Transcript CYP2D6 - PGXL Laboratories

PGX Applications in
Pain Management
Kristen K. Reynolds, PhD
VP Laboratory Operations
Copyright 2012-2013 PGXL Laboratories, Louisville KY
All materials herein are the exclusive property of PGXL Laboratories
Panels*
Core:
Panel Add-Ons:
CYP2D6
CYP2C9
CYP2C19
CYP3A4
CYP3A5
CYP1A2
OPRM1 (opioids)
*All genes always orderable a la carte
SLC6A4 (SSRIs)
Common pain medications with PGXL tests
**prodrug;
+
Generic
Brand
Metabolic Route
Alfentanil
Carisoprodol**
Celecoxib
Codeine**
Cyclobenzaprine
Fentanyl
Hydrocodone**
Hydromorphone
Alfenta
Soma
Celebrex
Various brands
Flexaril
Actiq, Duragesic
Lortab, Vicodin
Dilaudid
CYP3A4/CYP3A5
CYP2C19
CYP2C9
CYP2D6
CYP1A2, CYP3A4/CYP3A5
CYP3A4/CYP3A5
CYP2D6
UGT2B7+
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+
CYP2C9
CYP2D6, CYP3A4/5
UGT2B7+
CYP1A2
CYP1A2
CYP2D6
CYP1A2
test not yet available
Opioids
Pharmacokinetic Gene
Metabolism
Pharmacodynamic Gene
Clinical Effect
CYP2D6 - Opioids
Hydrocodone
Oxycodone
Codeine
Propoxyphene
Tramadol
etc…
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
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
Morphine Overdose from Codeine
8-15-12 FDA Drug Safety
Codeine use in certain children after tonsillectomy and/or adenoidectomy
may lead to rare, but life-threatening adverse events or death
• 3 deaths reported in children (2-5yo) who received codeine after undergoing
tonsillectomy and/or adenoidectomy for obstructive sleep apnea
• 3 deaths in children who were CYP2D6 UMs
• All children received typical codeine doses
• Morphine toxicity signs developed within 1-2 days after starting codeine
• Supratherpeutic post-mortem morphine concentrations in the 3 death cases
FDA recommendations for Physicians:
•
•
Use the lowest effective codeine dose for the shortest period of
time on an as-needed basis (i.e., not scheduled around the clock)
Counsel parents:
– how to recognize the signs of morphine toxicity
– Advise them to stop giving the child codeine
– Seek medical attention immediately if child exhibits these signs
•
•
Tests are available for determining CYP2D6 genotype
Consider prescribing alternative analgesics for children
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 †
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
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
RESULTS
Gene
X CYP2D6
*4/*4
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Phenotype
Poor
Metabolizer
Avoid
Codeine*
Hydrocodone*
Oxycodone*
Tramadol*
Normal metabolic clearance expected.
Adjustment
10 mg/day maximum
50%
60%
50%
50%
70%
60%
70%
75%, or atenolol, bisoprolol,
carvedilol
†
Zuclopenthixol
50%, or flupenthixol,
quetiapine, olanzapine,
clozapine
Common CYP2D6 medications next page
Oxycodone*
Hydrocodone*
†
Propafenone
Oxymorphone, non-opioid
Hydromorphone, non-opioid
Sotalol, disopyramide,
quinidine, amiodarone
Quetiapine, olanzapine,
clozapine
Citalopram, sertraline
Codeine*
Tramadol*
Tamoxifen*
Morphine, non-opioid
Hydromorphone, non-opioid
Oxymorphone, non-opioid
Citalopram, sertraline
Citalopram, sertraline
Citalopram, sertraline
Methylphenidate
Quetiapine, olanzapine,
clozapine
Flupenthixol, quetiapine,
olanzapine, clozapine
Sotalol, disopyramide,
quinidine, amiodarone
Tramadol*
†
Imipramine
†
Nortriptyline
†
Venlafaxine
Tamoxifen*
Amitriptyline
†
Venlafaxine
†
Risperidone
 CYP2D6
*1/*1
! CYP2D6
*1/*4
Extensive
Metabolizer
Intermediate
Metabolizer
Risperidone
†
†
†
Velafaxine
X CYP2D6
*1/*1xN
Ultra-Rapid
Metabolizer
Codeine*
Hydrocodone*
Oxycodone*
†
Amitriptyline
†
Clomipramine
†
Paroxetine
†
Atomoxetine
†
Risperidone
Zuclopenthixol
Propafenone
†
†
Alternative Consideration
Morphine, non-opioid
Hydromorphone, non-opioid
Oxymorphone, non-opioid
Consider active drug, nonopioid
Anastrozole, exemestane,
letrozole
Citalopram, sertraline
Citalopram, sertraline
Quetiapine, olanzapine,
clozapine
Adjust Dosage
†
Aripiprazole
†
Clomipramine
†
Doxepin
†
Flecainide
†
Haloperidol
†
Imipramine
†
Nortriptyline
†
Propafenone
†
Metoprolol
†
Amitriptyline
†
Imipramine
†
Nortriptyline
†
Zuclopenthixol
†
Doxepin
†
Flecainide
†
Metoprolol
Haloperidol
†
†
Doxepin
†
Metoprolol
15-60 mg/hr
titrate to pain relief
Avoid CYP2D6 inhibitors, e.g.
paroxetine, or consider
aromatase inhibitor in postmenopausal women
25%
30%
40%
25%
20%
25%
50%, or atenolol, bisoprolol,
carvedilol
30%
70%
60%
150%, or citalopram,
sertraline
based on plasma
measurement, or pimozide,
flupenthixol, fluphenazine,
quetiapine, olanzapine,
clozapine
100%
up to 250%, or atenolol,
bisoprolol, carvedilol
Pharmacokinetic Gene
Metabolism
Pharmacodynamic Gene
Clinical Effect
OPRM1: Mu Opioid Receptor
Analgesia
Sedation
Euphoria
Respiratory depression
Itching
Morphine
Mu opioid receptor
OPRM1 118A>G Genotypes
AG
AA
GG
Mean effective
analgesic
concentration
=
Therapeutic
target range
OPRM1: Mu Opioid Receptor
250
Opioid binds
OPRM1 to elicit
pain relief
200
Morphine mg/24hr
150
100
50
0
AA
AG
GG
118A>G variant decreases receptor availability
and may increase dose requirements
Reynolds 2008; Reyes-Gibby 2007; Klepstad 2004
OPRM1 helps predict dose of active opioids
Morphine
Hydromorphone
Oxymorphone
Generic
Brand
Metabolic Route
Receptor/Dose
Alfentanil
Carisoprodol**
Celecoxib
Codeine**
Cyclobenzaprine
Alfenta
Soma
Celebrex
Various brands
Flexaril
Fentanyl
Hydrocodone**
Hydromorphone
Actiq, Duragesic
Various brands
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, various
Opana
Various brands
Zanaflex
Ultram, various
Zomig
CYP1A2
CYP2C19, CYP2B6+
UGT2B7+
CYP2C9
CYP2D6, CYP3A4/5
UGT2B7+
CYP1A2
CYP1A2
CYP2D6
CYP1A2
**prodrug;
+
test not yet available
OPRM1
OPRM1
OPRM1 Opioid Interpretations
OPRM1 AA
OPRM1 Phenotype Therapeutic Implications (adapted from published resources)
Normal Opioid
Opioid response: Average doses of morphine typically required (may also apply to other active opioids, eg,
Responder
hydromorphone, oxymorphone). Note: Formation of active opioid metabolites (e.g., morphine) from
prodrugs (eg, codeine) is dependent on CYP2D6 activity.
OPRM1 AG
OPRM1
Phenotype
Intermediate
Opioid
Responder
OPRM1 GG
OPRM1
Phenotype
Poor Opioid
Responder
Therapeutic Implications (adapted from published resources)
Opioid response: Higher then average doses of morphine typically required
(may also apply to other active opioids, eg, hydromorphone, oxymorphone).
Note: Formation of active opioid metabolites (e.g., morphine) from prodrugs
(eg, codeine) is dependent on CYP2D6 activity.
Adjust Dosage Adjustment
Morphine
Increase 10%
Therapeutic Implications (adapted from published resources)
Opioid response: Higher then average doses of morphine typically required (may Adjust Dosage Adjustment
also apply to other active opioids, eg, hydromorphone, oxymorphone). Note:
Morphine
Increase up to
Formation of active opioid metabolites (e.g., morphine) from prodrugs (eg,
80%
codeine) is dependent on CYP2D6 activity.
OPRM1 and
Naltrexone for
Alcohol dependence
OPRM1 and Naltrexone
Naltrexone is a competitive
mu opioid receptor
antagonist
– Decreases alcohol cravings
– Inhibits endorphin “reward”
effects in EtOH/opioid abuse
– Decreases relapse risk
EtOH
OPRM1 and risk of alcohol relapse
• 40% of patients treated with naltrexone will relapse
• 80% of those who relapse have AA genotype
Chamorro et al. Addiction Biology 2012;17:505-12.
OPRM1 AA carriers treated with naltrexone have
highest risk of relapse
AA genotype pts are 2x more likely to relapse that G carriers
Chamorro et al. Addiction Biology 2012;17:505-12.
OPRM1 Combined Interpretations
OPRM1 AA
OPRM1 Phenotype Therapeutic Implications (adapted from published resources)
Normal Opioid
Opioid response: Average doses of morphine typically required (may also apply to other active opioids, eg,
Responder /
hydromorphone, oxymorphone). Note: Formation of active opioid metabolites (e.g., morphine) from
Impaired
prodrugs (eg, codeine) is dependent on CYP2D6 activity.
Naltrexone
Responder
Naltrexone response: With respect to naltrexone treatment for alcohol dependence, 80% of treated
patients who relapse have the OPRM1 AA genotype. Relapse rate among AA genotype patients is 5% higher
than the typical on-treatment relapse rate, and is 2-fold greater than for patients with the AG or GG
genotypes.
OPRM1 Combined Interpretations
OPRM1 GG
OPRM1
Phenotype
Poor Opioid
Responder /
Normal
Naltrexone
Responder
Therapeutic Implications (adapted from published resources)
Opioid response: Higher then average doses of morphine typically required (may also Adjust Dosage
apply to other active opioids, eg, hydromorphone, oxymorphone). Note: Formation of Morphine
active opioid metabolites (e.g., morphine) from prodrugs (eg, codeine) is dependent on
CYP2D6 activity.
Naltrexone response: In patients treated with naltrexone for alcohol dependence,
those with the GG genotype have a 15% lower average relapse rate compared to the
typical on-treatment relapse rate. Overall, relapse rate among G allele carriers is 25%
compared to 54% in patients with AA genotype.
Adjustment
Increase up to 80%
OPRM1 Combined Interpretations
OPRM1 GG
OPRM1
Phenotype
Poor Opioid
Responder /
Normal
Naltrexone
Responder
Therapeutic Implications (adapted from published resources)
Opioid response: Higher then average doses of morphine typically required (may also Adjust Dosage
apply to other active opioids, eg, hydromorphone, oxymorphone). Note: Formation of Morphine
active opioid metabolites (e.g., morphine) from prodrugs (eg, codeine) is dependent on
CYP2D6 activity.
Naltrexone response: In patients treated with naltrexone for alcohol dependence,
those with the GG genotype have a 15% lower average relapse rate compared to the
typical on-treatment relapse rate. Overall, relapse rate among G allele carriers is 25%
compared to 54% in patients with AA genotype.
Adjustment
Increase up to 80%
NSAIDs
NSAIDs
•
•
•
Non-steroidal anti-inflammatory drugs
Ibuprofen, naproxen, celecoxib, diclofenac, etc
Individual or combination preparations
• Celebrex (celecoxib)
• Vicoprofen (hydrocodone + ibuprofen)
NSAID Adverse Events
Severe ADRs
• Ulcer
• GI bleed
• Kidney failure
• MI
• Stroke
Metabolized by CYP2C9
CYP2C9 variants increase risk of
NSAID-induced bleeding
• Case control study:
26 patients taking NSAID <1 month with confirmed GI bleed vs
52 NSAID users without GI bleeds
• CYP2C9 genotyping performed
CYP2C9 Genotype
Risk of GI bleed taking NSAID
*1/*1
1
*1/*2
3.8
*1/*3
7.3
Pilotto et al Gastroenterology 2007;133(2):465-71.
CYP2C9 and NSAID use
• CYP2C9 genotyping may identify
patient subgroups at increased risk of
NSAID-related GI bleeding
• Use with caution based on other
clinical factors
Summary Pearls
•
•
•
•
•
Opioid prodrug efficacy/ADR: 2D6
Active opioid dose: OPRM1
Naltrexone efficacy: OPRM1
NSAID ADR: 2C9
Other opioids and muscle relaxers:
3A4/5, 2C19, 1A2