Transcript Building Better Panels

PGXL Psychiatry Panels
Kristen K. Reynolds, PhD
VP Laboratory Operations
Copyright 2012 PGXL Laboratories, Louisville KY
All materials herein are the exclusive property of PGXL Laboratories
Building Better Panels
• Targeted panels that maximize guidance for
drug selection and dose
• Metabolism targets: dose and adverse event risk
• Receptor targets: drug choice
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
EMs
UMs
Ramey-Hartung, El-Mallakh, Reynolds. Clin Lab Med 2008;28:627-43.
X
Clearance
Application of Pharmacogenetics
to behavioral health
PGXL Psych Panels*
PGXL Depression Panel
STA2R Panel = Psychosis
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2D6
2C19
2C9
1A2
3A4
3A5
Add on: SLC6A4
*updated as of 11-20-12
SULT4A1:olanzapine
2D6
2C19
2C9
1A2
3A4
3A5
SLC6A4
PGXL Psychiatry Panels – 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
Paxil
Edronax
Zoloft
Desyrel
Surmontil
Effexor
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
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
Genotype Frequency %
Gene
EM
IM
PM
UM
2D6
53
35
10
2
2C19
36
32
4
28
2C9
57
40
3
NA
3A4
87
12
1
NA
3A5
1
18
81
NA
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
2D6 Paroxetine
P aroxetine A ccumulation (20 mg q 24 hr)
Plasma paroxetine (ng/mL)
70
PM
56
144 hr
42
28
EM
14
0
0
92
184
276
S S ;P M
S S ;E M
Tim e (hr s)
368
460
CYP2D6 *4/*4
CYP2D6
Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Poor Metabolizer
Avoid
Codeine**
Hydrocodone**
Oxycodone**
Tramadol**
Tamoxifen**
Amitriptyline †
Venlafaxine †
Risperidone †
Alternative Consideration
Adjust Dosage
Adjustment
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 †
10 mg/day maximum
decrease 50%
decrease 60%
decrease 50%
decrease 50%
decrease 70%
decrease 60%
decrease 70%
decrease 75%, or
atenolol, bisoprolol,
carvedilol
decrease 50%, or
flupenthixol, quetiapine,
olanzapine, clozapine
Clomipramine †
Doxepin †
Flecainide †
Haloperidol †
Imipramine†
Nortriptyline †
Propafenone †
Metoprolol †
Zuclopenthixol †
**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
Drug selection “algorithm” using CYPs
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012
SLC6A4 add-on
Serotonin Transporter
SLC6A4
• 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
• S/S, S/LG, or LG/LG should be considered for non-SSRI
therapies
SLC6A4 interpretations
SLC6A4
Phenotype
Normal Responder
SLC6A4
Phenotype
Intermediate Responder
SLC6A4
Phenotype
Poor Responder
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Normal serotonin transporter expression expected. Patients with the LA/LA genotype are
more likely to respond within the first 4 weeks of therapy, achieve remission, and are less
likely to have adverse effects when treated with SSRIs.
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Carriers of S or LG alleles may have decreased serotonin transporter expression compared
to LA/LA subjects. Possible risk of decreased or slower response to SSRIs or increased risk
of adverse events.
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Decreased serotonin transporter expression expected. Risk of decreased response to
SSRI-based therapies and increased risk of adverse events. Consider non-SSRI
antidepressant therapies, such as SNRIs or tricyclic antidepressants alternatives.
Antidepressants
2C19
2C19
2D6
2D6,1A2
2D6
2C19
3A4/5
SSRIs
citalopram
escitalopram
fluoxetine
fluvoxamine
paroxetine
sertraline
vilazodone
Celexa
Lexapro
Prozac
Luvox
Paxil
Zoloft
Viibryd
2D6,1A2,3A4/5
2D6,1A2
2D6,2C19
2D6
2D6
2D6,3A4/5
2D6,3A4/5,2C19
TCAs
amitriptyline
clomipramine
desipramine
doxepin
imipramine
nortriptyline
trimipramine
Elavil
Anafranil
Norpramin
Sinequan
Tofranil
Pamelor, Aventyl
Surmontil
2C19
MAOIs
phenelzine
tranylcyromine
isocarboxazid
moclobemide
Nardil
Parnate
Marplan
Black, major pathway; gray, minor pathway
SNRIs
2D6,1A2
duloxetine
2D6
venlafaxine
3A4/5
desvenlafaxine
renal
milnacipran
2D6,1A2,3A4/5 mirtazapine
2B6,1A2
3A4/5
3A4/5
2D6
2D6,1A2
3A4/5
Cymbalta
Effexor
Pristiq
Savella
Remeron
Atypicals (NRIs, NDRIs)
bupropion
Wellbutrin
trazadone
Desyrel
nefazadone
Serzone
maprotiline
Ludiomil
mianserin
reboxetine
Edronax
PGXL
Depression
Panel
(Core Panel
+ SLC6A4
add-on)
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.
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012
CYP3A4
Phenotype
Partially
Decreased
Metabolizer
CYP3A5
Phenotype
Decreased
Metabolizer
CYP1A2
Phenotype
Hyperinducer
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Decreased metabolic clearance expected with increased risk of dose-dependent side
effects. Common CYP3A4 medications below.
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Genotype consistent with reduced CYP3A5 enzymatic activity and represents the majority
(60-80%) of the population. For DMs, maintenance dosages for most CYP3A drugs are
lower than extensive metabolizers. Common CYP3A5 medications below.
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Rapid metabolism expected, especially in smokers. Consider dose increases for
medications inactivated by CYP1A2 particularly in smokers, or alternative medications not
metabolized by CYP1A2. Common CYP1A2 medications below.
Patients who are homozygous for the CYP1A2*1F/*1F genotype may exhibit even higher rates of CYP1A2 enzymatic activity and have
been described as ultra-rapid metabolizers for olanzapine. As an example, carriers of CY1A2*1F with the hyperinduction phenotype
may exhibit as much as 50% lower than expected plasma levels of olanzapine, clozapine, and haloperidol, which could lead to subtherapeutic response. Hyperinducers may require increased dosages of CYP1A2 substrates due to higher than normal rates of drug
metabolism in the presence of an inducer.
PGXL Psychiatry Panels – 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
Paxil
Edronax
Zoloft
Desyrel
Surmontil
Effexor
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
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
• PGXL exclusive provider of SULT4A1 marker
(schizophrenia, bipolar disorder)
– Enhanced efficacy on olanzapine
– Reduced risk of hospitalization
– Reduced hospitalization costs
SULT4A1
• Brain enzyme that interacts with neurochemicals
• Efficacy advantage with olanzapine
Efficacy
Hospitalization
SULT4A1 Interpretations
Gene
THERAPEUTIC IMPLICATIONS (adapted from published resources)
SULT4A1-1 Consider olanzapine. SULT4A1-1 positive patients have been shown to demonstrate
POSITIVE
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.
SULT4A1-1 SULT4A1-1 negative patients treated with olanzapine do not display the expected efficacy
NEGATIVE advantage compared to other atypical antipsychotics.
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.
CYP3A4
Phenotype
Partially
Decreased
Metabolizer
CYP3A5
Phenotype
Decreased
Metabolizer
CYP1A2
Phenotype
Hyperinducer
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Decreased metabolic clearance expected with increased risk of dose-dependent side
effects. Common CYP3A4 medications below.
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Genotype consistent with reduced CYP3A5 enzymatic activity and represents the majority
(60-80%) of the population. For DMs, maintenance dosages for most CYP3A drugs are
lower than extensive metabolizers. Common CYP3A5 medications below.
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Rapid metabolism expected, especially in smokers. Consider dose increases for
medications inactivated by CYP1A2 particularly in smokers, or alternative medications not
metabolized by CYP1A2. Common CYP1A2 medications below.
Master Drug Lists
• Gene-based drug lists in back of report
• Recall for additional drugs possibly affected by
genotype that were not on 1st page
CYP3A4/5
master
drug list
CYP3A4/CYP3A5 Substrates
PSYCHIATRY
Benzodiazepines
Alprazolam
Xanax
Midazolam
Versed
Triazolam
Halcion
Antipsychotics
Quetiapine
Seroquel
Ziprasidone
Geodon
Buspirone
Buspar
Lurasidone
Latuda
Carbamazepine
Various brands
Antidepressants
Desvenlafaxine
Pristiq
Vilazodone
Viibryd
Trazadone
Desyrel
Nefazadone
Serzone
Reboxetine
Edronax
Nortriptyline
Pamelor, Aventyl
CARDIOLOGY
Quinidine
Ticareglor
Rivaroxaban
Statins
Atorvastatin
Lovastatin
Mevastatin
Simvastatin
Ca Channel Blockers
Amlodipine
Diltiazem
Felodipine
Lercanidipine
Nifedipine
Nisoldipine
Nitrendipine
Verapamil
Various brands
Brilinta
Xarelto
Lipitor
Mevacor, Advicor
Compactin
Zocor, Vytorin, Caduet, Simcor
Norvasc
Cardizem
Plendil
Zanidip
Adalat
Sular
Various brands
Various brands
OTHER
Antimicrobials/antivirals
Clarithromycin
Erythromycin
Telithromycin
Indinavir
Nelfinavir
Ritonavir
Saquinavir
Biaxin
E-Mycin
Ketek
Crixivan
Viracept
Norvir
Fortovase
Steroids
Estradiol
Hydrocortisone
Progesterone
Testosterone
Various brands
Various brands
Various brands
Various brands
Chemotherapeutics
Vincristine
Docetaxel
Oncovin
Taxotere
Pain Management
Cyclobenzaprine
Fentanyl
Alfentanil
Flexaril
Actiq, Duragesic
Alfenta
Immunosuppressants
Cyclosporine
Tacrolimus
Gengraf
Prograf
CYP2D6
Pain Management
Codeine**
Oxycodone**
Hydrocodone**
Tramadol**
Various brands
Oxycontin, various
Various brands
Ultram, various
Cardiology
Carvedilol
Metoprolol
Propanolol
Timolol
Propafenone
Flecainide
Coreg
Toprol-XL
Inderal, various
Blocadren
Rythmol
Tambocor
Other
Loratadine
Donepezil
Dextromethorphan
Tamoxifen**
Claritin
Aricept
Various brands
Various brands
Psychiatry
Antidepressants
Fluoxetine
Fluvoxamine
Paroxetine
Venlafaxine
Duloxetine
Maprotiline
Mirtazapine
Amitriptyline
Clomipramine
Desipramine
Doxepin
Imipramine
Nortriptyline
Trimipramine
Prozac
Luvox
Paxil
Effexor
Cymbalta
Ludiomil
Remeron
Various brands
Ananfranil
Norpramin
Sinequan
Tofranil
Pamelor,
Aventyl
Surmontil
Antipsychotics
Haloperidol
Risperidone
Aripiprazole
Zuclopenthixol
Perphenazine
Thioridazine
Iloperidine
Chlorpromazine
Atomoxetine
Amphetamine
Haldol
Risperidol
Abilify
Various brands
Trilafon
Mellaril
Fanapt
Thorazine
Strattera
Adderall
Psych Req Form
Thank You!
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