Transcript Behavioral Health - PGXL Laboratories

Kim Dolan
Sales Trainer for PGXL
Laboratories
502-836-3361
The Human
Genome
© 2009 - 2014 PGXL Laboratories
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
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…
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
Pharmacogenetics
Why It Matters
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
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; 279:1200-1205; Phillips KA et al JAMA 2001;286:2270-2279;
Kalow W et al. Pharmacogenetics 1998;8:283-289
Pharmacogenetics
Same Diagnosis, Same Medications, Different
Outcomes
Typical Clinic
Day N=30
No Variance
Variance
Variance
Variance
Normal Response
Risk Decreased
Lack of Efficacy
High Risk
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:
o Be of no consequence to the drug’s safety and efficacy
o Render a medication useless
o Result in a medication causing serious adverse reactions
Incidence of Genetic Variants Important to
Drug Selection and Drug Dose
Gene
% of Extensive
Metabolizers
% of
Intermediate
Metabolizers
2D6
2C19
2C9
VKOR
3A4
3A5
SLC6A4
53%
36%
57%
35%
32%
40%
10%
4%
3%
2%
28%
NA
87%
1%
25%
12%
18%
50%
1%
81%
25%
N/A
N/A
N/A
% of Poor % of Ultra-Rapid
Metabolizers Metabolizers
1. Pharmacogenetics Knowledge Base Implementation: www.pharmgkb.org
VARIANTS
47%
64%
43%
>70%
13%
99%
75%
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Leading ADRs resulting in hospitalizations
Drug group/drug
No (%) of
cases
NSAIDs
363 (29.6)
Diuretics
334 (27.3)
Warfarin
129 (10.5)
Individual drugs
Aspirin (218), diclofenac (52), ibuprofen (34),
rofecoxib (33), celecoxib (8), ketoprofen (6)
naproxen (5)
Furosemide (128), bendroflumethiazide (103),
bumetanide (43), spironolactone (37), amiloride
(19), metolazone (11), indapamide (6)
—
ACE inhibitors/All
receptor antagonists
94 (7.7)
Antidepressants
87 (7.1)
β blockers
83 (6.8)
Opiates
73 (6.0)
Digoxin
36 (2.9)
Ramipril (28), enalaparil (25), captopril (12),
lisinopril (9), irbesartan (6), losartan (5),
perindopril (4)
Fluoxetine (17), paroxetine (14), amitriptyline (13),
citalopram (9), lithium (8), venlafaxine (8)
dosulepin (7)
Atenolol (69), propranolol (6), sotalol (3),
bisoprolol (2), metoprolol (2), carvedilol (1)
Morphine (20), dihydrocodeine (20), co-codamol
(8), tramadol (8), co-dydramol (6), fentanyl (5)
—
Prednisolone
31 (2.5)
—
Clopidogrel
29 (2.4)
—
Pirmohamed et al. BMJ 2004;329(7456):15–9.
Adverse reactions
GI bleeding, peptic ulceration,
haemorrhagic cerebrovascular accident,
renal impairment, wheezing, rash
Renal impairment, hypotension,
electrolyte disturbances, gout
GI bleeding, haematuria, high INR,
haematoma
Renal impairment, hypotension,
electrolyte disturbance, angioedema
Confusion, hypotension, constipation, GI
bleed, hyponataemia
Bradycardia, heart block, hypotension,
wheezing
Constipation, vomiting, confusion,
urinary retention
Symptomatic toxic digoxin levels
Gastritis, GI bleeding, hyperglycaemia,
osteoporotic fracture
GI bleeding
State-of-the-Art -- 2014
Cardiovascular
Anti-Platelet Activation
Anti-Coagulation
Behavioral
Health
Pain
Management
Treatment Resistant
Depression
Schizophrenia
Opioids
Benefits of
Molecular PGx
Guided Therapy
Decision Making
Patient Improvement
Cost Savings
Patient Satisfaction &
Compliance
Risk Reduction
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)
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