Pharmacogenetics and
Personalized Medicine:
Reaping the Benefits for Your Patients
Kristen K. Reynolds, PhD
VP Laboratory Operations
Copyright 2012-2013PGXL Laboratories, Louisville KY
All materials herein are the exclusive property of PGXL Laboratories
Overview
• Scope of PGx utility
• Application examples
•
•
•
•
Hydrocodone
Plavix
Warfarin
SSRIs and antipsychotics
• PGXL interpretive report
~60% of meds in top 20
list causing ADRs are
linked to a genetic
variation
122 drugs have FDA box
warnings related to
genetics
Clinical Applications of Pharmacogenetic Information
Cardiology
– Warfarin
– Clopidogrel
– Statins
Psychiatry
– Anti-depressants
– Anti-psychotics
Oncology
– Thiopurines
– Tamoxifen
– EGFRi’s
Pain management
–
–
–
–
Codeine
Hydrocodone
Oxycodone
NSAIDs
Neurology
– Phenytoin
– Carbamazepine
Diabetes
– Glipizide
– Glyburide
PGXL Core Panel
Metabolism of >85% of medications
CYP2D6
CYP2C9
CYP2C19
CYP3A4
CYP3A5
CYP1A2
Panels*
Core:
Panel Add-Ons:
Thrombophilia:
CYP2D6
CYP2C9
CYP2C19
CYP3A4
CYP3A5
CYP1A2
VKORC1 (warfarin)
SLC6A4 (SSRIs)
SULT4A1 (STA2R,
Olanzapine)
SLCO1B1 (statins)
OPRM1 (opioids)
FVL
FII
MTHFR
*All genes always orderable individually
Warfarin:
CYP2C9
VKORC1
Pain Management
Common pain medications with PGXL tests
**prodrug;
+
Generic
Brand
Metabolic Route
Alfentanil
Carisoprodol**
Celecoxib
Codeine**
Cyclobenzaprine
Fentanyl
Hydrocodone**
Hydromorphone
Alfenta
Soma
Celebrex
Various brands
Flexeril
Actiq, Duragesic
Lortab, Vicodin
Dilaudid
CYP3A4/CYP3A5
CYP2C19
CYP2C9
CYP2D6
CYP1A2, CYP3A4/CYP3A5
CYP3A4/CYP3A5
CYP2D6
UGT2B7+
(OPRM1)
Ibuprofen
Advil, Motrin
CYP2C9
Lidocaine
Methadone
Morphine
Naproxen
Oxycodone**
Oxymorphone
Ropivicaine
Tizanidine
Tramadol**
Zolmipitran
Various brands
Various brands
Various brands
Aleve
Oxycontin, Percocet
Opana
Various brands
Zanaflex
Ultram, various
Zomig
CYP1A2
CYP2C19, CYP2B6+
UGT2B7+
(OPRM1)
CYP2C9
CYP2D6, CYP3A4/5
UGT2B7+
(OPRM1)
CYP1A2
CYP1A2
CYP2D6
CYP1A2
test not yet available
Pharmacokinetic Gene
Metabolism
Pharmacodynamic Gene
Clinical Effect
CODEINE
CYP2D6 PM: inadequate morphine
CYP2D6 UM: morphine toxicity
CYP3A4
CYP2D6
Morphine
Norcodeine
Morphine-6-glucuronide
Morphine-3-glucuronide
Renal Excretion
Reynolds KR et al. Clin Lab Med 2008;28:581–598.
Active
opioid
effects
CYP2D6 *4/*4
CYP2D6
Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Poor Metabolizer
Avoid
Alternative Consideration
Adjust Dosage
Adjustment
Codeine**
Hydrocodone**
Oxycodone**
Tramadol**
Tamoxifen**
Amitriptyline †
Venlafaxine †
Risperidone †
Morphine, non -opioid
Hydromorphone, non -opioid
Oxymorphone, non -opioid
Consider active drug, non -opioid
Anastrozole, exemestane, letrozole
Citalopram, sertraline
Citalopram, sertraline
Quetiapine, olanzapine, clozapine
Aripiprazole †
Clomipramine †
Doxepin †
Flecainide †
Haloperidol †
Imipramine †
Nortriptyline †
Propafenone †
Metoprolol †
decrease 50%
decrease 50%
decrease 60%
decrease 50%
decrease 50%
decrease 70%
decrease 60%
decrease 70%
decrease 75%, or
atenolol, bisoprolol
Zuclopenthixol
†
decrease 50%, or
flupenthixol, quetiapine,
olanzapine, clozapine
**Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to diminished
drug clearance.
CYP2D6 Poor Metabolizer (PM): This patient’s genotype is consistent with a lack of
CYP2D6 enzymatic activity. PMs are at increased risk of drug-induced side effects due to
diminished drug elimination of active drugs or lack of therapeutic effect resulting from
failure to generate the active form of the drug, as is the case with pro-drugs.
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012
Case study
•
•
•
Middle-aged male, chronic pain patient
2 pain clinics released him due to negative UDT when
prescribed hydrocodone
3rd pain clinic ordered PGXL testing:
2D6 POOR METABOLIZER:
Pt does not produce hydromorphone = negative UDT and
lack of pain relief
2C19 EXTENSIVE METABOLIZER :
Pt now taking low dose methadone and pain is controlled
Morphine Overdose from Codeine
8-15-12 and 2-20-13
FDA Drug Safety Advisories
Codeine use in certain children after tonsillectomy and/or
adenoidectomy may lead to rare, but life-threatening adverse
events or death
• 3 deaths in children (2-5yo) taking codeine after tonsillectomy and/or
adenoidectomy for obstructive sleep apnea
• 3 deaths in children who were CYP2D6 UMs
• All children received typical codeine doses, developed toxic levels
Application of PGx to
Cardiology
Cardiology
Med List
CARDIOLOGY
Anti-Arrhythmics, Anti-Hypertensives
Amlodipine
Norvasc
Carvedilol
Coreg
Diltiazem
Cardizem
Felodipine
Plendil
Flecainide
Tambocor
Lercanidipine
Zanidip
Losartan
Cozaar
Metoprolol
Toprol-XL
Nifedipine
Adalat
Nisoldipine
Sular
Nitrendipine
Various brands
Propafenone
Rythmol
Propanolol
Inderal, various
Quinidine
Various brands
Timolol
Blocadren
Verapamil
Various brands
CYP3A4/CYP3A5
CYP2D6
CYP3A4/CYP3A5
CYP3A4/CYP3A5
CYP2D6
CYP3A4/CYP3A5
CYP2C9
CYP2D6
CYP3A4/CYP3A5
CYP3A4/CYP3A5
CYP3A4/CYP3A5
CYP2D6
CYP2D6
CYP3A4/CYP3A5
CYP2D6
CYP3A4/CYP3A5
Antithrombotics
Clopidogrel**
Rivaroxaban
Ticareglor
Warfarin
Plavix
Xarelto
Brilinta
Coumadin
CYP2C19
CYP3A4/CYP3A5
CYP3A4/CYP3A5
CYP2C9
Lipitor, Caduet
Lescol
Mevacor, Advicor
Compactin
Crestor
Zocor, Vytorin, Simcor
CYP3A4/CYP3A5
CYP2C9
CYP3A4/CYP3A5
CYP3A4/CYP3A5
CYP2C9
CYP3A4/CYP3A5
Statins
Atorvastatin
Fluvastatin
Lovastatin
Mevastatin
Rosuvastatin
Simvastatin
**indicates prodrug
CYP2C19 - Plavix
Clopidogrel (Plavix) is a
PRODRUG
Active metabolite elicits
the desired antiplatelet
response
~ 30% of patients have
deficiency in CYP2C19
– Decreased amount of
active metabolite
– High on-treatment
platelet reactivity
Clopidogrel
Influence of CYP2C19 on Clopidogrel Response
Incidence of Adverse events in patients prescribed standard dosages of
Clopidogrel by CYP2C19 Phenotype.
PHENOTYPE
Stent Thrombosis
EM
CV death, MI,
Ischemic Stroke
8%
(BASELINE)
8.9%
1.4%
IM
10%
2.4%
PM
12.7%
5.7%
Mega et.al., JAMA. 2010;304(16);1821-1830.
0.9%
Gene-Dose dependency of therapeutic platelet inhibition
Mega et al. JAMA 2011;23/30; 306(20)
Cost-effectiveness
• Cost model based on event occurrence in TRITON-TIMI 38
Treatment
CV Events
Bleed Events
ICER
Genotype guided
813
340
Clopidogrel
1210
380
$ 6,790
$2.9M
Prasugrel
990
500
$ 11,710
$3.9M
• Genotype-guided therapy selection may be more cost effective and lead to
fewer adverse outcomes
Reese, E.S. et. al., Pharmacotherapy 2012;32(4):323–332
2C19
CYP2C19 *2/*2
CYP2C19
Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Poor Metabolizer Avoid
Clopidogrel**
Alternative Consideration
Adjust Dosage Adjustment
Prasugrel
Imipramine†
Sertraline†
decrease 30%
decrease 50%
**Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to
diminished drug clearance.
CYP2C19 Poor Metabolizer (PM): This patient’s genotype is consistent with significantly
reduced CYP2C19 enzymatic activity. PMs are at increased risk of drug-induced side effects
due to diminished drug elimination of active drugs. Patients with no CYP2C19 function (PMs)
taking clopidogrel lack adequate antiplatelet response and remain at risk for cardiovascular
events, including thrombosis, myocardial infarction, stroke, and death.
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012
Anticoagulation
Therapy
40% 2C9 deficient
>70% VKOR
sensitivity variant
Reynolds et al. Pers Med 2007;4(1):11-31.
n
i
r
a
.
0
2
.
4
1
.
8
W
0
0
1
.
2
0
0
.
6
0
0
.
0
0
a
3
-
r
f
Warfarin Genotyping
C
Y
P
2
C
9
*
C
Y
P
2
C
9
*
C
Y
P
2
C
9
*
S
CYP2C9 sets the rate,
affects time to SS
0
(accumulation and elimination)
0
3
6
9
1
21
T
51
i
82
m
0.8
(predicts warfarin sensitivity)
0.6
42
e
73
(
6.7 ± 3.3 mg
0.7
S-warfarin
VKORC1 sets the target
concentration
12
4.2 ± 2.2 mg
2.7 ± 1.2 mg
0.5
0.4
0.3
A/A
A/G
VKORC1
Linder et al. 2002 Thrombosis Thrombolysis; Zhu et al 2007 Clin Chem; Reynolds et al Pers Med 2007
G/G
0
d
a
y
CYP2C9 *2/*3
CYP2C9
Phenotype
Poor Metabolizer
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Decreased metabolic clearance expected.
Adjust Dosage
Adjustment
Phenytoin†
decrease 50%
Adjust based on multiple
factors
Warfarin†
VKORC1 GA
VKORC1
Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Intermediate
Average VKORC1 enzyme expression and average warfarin dose requirement expected.
warfarin sensitivity
WARFARIN DOSE INFORMATION
Estimated time to steady-state: Delayed, 16-22 days
Estimated warfarin maintenance dose requirement: 3.9 mg/day‡ _
CYP2C9 Poor Metabolizer (PM): This patient’s genotype is consistent with significantly
reduced CYP2C9 enzymatic activity. Reduced CYP2C9 activity leads to lower dose
requirement (e.g., warfarin) due to decreased clearance, increased elimination half-life, and
increased time to reach steady-state blood concentrations.
VKORC1 Intermediate Warfarin Sensitivity: ‡The warfarin maintenance dose estimate was
derived using a published formula that accounts for age, gender, weight, and CYP2C9 and
VKORC1 genotypes. This estimate should be viewed as an example of how this information can
be taken into consideration by the physician as part of the overall patient management strategy.
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012
Application of PGx to
behavioral health
Psychiatry Medications – Metabolic Routes
PSYCHIATRY
Antidepressants
Antipsychotics, Mood Stabilizers
Generic
Amitriptyline
Bupropion
Citalopram
Clomipramine
Brand
Various brands
Wellbutrin
Celexa
Ananfranil
Metabolic Route
CYP2D6
CYP1A2, (CYP2B6)
CYP2C19
CYP2D6, CYP1A2
Desipramine
Desvenlafaxine
Doxepin
Duloxetine
Escitalopram
Fluoxetine
Fluvoxamine
Imipramine
Norpramin
Pristiq
Sinequan
Cymbalta
Lexapro, various
Prozac
Luvox
Tofranil
Maprotiline
Mianserin
Mirtazapine
Nefazadone
Nortriptyline
Ludiomil
Various brands
Remeron
Serzone
Pamelor, Aventyl
Paroxetine
Reboxetine
Sertraline
Trazadone
Trimipramine
Venlafaxine
Vilazodone
Paxil
Edronax
Zoloft
Desyrel
Surmontil
Effexor
Viibryd
CYP2D6
CYP3A4/CYP3A5
CYP2D6
CYP2D6, CYP1A2
CYP2C19
CYP2D6
CYP2D6
CYP2D6, CYP2C19,
CYP1A2
CYP2D6
CYP2D6, CYP1A2
CYP2D6, CYP1A2
CYP3A4/CYP3A5
CYP2D6,
CYP3A4/CYP3A5
CYP2D6
CYP3A4/CYP3A5
CYP2C19
CYP3A4/CYP3A5
CYP2D6
CYP2D6
CYP3A4/CYP3A5
Generic
Alprazolam
Amphetamine
Aripiprazole
Asenapine
Atomoxetine
Buspirone
Carbamazepine
Chlorpromazine
Clozapine
Diazepam
Haloperidol
Iloperidine
Lurasidone
Brand
Xanax
Adderall
Abilify
Saphris
Strattera
Buspar
Various brands
Thorazine
Clozaril
Valium
Haldol
Fanapt
Latuda
Metabolic Route
CYP3A4/CYP3A5
CYP2D6
CYP2D6
CYP1A2
CYP2D6
CYP3A4/CYP3A5
CYP3A4/CYP3A5
CYP2D6
CYP1A2
CYP2C19
CYP2D6
CYP2D6
CYP3A4/CYP3A5
Midazolam
Olanzapine
Perphenazine
Promazine
Quetiapine
Versed
Zyprexa
Trilafon
Sparine
Seroquel
CYP3A4/CYP3A5
CYP1A2
CYP2D6
CYP1A2
CYP3A4/CYP3A5
Risperidone
Thioridazine
Triazolam
Ziprasidone
Zuclopenthixol
Risperidol
Mellaril
Halcion
Geodon
Various brands
CYP2D6
CYP2D6
CYP3A4/CYP3A5
CYP3A4/CYP3A5
CYP2D6
CYP2D6 and serotonin transporter variants
alter drug dose and/or selection
SSRI
Antidepressants
PD
Response
SLC6A4
Dependent on drug
concentration, receptor
expression and affinity
PK
Metabolism
PMs
CYP2D6
X
EMs
UMs
Ramey-Hartung, El-Mallakh, Reynolds. Clin Lab Med 2008;28:627-43.
Clearance
CASE: Depression/ADHD
•51 y/o male
•Problematic Polypharmacy (Atomoxetine, Topiramate,
Oxcarbazapine, Aripaprazole,Valproic acid)
•Genotyping results
Locus
CYP2D6
CYP2C9
CYP2C19
Genotype
CYP2D6*4/*6
CYP2C9*2/*3
CYP2C19*1/*1
Phenotype
PM
PM
EM
Relevance to case (drugs affected)
Medication
atomoxetine
aripiprazole
PGx
Gene
PM Effect
CYP2D6
Reduced clearance
Half life ~ 5x longer
CYP2D6
80% increase in exposure
half-life 2x longer
2D6 Atomoxetine
PMs
• 4x longer to SS
• 4x higher drug levels
• 4x longer to wash-out
• More likely to have AE
Plasma atomoxetine (ng/mL)
2600
20 mg q12h
PM
2080
7 2 h rs
1560
1040
EM
520
0
0
24
48
72
96 120 144 168 192 216 240 264
Time (hrs)
S S ;E M
S S ;P M
How to apply PGx to atomoxetine therapy
Adjust dosage based on
PK: decrease by 50%
Goal to normalize
exposure and ADR risk
Adjust monitoring and
wash-out expectations
Plasma atomoxetine (ng/mL)
1500
P M 2 0 mg q12 h
1200
900
600
P M 10 mg q12 h
300
EM
0
0
24
48
72
96 120 144 168 192 216 240 264
Time (hrs)
S S ;E M
S S ;P M
Aripiprazole Accumulation
Aripirazole blood concentrations (ng/mL)
According to CYP2D6 Genotype
EM
10 mg/d
PM
10 mg/d
PM
5 mg/d
400
Abilify monograph:
50% dose reduction for 2D6 PMs
300
200
100
0
0
200
400
600
800
1000
1200
Time (hrs)
CYP2D6 genotyping may be useful in predicting which patients are at
increased risk of atomoxetine and aripiprazole–induced ADRs.
Surja, Reynolds, Linder, El-Mallakh. Pers Med 2008;5(4):361-365
Serotonin Transporter and Antidepressants
• 50-60% depressed patients have recurrence and
20% fail 1st line Rx (SSRIs)
– TRD  increased # of Rx, hospitalization risk, costs (19x higher)
• 75% people carry S or LG version of SLC6A4
Risk of SSRI failure
Increased ADR risk
Greatest SSRI
efficacy
PGXL exclusive provider of SULT4A1 marker
(schizophrenia, bipolar disorder)
– Rule-in for olanzapine
– Reduced risk of hospitalization
– Reduced hospitalization costs
SULT4A1
Brain enzyme that interacts with neurochemicals
Efficacy advantage with olanzapine
Efficacy
Hospitalization
Liu et al. Prim Care Comp 2012; Ramsey et al. Pharmacogenomics 2011
Is olanzapine likely to have increased efficacy?
Yes
See SULT4A1
Does consensus data suggest alternatives to risperidone? Yes
See CYP2D6
Are SSRIs likely to have decreased efficacy and increased Yes
risk of side effects?
See SLC6A4
See below for possible dosage considerations.
STA2R Panel
Report
SULT4A1 rs763120 CC rs5764010 TT
SULT4A1-1
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Phenotype
POSITIVE
Consider olanzapine. SULT4A1-1 positive patients have been shown to demonstrate
enhanced treatment efficacy and reduced hospitalization risk when treated with olanzapine
compared to both SULT4A1-1 negative patients treated with olanzapine and SULT4A1-1
positive patients treated with risperidone.
CYP2D6 *4/*4
CYP2D6
Phenotype
Poor Metabolizer
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Avoid
Alternative Consideration
Adjust Dosage
Adjustment
Risperidone†
Venlafaxine†
Amitriptyline†
Quetiapine, olanzapine, clozapine
Citalopram, sertraline
Citalopram, sertraline
Aripiprazole†
Clomipramine†
Doxepin†
Haloperidol†
Imipramine†
Nortriptyline†
Zuclopenthixol†
10 mg/day maximum
Decrease 50%
Decrease 60%
Decrease 50%
Decrease 70%
Decrease 60%
Decrease 50%, or
flupenthixol, quetiapine,
olanzapine, clozapine
SLC6A4 S/S
SLC6A4
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Phenotype
Poor Responder Decreased serotonin transporter expression expected. Risk of decreased response to SSRIbased therapies and increased risk of adverse events. Consider non-SSRI antidepressant
therapies, such as SNRIs or tricyclic antidepressant alternatives.
CYP2C19 *2/*2
CYP2C19
Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Poor Metabolizer
Decreased metabolic clearance expected.
Adjust Dosage Adjustment
Imipramine†
Sertraline†
Decrease 30%
Decrease 50%
CYP1A2 *1F/*1F
CYP1A2
THERAPEUTIC IMPLICATIONS (adapted from published resources)
SLC6A4
S/S
Phenotype
SLC6A4
THERAPEUTIC IMPLICATIONS (adapted from published resources)
HYPERINDUCER Rapid metabolism expected, especially in smokers. Consider dose increases for
Phenotype
medications
inactivated
by CYP1A2
particularly
in smokers,
or decreased
alternative medications.
Poor Responder Decreased
serotonin
transporter
expression
expected.
Risk of
response to SSRICommon
CYP1A2
next
based
therapies
andmedications
increased risk
ofpage.
adverse events. Consider non-SSRI antidepressant
*Lack of efficacy duetherapies,
to failure tosuch
produce
active metabolite;
risk of adverse
events due to
as SNRIs
or tricyclic†Increased
antidepressant
alternatives.
diminished drug clearance.
Applications of pharmacogenomics
• Individualize drug therapy selection
• Predict adverse reactions, dosing,
response
• Identify increased sensitivity to drug
interactions
Stay tuned for future webinars!
• Pain Management
• Cardiology
• Behavioral Health
• Personalized medicine “program”
implementation
Thank You!
kreynolds@pgxlab.com
Key Service Lines
Pain Management
– opioid resistance and opioid toxicity
Behavioral Health
– Drug selection to manage treatment resistant depression and psychosis
– Dosing information to minimize adverse drug reactions
Statin therapy
– Minimum effective statin dose and myopathy risk
Anti-platelet therapy
– Clopidogrel resistance and increased bleeding risk
Anti-coagulant therapy
– warfarin dose estimation and optimal INR interpretation guidance
Thrombotic risk assessment