Transcript CYP2D6 - PGXL Laboratories

IF:Pain
© 2009 - 2014 PGXL Laboratories
Pain Management - Opioids
Problem and Implications
•
2% to 40% of adults suffer from chronic pain1
•
90% of patients in the pain management setting receive opioids2
•
Prescriptions for opioids have skyrocketed in recent years3
• 178% increase in hydrocodone3
• 556% increase in oxycodone3
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Opioid poisoning increased 91.2% between 1992 and 20024
•
80% of patients with adverse events from opioids had impaired CYP2D6 metabolism5
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Increased regulatory oversight and guidelines
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Codeine has pharmacogenetic language in label
1. Statement of Laxmaiah Manchikanti, MD, CEO, American Society of Interventional Pain Physicians Before the Sub- committee On Criminal
Justice, Drug Policy, And Human Resources, July 26, 2006, Prescription Drug Abuse: What Is Being Done To Address This Drug Epidemic?
2. Manchikanti L, Damron KS, McManus CD, Barnhill RC. Patterns of illicit drug use and opioid abuse in patients with chronic pain at initial
evaluation: A pro- spective, observational study. Pain Physician 2004; 7:431-437.
3. Testimony of Nora D. Volkow, M.D., Director, National Institute On Drug Abuse, National Institutes Of Health, U.S. Department Of Health
And Human Services, Before The Subcommittee On Criminal Justice, Drug Policy, And Hu- man Resources Committee, July 26, 2006.
4. Paulozzi LJ, Budnitz DS, Yongli X. In- creasing deaths from opioid analgesics in the United States. Pharmacoepidemiol Drug Saf 2006;
15:618-627.
5. Utilization of Pharmacogenetics and therapeutic drug monitoring for opioid pain management. Pharmacogenomics 2009;10(7):1157-1167
Pain Management: Opioids
Clinical Fact
Response to opioids can very as much
as 40 fold among patients. Blood
concentrations of opioids does not
predict analgesia. Pain medications are
involved in 30% of all adverse drug
events involve pain medications.
80% of patients reporting adverse drug
reactions had impaired 2D6 metabolism
Economic Implication
1,2
Adverse drug events cost an average of
$5.6M per hospital. Patients with adverse
drug events average 8-12 additional hospital
days at cost of $16,000 to $24,000
51% of patients taking oral opioids
experience at least one adverse event
or adverse effect.
29% of preventable adverse drug
events were associated with analgesics
Ref
3,2
4,2
Increased length of stay by 2.2 days and
costs by $3,244
5
1. Relationships between the measurement of pain using visual score analog and morphine requirements during post operative
intravenous morphine titration. Anesthesiology 2003;98(6):1415-1421.
2. Agency for Healthcare Research and Quality. Publication # 01-0020
3. Utilization of Pharmacogenetics and therapeutic drug monitoring for opioid pain management. Pharmacogenomics
2009;10(7):1157-1167
4. ACPA Guide to Chronic Pain Medication and Treatment. 2013 Edition
5. The cost of drug events in hospitalized patients. Journal of the American Medical Association 1997;277:307-311.
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Biochemical
and Physiological Effects
Pharmacokinetics and Pharmacodynamics
of Drugs
Pharmacokinetics
•
What the body does to a drug
•
Think metabolism, bioavailability
• Converting Pro-Drug to active agent
• Washing the active agent out of the body
Distribution
Pharmacodynamics
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What the drug does to the body
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Think therapeutic, sub-therapeutic or toxic
Pharmacogenetics in Pain Management
Leading pain management drugs are metabolized by genes in the
CYP450 Super Family
Cytochrome P450 Enzymes
• Enzymes bound to membranes within a cell (cyto)
• Contain a heme pigment (chrom and P)
• Heme pigment absorbs light at a wavelength of 450nm (450)
More than 50 enzymes in CYP450
• CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5
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90% of drugs are metabolized by these 6 enzymes1,2
1. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352:2211–21.
2. Slaughter RL, Edwards DJ. Recent advances: the cytochrome P450 enzymes. Ann Pharmacother. 1995;29:619–24.
Phenotypes
Categories of people with specific CYP450 variants (polymorphisms)
• Extensive Metabolizer (EM):
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Normal Genetics
Two Good Copies of the genetic code required for metabolism
• Intermediate Metabolizer (IM):
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Reduced enzymatic activity
1 Good Copy and 1 Bad Copy of code required for metabolism
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May render the drug a No Go or require a dose adjustment
• Poor Metabolizer (PM):
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Complete lack of enzymatic activity
2 Bad Copies code required for metabolism
Usually renders a drug a No Go
• Ultra Rapid Metabolizer (UM):
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Higher than average enzymatic activity
2 Bad Copies causing much higher than normal metabolism
May render the drug a No Go or require a dose adjustment
Incidence of Variants in the Population
Are variants rare or common?
Gene
EM
IM
PM
UM
Total
CYP2D6
53%
35%
10%
2%
47%
CYP2C19
36%
32%
4%
28%
64%
CYP2C9
57%
40%
3%
NA
43%
CYP3A4
87%
12%
1%
NA
13%
CYP3A5
1%
18%
81%
NA
99%
OPRM1
Caucasians
African
Americans
Asians
Normal
60%
80%
30%
Intermediate
30%
19%
50%
5%
1%
20%
Poor
Pharmacogenetics in Pain Management
Pharmacogenetics is only relevant if the drug is metabolized by a CYP450 enzyme
** Prodrug
Consensus Recommendations
Our report will suggest specific actions for these drugs only
Gene
CYP2D6
Phenotype
Intermediate
Metabolizer

35% of the population
Poor Metabolizer

10% of the population
Ultra Rapid Metabolizer



approx 2-6% of
Caucasian population
29% of North African
and Ethiopian
populations
6% of African American
populations
Drug
oxycodone
hydrocodone
codeine
nortriptyline
amitriptyline
imipramine
Consensus Based
Action Examples
Avoid
Avoid
Dose Adjustment
Dose Adjustment
Dose Adjustment
Dose Adjustment
codeine
hydrocodone
oxycodone
tramadol
amitriptyline
clomipramine
imipramine
Avoid
Avoid
Avoid
Avoid
Avoid
Dose Adjustment
Dose Adjustment
codeine
hydrocodone
oxycodone
tramadol
nortriptyline
imipramine
clomipramine
Amitriptyline
Avoid
Avoid
Avoid
Dose Adjustment
Dose Adjustment
Dose Adjustment
Avoid
Avoid
Consensus Recommendations
Our report will suggest specific actions for these drugs only
Gene
CYP2C19
Phenotype
Intermediate Metabolizer
Drug
Consensus Based
Action Examples
Imipramine
Dose Adjustment
Methadone (active
portion)
Possible dose
adjustment
Carisoprodol
Avoid, or use with
caution
25% of the population
Poor Metabolizer
2% of the population
Ultra Rapid Metabolizer

OPRM1
Carisoprodol
28% of the population
Poor Responder
Active Opioids (eg,
morphine)
Dose Adjustment
Intermediate Responder
Active Opioids
Dose Adjustment
IF:Pain
We test and report on Kinetics and Dynamics
Common Opioids
Hydrocodone
Oxycodone
Codeine
Tramadol
Morphine
Hydromorphone
Oxymorphone
Fentanyl
Poor Metabolizer =
decreased metabolic activity
Ultrarapid Metabolizer =
Super-fast metabolic activity
Prodrug = lack of efficacy
from no active metabolite
Prodrug = risk of side effects
from active metabolite
Active Drug = risk of side
effects
Active drug = risk of
therapeutic failure
Incorporating PGX into Pain Management
What to do with results?
– CYP2D6 abnormal results (PM, UM): AVOID prodrugs due to
potential lack of efficacy/risk ADRs
PM = decreased metabolic activity
UM = fast metabolic activity
Prodrug = lack of efficacy from no active metabolite
Prodrug = risk of side effects from active metabolite
Active Drug
= risk of side
effects
– CYP2D6
EM
or IM
Active druguse
= riskcaution
of therapeutic failure
results with inhibitor:
– OPRM1 G carriers: pts may need higher than average doses
CODEINE
CYP2D6 PM: inadequate morphine
CYP2D6 UM: morphine toxicity
CYP3A4
CYP2D6
Morphine
Norcodeine
Active
opioid
effects
(OPRM1)
Morphine-6-glucuronide
Morphine-3-glucuronide
Renal Excretion
Reynolds KR et al. Clin Lab Med 2008;28:581–598.
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Report
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.
Property of PGxl Laboratories
IF:Pain
We test and report on Kinetics and Dynamics
Pharmacogenetics in Opioids
In addition to CYP450, we also test for OPRM1
Cytochrome P450 Enzymes
• Enzymes bound to membranes within a cell (cyto)
• Contain a heme pigment (chrom and P)
• Heme pigment absorbs light at a wavelength of 450nm (450)
More than 50 enzymes in CYP450
• CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5
• 90% of drugs are metabolized by these 6 enzymes1,2
• OPRM1: Mu Opioid Receptor
• Variant decreases receptor availability3
• May lead to increased dose requirements3
1. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352:2211–21.
2. Slaughter RL, Edwards DJ. Recent advances: the cytochrome P450 enzymes. Ann Pharmacother. 1995;29:619–24.
3. Reynolds 2008; Reyes-Gibby 2007; Klepstad 2004