Sales Trainer for PGXL Laboratories502-836-3361

Kim Dolan

© 2009 - 2014 PGXL Laboratories

The Human Genome

Human Genome Research Initiative“As important a breakthrough as understanding human anatomy”

Francis Collins, Director National Institutes of HealthGoals• Determine the sequence of chemical pairs that make up Human

DNA

• Identify and map the 25,000 genes and 3.1 million base pairs of the human genome from a physical and functional standpoint

• Understand genes and how they work to understand how diseases are caused and how best to cure them

• Switch from reacting to a disease to prevention

• 1988 – International Human Genome Initiative (HGRI) launched

• 1989 – Dr. Roland Valdes launches post-PhD Molecular Clinical Chemistry program

• 1993 – Dr. Francis Collins assumes leadership of HGRI• 1997 – Dr. Valdes and Dr. Mark Linder publish seminal

pharmacogenetics paper

Evolution of PharmacogeneticsPGXL Founders Are Pioneers in the Field

Continued…

• 2001 – PGXL Laboratories is first CLIA-certified pharmacogenetics specialist in U.S.

• 2004 – Human genome sequenced and published• 2010 – Drs. Valdes and Linder publish guidelines for

operating a pharmacogenetics laboratory

Evolution of PharmacogeneticsPGXL Founders Are Pioneers in the Field

…Continued

1. There can be wide variability in patient response to commonly prescribed medications

2. Genetics is estimated to account for 20-95% of the variability in drug effects

3. Adverse Drug Reactions (ADRs) are the 6th leading cause of death

4. A review of drugs most commonly associated with ADRs found that 57% (16 of 27) were metabolized by a gene with a known genetic polymorphism

PharmacogeneticsWhy It Matters

57% of meds in top 20 list causing ADRs are linked to a genetic variation

20-90% variability in patient response to medications can be explained by genetics

>120 drugs have FDA box warnings related to genetics

Lazarou et al. JAMA 1998; 279:1200-1205; Phillips KA et al JAMA 2001;286:2270-2279;Kalow W et al. Pharmacogenetics 1998;8:283-289

Current Situation/Implications

PharmacogeneticsSame Diagnosis, Same Medications, Different Outcomes

No VarianceNormal Response

VarianceRisk Decreased

VarianceLack of Efficacy

VarianceHigh Risk

Typical Clinic Day N=30

• Every human has a genetic code that is unique to them• There is no perfect version of the code; we all have

variants• Variances in genes responsible for drug metabolism,

transport and uptake/binding can:o Be of no consequence to the drug’s safety and efficacyo Render a medication uselesso Result in a medication causing serious adverse reactions

PharmacogeneticsThe Study of How Our Genes Affect Our Response to Drugs

Incidence of Genetic Variants Important to Drug Selection and Drug Dose

Gene % of Extensive Metabolizers

% of Intermediate Metabolizers

% of Poor Metabolizers

% of Ultra-Rapid Metabolizers VARIANTS

2D6 53% 35% 10% 2% 47%2C19 36% 32% 4% 28% 64%2C9 57% 40% 3% NA 43%VKOR >70%3A4 87% 12% 1% N/A 13%3A5 1% 18% 81% N/A 99%SLC6A4 25% 50% 25% N/A 75%

1. Pharmacogenetics Knowledge Base Implementation: www.pharmgkb.orgProperty of PGxl Laboratories

Drug group/drug No (%) of cases Individual drugs Adverse reactions

NSAIDs 363 (29.6) Aspirin (218), diclofenac (52), ibuprofen (34), rofecoxib (33), celecoxib (8), ketoprofen (6) naproxen (5)

GI bleeding, peptic ulceration, haemorrhagic cerebrovascular accident, renal impairment, wheezing, rash

Diuretics 334 (27.3) Furosemide (128), bendroflumethiazide (103), bumetanide (43), spironolactone (37), amiloride (19), metolazone (11), indapamide (6)

Renal impairment, hypotension, electrolyte disturbances, gout

Warfarin 129 (10.5) — GI bleeding, haematuria, high INR, haematoma

ACE inhibitors/All receptor antagonists

94 (7.7) Ramipril (28), enalaparil (25), captopril (12), lisinopril (9), irbesartan (6), losartan (5), perindopril (4)

Renal impairment, hypotension, electrolyte disturbance, angioedema

Antidepressants 87 (7.1) Fluoxetine (17), paroxetine (14), amitriptyline (13), citalopram (9), lithium (8), venlafaxine (8) dosulepin (7)

Confusion, hypotension, constipation, GI bleed, hyponataemia

β blockers 83 (6.8) Atenolol (69), propranolol (6), sotalol (3), bisoprolol (2), metoprolol (2), carvedilol (1)

Bradycardia, heart block, hypotension, wheezing

Opiates 73 (6.0) Morphine (20), dihydrocodeine (20), co-codamol (8), tramadol (8), co-dydramol (6), fentanyl (5)

Constipation, vomiting, confusion, urinary retention

Digoxin 36 (2.9) — Symptomatic toxic digoxin levels

Prednisolone 31 (2.5) — Gastritis, GI bleeding, hyperglycaemia, osteoporotic fracture

Clopidogrel 29 (2.4) — GI bleeding

Pirmohamed et al. BMJ 2004;329(7456):15–9.

Leading ADRs resulting in hospitalizations

State-of-the-Art -- 2014

Benefits of Molecular PGx

Guided Therapy Decision Making

Behavioral Health

Treatment Resistant Depression

Schizophrenia

CardiovascularAnti-Platelet Activation

Anti-Coagulation

Pain Management

Opioids

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Patient Satisfaction &Compliance

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Antiplatelet therapyAnticoagulation managementHyperlipidemiaHypertension/arrhythmia

Pain OpioidsNSAIDsMuscle relaxants

Behavioral HealthTreatment-resistant depression

(TRD)PsychosisADHD

Internal Med/GP Antithrombotic therapies

CV health (arrhythmia, lipids, stroke)Chronic pain managementType II diabetes managementGU healthAntimicrobialsMultidrug sensitivity

Oncology (under development)Colorectal cancer (KRAS, BRAF, Lynch)Breast cancer (tamoxifen)Lung Cancer (EGFR, etc)

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