *6 rs Inactive *7 rs Inactive rs rs Decreased CYP3A5 CYP3A5 is very similar to CYP3A4 in structure and function, but it is only expressed in a limited number of individuals. Having functional CYP3A5 can speed the metabolism of the - enzyme s target drugs. Based on CYP3A5 genotype, the following phenotype categories can be predicted: Full CYP3A5 enzyme activity. This phenotype indicates two active alleles. Partially reduced CYP3A5 enzyme activity. Patients in this category have one normal and one inactive allele. This phenotype is associated with two inactive alleles. Poor metabolizers have low enzymatic activity, leading to reduced activation of prodrugs and slowed clearance of other drugs.

7 C YP2B6 Genetic Variants and their s *5 rs Decreased *9 rs Decreased *19 rs Decreased CYP2B6 CYP2B6 is responsible for the biotransformation of members of several different categories of drugs, including antidepressants, antiplatelet drugs, anti-hiv, anticancer drugs, anesthetics, and analgesics. High inter-individual variation (about fold) has been reported in CYP2B6 expression. Genetic polymorphism in the CYP2B6 gene can influence drug response and drug-mediated toxicity. Based on CYP2B6 genotype, the following phenotype categories can be predicted: CYP2B6 enzyme activity. This phenotype includes patients with two normal alleles. Partially reduced CYP2B6 enzyme activity. Patients in this category have one normal and one decreased-function allele. This phenotype is associated with two decreased-function alleles. s have reduced enzymatic activity, which can lead to reduced inactivation of the drugs and hence influence their activity.

8 C OMT Genetic Variants and their s rs6269 rs4633 rs4818 rs4680 G C G G activity A T C A Intermediate activity A C C G Low activity COMT Catechol O-methyl transferase (COMT) is a phase II metabolizing enzyme, primarily responsible for inactivating catecholamine neurotransmitters like dopamine, norepinephrine, and epinephrine. COMT maintains appropriate levels of these neurotransmitters and hence plays a broad regulatory role in brain chemistry. Genetic variation in the COMT gene can lead to abnormal levels of neurotransmitters in the brain and may increase the risk of developing psychiatric disorders. COMT has a role in the modulation of pain and stress, and genetic polymorphism in COMT has been implicated in inter-individual variability in the opioid dose required for the treatment of neuropathic pain. COMT genotype has been associated with some interesting personality traits: people with high levels of COMT activity may perform better stressful conditions while people with lower COMT activity may do better with memory and attention tasks. COMT also metabolizes L-DOPA (levodopa), a synthetic precursor of the neurotransmitter dopamine which is used in the clinical treatment of Parkinson s disease (PD). This is undesirable, and current PD therapy often includes a drug intended to inhibit COMT activity. Based on COMT genotype, the following phenotype categories can be predicted: activity COMT enzyme activity. Intermediate activity Somewhat reduced COMT enzyme activity. Low activity Reduced COMT enzymatic activity, leading to increased levels of catechol neurotransmitters in the brain. Please refer to PharmGKB for more information.

9 OPRM1 Genetic Variants and their s Haplotype rs (A) (wild type) rs (G) Decreased OPRM1 activity Consequence - Decreased analgesic response from opioid therapy. Better response from naltrexone de-addiction therapy. OPRM1 OPRM1 (µ-opioid or mu-opioid receptor 1) is the primary binding site for opioid drugs. Interaction of opioids with the OPRM1 receptor is essential for their analgesic effects. The addictive cravings induced by opioids, alcohol, nicotine, and other abusable substances are also mediated through OPRM1. Naltrexone acts as an OPRM1 antagonist and is used primarily in the management of alcohol and opioid dependence. Polymorphism in the OPRM1 gene can interfere with the receptor protein s ability to interact with drugs and therefore results in inter-individual variability in the sensitivity towards opioids. Mutation in OPRM1 can also influence naltrexone response in addiction therapy. The genetic change known as c.118a>g (or rs ) is one of the best-characterized variants of the OPRM1 gene. Individuals carrying this variant may require comparatively larger or more frequent doses of opioids for pain relief. Also, the presence of this variant makes them more likely to respond to naltrexone therapy. On average, patients carrying this variant will remain abstinent from opioid/alcohol/nicotine abuse for a longer duration and are less likely to relapse. Allelic frequency of rs varies among different ethnic populations. About 14% of the Caucasians and 4% of Africans carry this variation. Please refer to PharmGKB for more information. M

10 SLCO1B1 Genetic Variants and their s *5 rs Decreased SLCO1B1 SLCO1B1 (solute carrier organic anion transporter) is a transmembrane protein, meaning it forms a link between the outside and inside of cells. It mediates the active transport of many endogenous compounds, including bile acids, glucuronide-conjugated steroids, thyroid hormone, prostaglandins, and leukotrienes. SLCO1B1 takes up drugs from the blood and transports them into liver cells for metabolism, indirectly influencing drug clearance. Genetic polymorphism in the SLCO1B1 gene may affect therapeutic efficacy of drugs and is associated with drug-induced toxicity in some cases. For example, statins especially simvastatin are known ligands of SLCO1B1. These cholesterol-lowering drugs induce myopathy in certain populations of patients. Patients with reduced SLCO1B1 activity are more prone to developing statin-induced myopathy. To address this, the FDA has provided dosage recommendations for simvastatin based on patients SLCO1B1 genotype. There is some evidence that adverse reactions to other statins can be similarly predicted, but the magnitude of the effect of genotype is smaller in these cases. Based on rs genotype, the following phenotypes have been defined: activity This phenotype includes two wild type (normal) alleles in rs It predicts normal activity of SLCO1B1 protein and therefore normal risk of statin-induced myopathy. Intermediate activity This phenotype includes one wild type and one mutant allele in rs Patients with this phenotype have intermediate risk of statin-induced myopathy. Low activity The presence of two mutant SLCO1B1 alleles predicts a relatively low level of activity in SLCO1B1 protein. Patients with this phenotype have the highest risk of developing statin-induced myopathy. Please refer to PharmGKB for more information.