Kristen K. Reynolds, PhD
Associate Medical Director, VP Laboratory Operations
Copyright 2010 PGXL Laboratories LLC, Louisville KY
All materials herein are the exclusive property of PGXL Laboratories
Enabling Personalized Medicine
Intuitive
Medicine
Precision
Medicine
~60% of meds in top
20 list causing ADRs
are linked to a genetic
variation
~122 drugs have FDA
box warnings related
to genetics
Applications of pharmacogenomics
• Individualizing drug therapy selection
• Predicting adverse reactions, dosing,
response
• Identify increased sensitivity to drug
interactions
CYP2D6 and psychotropic receptor variants
alter drug dose and/or selection
SSRI
TCA
SNRI
PD
Response
5-HTT
5-HTR2A
DRD2
FGA
SGA
Dependent on drug
concentration, receptor
expression and affinity
PK
PMs
Metabolism
CYP2D6
EMs
X
Clearance
UMs
Ramey-Hartung, El-Mallakh, Reynolds. Clin Lab Med 2008;28:627-43.
Clinical Applications of Pharmacogenetic Information
• Anti-coagulation
– Warfarin
– Clopidogrel
• Psychiatry
– Anti-depressants
• Oncology
– Thiopurines
– Tamoxifen
– EGFRi’s
• Pain management
– Codeine
– Methadone
• Epilepsy
– Phenytoin
– Carbamazepine
• Diabetes
– Glipizide
Application of Pharmacogenomics to
warfarin therapy
The Problem
Reynolds et al. Pers Med 2007;4(1):11-31.
Reynolds et al. Pers Med 2007;4(1):11-31.
Genetics of Warfarin metabolism and
response
• 40% of population have deficient CYP2C9
• > 70% of population have decreased VKOR and
are more sensitive to warfarin
r
a
f
r
.
0
0
Steady-State
a
3
CYP2C9 status increases magnitude of accumulation/unit
dose as well as time to achieve steady-state
4
0
1
.
8
1
.
2
0
.
6
0
0
.
0
0
0
0
C
Y
P
2
C
9
*
1
Accumulation
C
Y
P
2
C
9
*
1
C
Y
P
2
C
9
*
1
S
W
.
-
2
0
3
6
9
1
21
T
Linder et al. J Thrombosis & Thrombolysis 2002;14:227-232
51
i
82
m
12
e
42
73
(
0
d
a
y
s
)
VKORC1 -1639 G>A genotype dictates
S-warfarin therapeutic concentration
All within INR 2-3
Dose
2.7 ± 1.2 mg
Zhu Y et al. Clin Chem 2007;53(7):1199-1205.
Dose
4.2 ± 2.2 mg
Dose
6.7 ± 3.3 mg
PerMIT:Warfarin
©
Powered by PGXL Laboratories
• Calculation of estimated maintenance dose
• Modeling of individualized response to dose
changes
• Guidance for:
 Monitoring strategy
 Dosing modifications
 Transition: induction to maintenance therapy
All; 66 y/o, female, 130 lbs
No Loading Dose
PerMIT-guided
Loading Dose
Concentration/Response Time Profile
Genotype: CYP2C9*1*2 // VKORC1 GG
Estimated Maintenance dose: 6.3 mg/d (5.7 – 7.0)
Time to Steady-State: 11 to 15 days
Target therapeutic concentration: 0.8 mg/L
. . . . . . 6 mg/d. . . . . . .
10, 10, 8, 6 mg/d
CONFIDENTIAL
Linder MW et al. 2011 (unpublished results)
Application of Pharmacogenomics to
Anti-platelet therapy
CYP2C19 - Plavix
• Clopidogrel (Plavix) is a pro-drug which is
converted to an active metabolite by CYP2C19
• Active metabolite is what elicits the desired
antiplatelet response
• ~ 30% of patients have deficiency in CYP2C19
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%
New Draft Report
THERAPEUTIC IMPLICATIONS
Gene
X CYP2C19
*2/*2
Phenotype
Poor
Metabolizer
Avoid
Clopidogrel*
1
Alternative Consideration
Prasugrel
Adjust Dosage
†
Imipramine
†
Sertraline
Adjustment
30%
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
Application of Pharmacogenetics to
Pain Management
CYP2D6 - Opioids
•
•
•
•
Hydrocodone
Oxycodone
Methadone
Others…
• Propoxyphene
• Tramadol
• Codeine
CODEINE
CYP2D6 PM: inadequate morphine
CYP2D6 UM: morphine toxicity
CYP3A4
CYP2D6
Morphine
Norcodeine
Morphine-6-glucuronide Morphine3-glucuronide
Renal Excretion
Reynolds KR et al. Clin Lab Med 2008;28:581–598.
Active
opioid
effects
Effects of CYP2D6
• Decreased drug metabolism = lack of efficacy
– Poor pain control
– Mis-interpretation of drug seeking behavior
• Ultra-rapid drug metabolism = possible side effects
– Over-production of active compound
– Mis-interpretation of over-compliance
– Possible lower doses required
CYP2D6 Variants
Extensive Metabolizers (EM)
55 – 60 % of population
Intermediate Metabolizers (IM)
25 – 30% of population
Poor Metabolizers (PM)
7 – 10 % of population
Ultra-rapid Metabolizers (UM)
1 – 3 % of population
Application of Pharmacogenomics to
behavioral health
CASE: Depression/ADHD
• 51 y/o male
• Problematic Polypharmacy (Atomoxetine, Topiramate,
Oxcarbazapine, Aripaprazole,Valproic acid)
• Genotyping results
Locus
CYP2D6
CYP2C9
CYP2C19
28
Genotype
CYP2D6*4/*6
CYP2C9*2/*3
CYP2C19*1/*1
Phenotype
PM
PM
EM
Relevance to case (drugs affected)
Medication
atomoxetine
aripiprazole
29
PGx
Gene
PM Effect
CYP2D6
Reduced clearance. Half life ~ 5
times longer
CYP2D6
80% increase in exposure, half-life
twice as long
How to apply PGx to atomoxetine therapy?
•
•
•
•
Adjust dosage based on PK
Goal to achieve
normalized exposure and
ADR risk
Adjust monitoring
expectations for SS delay
Allow for adequate “washout” period
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
Medications to avoid by CYP2D6 phenotype
UM
CODEINE
AMITRIPTYLINE
CLOMIPRAMINE
OXYCODONE
RISPERIDONE
ZUCLOPENTHIXOL
IM
PROPAFENONE
RISPERIDONE
VENLAFAXINE
PM
CODEINE
AMITRYPTYLINE
OXYCODONE
RISPERIDONE
TAMOXIFEN
TRAMADOL
VENLAFAXINE
New Draft Report
RESULTS
Gene
X CYP2D6
*4/*4
THERAPEUTIC IMPLICATIONS
Phenotype
Poor
Metabolizer
Avoid
Codeine*
Hydrocodone*
Oxycodone*
Tramadol*
1
Alternative Consideration
Morphine, non-opioid
Hydromorphone, non-opioid
Oxymorphone, non-opioid
Consider active drug, nonopioid
Citalopram, sertraline
Citalopram, sertraline
Quetiapine, olanzapine,
clozapine
Anastrozole, exemestane,
letrozole
Adjust Dosage
†
Aripiprazole
†
Clomipramine
†
Doxepin
†
Flecainide
†
Haloperidol
†
Imipramine
†
Nortriptyline
†
Propaphenone
†
Metoprolol
Adjustment
10 mg/day maximum
50%
60%
50%
50%
†
Amitriptyline
70%
†
Venlafaxine
60%
†
Risperidone
70%
75%, or atenolol,
Tamoxifen*
bisoprolol, carvedilol
Zuclopenthixol
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
Fundamental Principles
• Genetic variability in drug metabolism significantly increases risk of
ADRs and non-response
• Genetic variation can be managed:
• Poor Metabolizers
•
•
•
•
•
•
Decreased maintenance dosing (20 – 70% )
Increased pro-drug dosing
Allow longer time to reach Steady-State
Allow longer time between medication changes
Increased observation
Choose alternative medication
• Rapid metabolizers
• Increased dosages (50 – 200%)
• Decreased pro-drug dosages
Medications and metabolic pathways
CYP2C9
CYP2C19
CELECOXIB
IBUPROFEN
NAPROXEN
GLYBURIDE
GLIPIZIDE
TOLBUTAMIDE
GLIMEPIRIDE
PHENYTOIN
FLUVASTATIN
LOSARTAN
CELEBREX
ADVIL, MOTRIN
ALEVE
DIABETA
GLUCOTROL
ORINASE
AMARYL
DILANTIN
LESCOL
COZAAR
CYP2C9/VKORC1
WARFARIN
COUMADIN
CLOPIDOGREL
CITALOPRAM
ESCITALOPRAM
IMIPRAMINE
SERTRALINE
OMEPRAZOLE
ESOMEPRAZOLE
PANTOPRAZOLE
RABEPRAZOLE
LANSOPRAZOLE
DIAZEPAM
NELFINAVIR
PLAVIX
CELEXA
VARIOUS BRANDS
TOFRANIL
ZOLOFT
PRILOSEC
NEXIUM
PROTONIX
ACIPHEX
PREVACID
VALIUM
VIRACEPT
Medications and CYP2D6 pathway
Pain Management
Psychiatry
Codeine
Oxycodone
Hydrocodone
Dextromethorphan
Tramadol
Various brands
Oxycontin, various
Various brands
Various brands
Ultram, various
Cardiology
Carvedilol
Metoprolol
Propanolol
Propafenone
Flecainide
Coreg
Toprol-XL
Inderal, various
Rythmol
Tambocor
Other
Loratadine
Donepezil
Tamoxifen
Claritin
Aricept
Various brands
Amitriptyline
Clomipramine
Desipramine
Doxepin
Imipramine
Nortriptyline
Fluoxetine
Paroxetine
Venlafaxine
Risperidone
Aripiprazole
Zuclopenthixol
Maprotoline
Duloxetine
Various brands
Ananfranil
Norpramin
Sinequan
Tofranil
Pamelor, Aventyl
Prozac
Paxil
Effexor
Risperidol
Abilify
Various brands
Ludiomil
Cymbalta