1. Sales Trainer for PGXL Laboratories 502-836-3361
Kim Dolan
Sales Trainer for PGXL Laboratories

2. The Human Genome
© PGXL Laboratories

3. Human Genome Research Initiative
“As important a breakthrough as understanding human anatomy”
Francis Collins, Director National Institutes of Health
Goals
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

4. Evolution of Pharmacogenetics
PGXL Founders Are Pioneers in the Field
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
Continued…

5. Evolution of Pharmacogenetics
PGXL Founders Are Pioneers in the Field
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
…Continued

6. Pharmacogenetics Why It Matters
There can be wide variability in patient response to commonly prescribed medications
Genetics is estimated to account for 20-95% of the variability in drug effects
Adverse Drug Reactions (ADRs) are the 6th leading cause of death
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

7. Current Situation/Implications
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: ; Phillips KA et al JAMA 2001;286: ;
Kalow W et al. Pharmacogenetics 1998;8:

8. Pharmacogenetics Same Diagnosis, Same Medications, Different Outcomes
Typical Clinic Day N=30
No Variance
Normal Response
Variance
Risk Decreased
Variance
Lack of Efficacy
Variance
High Risk

9. Pharmacogenetics
The Study of How Our Genes Affect Our Response to Drugs
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:
Be of no consequence to the drug’s safety and efficacy
Render a medication useless
Result in a medication causing serious adverse reactions

10. Incidence of Genetic Variants Important to Drug Selection and Drug Dose
% 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
18%
81%
99%
SLC6A4
25%
50%
75%
1. Pharmacogenetics Knowledge Base Implementation:
Property of PGxl Laboratories

11. Leading ADRs resulting in hospitalizations
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.

12. State-of-the-Art -- 2014 Cardiovascular Behavioral Health
Benefits of Molecular PGx Guided Therapy Decision Making
Behavioral Health
Treatment Resistant Depression
Schizophrenia
Cardiovascular
Anti-Platelet Activation
Anti-Coagulation
Pain Management
Opioids
Patient Improvement
Cost Savings
Patient Satisfaction &
Compliance
Risk Reduction

13. CIPHER™ strength of evidence
CV Antiplatelet therapy Anticoagulation management Hyperlipidemia Hypertension/arrhythmia Pain Opioids NSAIDs Muscle relaxants Behavioral Health Treatment-resistant depression (TRD) Psychosis ADHD
Internal Med/GP
Antithrombotic therapies
CV health (arrhythmia, lipids, stroke)
Chronic pain management
Type II diabetes management
GU health
Antimicrobials
Multidrug sensitivity
Oncology (under development)
Colorectal cancer (KRAS, BRAF, Lynch)
Breast cancer (tamoxifen)
Lung Cancer (EGFR, etc)
Property of PGxl Laboratories

14. Personalized Medicine Program
PM Program Core Team Creation
PGxl & Client
Project Planning Meeting Schedule
Design Program
Launch and Support Program
Track and Modify Program