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Opioid Pharmacogenomics:
The Path to Personalized Medicine
Leigh M. Boehmer, Pharm.D., BCOP
Clinical Pharmacist, Medical Oncology
Barnes Jewish Hospital
March 8, 2014
Disclosure
• Leigh M. Boehmer, Pharm.D., has no
real or apparent conflicts of interest to
report
Objectives
• Describe the principles and therapeutic
implications of pharmacogenomics related
to pain management
• Review several novel analgesic drug
targets identified from pharmacogenomic
studies
• Evaluate limitations and practical
challenges of pharmacogenomic testing
and adoption of results
Objectives
• Describe the principles and therapeutic
implications of pharmacogenomics related
to pain management
• Review several novel analgesic drug
targets identified from pharmacogenomic
studies
• Evaluate limitations and practical
challenges of pharmacogenomic testing
and adoption of results
Clinical Genetics Defined
• Pharmacodynamics: drug activity at the
target site/receptor
• Pharmacokinetics: drug absorption,
distribution, metabolism, elimination
(ADME)
• Pharmacogenomics (PGx): how variations
in human genome affect drug response
Jannetto P and Bratanow N. Expert Opin Drug Metab Toxicol. 2011; 7(6): 745-52.
Anticipated Benefits of Genomics
•
•
•
•
•
•
Earlier detection of genetic predispositions
Improved diagnostic accuracy and speed
Gene therapies
Decrease in healthcare costs
Personalized treatment plans
Rational drug design
Available at ornl.gov/hgmis. Accessed on 12.28.13.
Clinical Genetics Defined
• Genotype: genetic makeup of an organism
• Phenotype: physical characteristics of an
organism
• Epigenetics: phenotypes resulting from
environment-caused chromosomal changes
• Allele: one of two copies of a gene inherited from
each parent
• Mutation: any heritable change in a DNA
sequence
• Polymorphism: DNA sequence differences
present in >1% of the population
Available at ornl.gov/hgmis. Accessed on 12.28.13.
Heritability Analysis
81 mono- and 31 di-zygotic twin pairs
Study
evaluated for genetic and environmental
population contributions to pain sensitivity and analgesia
Randomized, double-blind, placebo-controlled
twin paradigm; alfentanil infusion with heat
Design
and cold pressor pain model
•Significant heritability for cold pain tolerance
and opioid-mediated ↑ heat/cold pain
thresholds
Results
•Genetics accounted for 12-60% of observed
variance
Angst M, et al. Pain. 2012. 153(7):1397-1409.
Pain Management Genetic Analysis
Analgesic
Polymorphic Genes
Codeine
CYP2D6
Fentanyl
ABCB1, CYP3A4, CYP3A5, OPRM1
Oxycodone
CYP2D6
Methadone
ABCB1, CYP2B6, CYP3A4,
CYP2D6
Morphine
ABCB1, COMT, UGT2B7, OPRM1
Tramadol
CYP2D6
ABCB1=ATP-binding cassette, subfamily B, member 1
OPRM1=mu-opioid receptor gene
COMT=catechol-O-methyltransferase
UGT=uridine 5’-diphosphate-glucuronosyltransferase
Jannetto P and Bratanow N. Expert Opin Drug Metab Toxicol. 2011; 7(6): 745-52.
Opioid Metabolism:
CYP450 variations
• Phase I metabolism in liver
– CYP2D6, CYP3A4, CYP2C19, and others
• Spectrum of enzymatic activity
– Poor, intermediate, extensive, ultra rapid
• Tramadol to active metabolite via -2D6
• Codeine conversion to morphine via -2D6
• Oxycodone to active metabolite via -2D6
Jannetto P and Bratanow N. Expert Opin Drug Metab Toxicol. 2011; 7(6): 745-52.
Ma J, et al. Journal of Pharmacy Practice. 2012; 25(4): 417-27.
CYP2D6 Phenotype Correlation
Phenotype Frequency
Phenotype
CYP2D6 Variant
Alleles
Asians
African
Americans
Caucasians
Poor
metabolizer
*3, *4, *5, *6
1-2%
7%
7-10%
Intermediate
metabolizer
*9, *10, *17, *29,
*41
30%
30%
11%
Extensive
metabolizer
*1
51.5%
37%
71%
Ultra rapid
metabolizer
*1, *2 gene
duplication,
*35 enhanced
activity
<1%
<1%
2-10%
Gaston C and Kolesar J. Clin Adv Hematol Oncol. 2008;6:825-33.
CYP2D6: Tramadol Experience
Study
population
Design
Treatment
regimen
Results:
PM vs. EM
Adult post-operative analgesia
patients (N= 271)
Prospective study of CYP2D6 PM
and EM phenotypes
24-hour post-op tramadol dosing
relative to phenotype
Non-responders: 47% vs. 22%
Needing rescue meds: 43% vs. 22%
PM=Poor metabolizer
EM=Extensive metabolizer
Stamer UM, et al. Pain. 2003; 105: 231-8.
PGx and Toxicity: Paclitaxel-Induced
Peripheral Neuropathy (PIPN)
• Expression of drug target
– β-tubulin promoter gene, TUBB2A
– SNP 112A > G, rs909965: ↑ gene
transcription and protection from PIPN
• Inadequate stimulus response
– DNA repair gene, FANCD2
– ↑ expression led to ~80% ↑ in risk of Grade
3/4 neurological toxicities
SNP=single nucleotide polymorphism
Hertz D and McLeod H. J Hum Genet. 2013. 58(6): 346-52.
CYP2C8*3 Genotype and PIPN
Study
population
Design
Treatment
regimen
Results
European patients treated with paclitaxel for
breast cancer (N=209); African American
subset analysis (N=107)
Genomic data collected for all newly
diagnosed patients, 2005-2011
Neoadjuvant and adjuvant paclitaxelcontaining regimens
•Carriers of *3 variant allele had ↑ risk of
Grade 2+ neuropathy (HR 1.93; p=0.006)
•Each *3 allele copy doubled a patient’s risk
of Grade 2+ neuropathy (p=0.004)
Hertz D, et al. Annals of Oncology. 2013. 24:1472-8.
Grade 2+ Neuropathy in
Mixed-Race Cohort (N=411)
Hertz D, et al. Annals of Oncology. 2013. 24:1472-8.
Opioid Absorption/Elimination:
ABCB1 variations
• Encodes P-glycoprotein (P-gp) 170
– Pumps drugs out of intracellular domain
– Regulates CNS drug exposure
• Fentanyl, methadone, and morphine are
all P-gp substrates
• Homozygous (TT) carriers of 3435C > T
variant experience greater pain relief
• 50-60% Caucasian population prevalence
Jannetto P and Bratanow N. Expert Opin Drug Metab Toxicol. 2011; 7(6): 745-52.
ABCB1: Methadone Experience
Adult methadone maintenance
Study
population patients (N= 120)
Retrospective study of ABCB1
genetic variability
Daily methadone dose relative to
CC, CT, and TT carriers
Wild-type CC: 98.3 mg ± 10.4
CT: 58.6 mg ± 20.9
Homozygous TT: 55.4 mg ± 26.1
Design
Treatment
regimen
Results
(p=0.029)
.
Coller JK, et al. Clin Pharmacol Ther. 2006; 80(6): 682-92.
Opioid Receptor:
OPRM1 variations
• Encodes μ-opioid receptor
• 118A > G variation = substitution of
asparagine for aspartate
• ↓ morphine, alfentanil, fentanyl, and
methadone response
• 20-30% population prevalence
– 1-2% African Americans
– 50% Japanese
Argoff C. Clin J Pain. 2010;26(1):S16-20.
Jannetto P and Bratanow N. Expert Opin Drug Metab Toxicol. 2011; 7(6): 745-52.
ABCB1/OPRM1:
Morphine Pain Relief
Study
population
Design
Responder
Groups
Results
Adult patients receiving morphine for
acute pain control (N= 145)
Prospective study of pain relief
relative to ABCB1/OPRM1 genotype
“Poor” pain control: CC/GG
“Best” pain control: TT/AA
Polymorphic association (p<0.00001)
Sensitivity: ~100%
Specificity: >70%
Campa D, et al. Clin Pharm Ther. 2007; 83(4): 559-66.
Catechol-O-methyltransferase
(COMT)
• Catecholamines are metabolized by COMT
and involved in pain modulation
• COMT activity may contribute to variable
analgesic response
• 1947G > A = 3-4 fold ↓ in COMT activity
• Homozygous GG patients require higher
morphine doses to achieve pain control
Jannetto P and Bratanow N. Expert Opin Drug Metab Toxicol. 2011; 7(6): 745-52.
Morphine Dose Adjustments:
Non-FDA Approved
ABCB1
(TT)
OPRM1
(GG)
COMT
(AA)
Phenotype
Cumulative
Dosing Factor
---
2
---
Effective efflux pump
2
---
---
0.67
↓ COMT activity
0.67
0.67
---
---
Functional μ receptor
0.67
---
2
0.67
Effective efflux/ ↓ COMT
1.33
0.67
2
---
Functional μ receptor/
effective efflux
1.33
0.67
---
0.67
Functional μ receptor/
↓ COMT
0.4
0.67
Functional μ receptor/
Effective efflux pump/
↓ COMT
0.89
0.67
2
Lotsch J, et al. Pain. 2006; 121: 1-5.
PGx Targets Summary
Gene
Variant
Opioids Affected
Outcome(s)
CYP2D6
Poor;
ultra rapid
metabolizers
Codeine, Tramadol,
Oxycodone
↓ analgesia;
excessive side effects
ABCB1
3435C > T
Morphine
TT carriers experience
greater pain relief
OPRM1
118A > G
Morphine, Alfentanil,
Fentanyl, Methadone
↑ dose requirements
due to ↓ efficacy
COMT
1947G > A
Morphine
GG carriers experience
less pain relief
Jannetto P and Bratanow N. Expert Opin Drug Metab Toxicol. 2011; 7(6): 745-52.
Select Variables Influencing
Analgesic Response
Pain related:
•Kind of pain
•Origin of pain
•History of pain control
Severity of:
•Trauma
•Surgery
•Tissue damage
Pharmacokinetics/
Pharmacodynamics
Analgesic response
Environmental factors:
•Culture
•Education
•Family
•Occupation
Pharmacogenomics
Psychological factors:
•Depression
•Anxiety
•Coping strategies
•Diagnosis
Adapted from Stamer U, et al. Pharmacogenomics. 2010;11(6):843-64.
Objectives
• Describe the principles and therapeutic
implications of pharmacogenomics related
to pain management
• Review several novel analgesic drug
targets identified from pharmacogenomic
studies
• Evaluate limitations and practical
challenges of pharmacogenomic testing
and adoption of results
Objectives
• Describe the principles and therapeutic
implications of pharmacogenomics related
to pain management
• Review several novel analgesic drug
targets identified from pharmacogenomic
studies
• Evaluate limitations and practical
challenges of pharmacogenomic testing
and adoption of results
2013 Pain Management Approvals
• Zohydro® (ER hydrocodone)
• Zubsolv® (buprenorphine and naloxone)
ER=extended release
Available at http://rogermontgomery.com/wp-content/uploads/2012/05/biotech-Fig-5.png. Accessed on 12.28.13.
Biomarkers in Drug Discovery
and Development
Discovery
10,000
targets
$
Development $$
Lead identification
Target validation
Preclinical safety
Animal models
$1.3 billion
Clinical $$$
Proof of target
Proof of mechanism
Biomarkers
Human tissue bank
Proteomics
Pathonomics
Proteonics
Clinical Samples:
Tissue, blood,
urine
250 in preclinical
5 in clinical
1 approved
From The Role of Biomarkers in Drug Discovery and Development. Available at www.criver.com.
Select Potential Future Targets
Transduction
TRPV1,2,3,4;
P2X3; P2Y;
Bradykinin B1/2;
PGE2; NGF
Modulation
ATP; BNF; GABA;
P2X4; P2X7;
CCL2; fractalkine
Transmission
Nav1.7, -1.8, -1.9,
-1.3; Kv9.1
Adapted from Heinzmann S and McMahon S. Current Opinion in Supportive and Palliative Care. 2011;5:111-5.
Protein Kinase (PK) Inhibitors
• PK are enzymes that enable/inhibit protein
function and interactions
• Profound upregulation of PK activity in
models of neuropathic & inflammatory pain
• p38 activation – allodynia/hyperalgesia;
↑ spontaneous pain perception
• JNK expression – release of proinflammatory cytokines
JNK=c-Jun n-terminal kinase
Heinzmann S and McMahon S. Current Opinion in Supportive and Palliative Care. 2011; 5:111-5.
Cytokine Antagonists
• Cytokines induce chronic pain seen in
inflammatory conditions
• Cause swelling, tissue damage, and
neuronal hypersensitivity
• Known cytokines which enhance pain:
– MCP-1 (and its receptor CCR2)
– Fractalkine (and its receptor CX3CR1)
– Tumor necrosis factor-α
Heinzmann S and McMahon S. Current Opinion in Supportive and Palliative Care. 2011; 5:111-5.
Nerve Growth Factor (NGF)
Inhibitors
• NGF mediates peripheral pain stimuli
via small diameter sensory neurons
• Upregulated in inflamed tissues
resulting in hyperalgesia
• Current trials exploring:
– Neutralizing antibodies against NGF
– NGF receptor (TrkA) antagonists
Heinzmann S and McMahon S. Current Opinion in Supportive and Palliative Care. 2011; 5:111-5.
Selective Sodium (Na)
Channel Blockers
• Nav1.7 mutation results in congenital
insensitivity to pain
• Nav1.7 plays large role in transduction of
painful stimuli into action potentials
• Many Na channel blockers available, but
only few selective for 1.7 channel
Heinzmann S and McMahon S. Current Opinion in Supportive and Palliative Care. 2011; 5:111-5.
Tetrodotoxin (TTX) Derivatives
• TTX-CINP-201
– Non-peptide, non-opioid neurotoxin
– Derived from the puffer fish
• Selectively blocks voltage-gated Na
channels (Nav1.3?)
• Phase II trial; recruiting participants
– Safety and efficacy in chemotherapyinduced peripheral neuropathy (CIPN)
Available at www.clinicaltrials.gov. Accessed on 12.29.13.
TTX Mechanism of Action
Available at www.mdpi.com. Accessed on 12.29.13.
Spicamycin Derivatives
• KRN-5500
– Non-opioid inhibitor of acetylcholinesterase
and fatty acid amide hydrolase
• Phase IIa, double-blind, placebo controlled
– Refractory neuropathic pain & cancer (N=19)
– 0.6-2.2 mg/m2; single, escalating doses
• 24% ↓ pain intensity vs. 0% (P=0.03)
• Most common AE: GI symptoms (92%)
Weinstein S, et al. Journal of Pain and Symptom Management. 2012; 43(4): 679-93.
Targeted Gene Therapy – NP2
• HSV vector delivers enkephalin to sensory
nerves to block pain signals
• Bypasses central nervous system
• Avoids “typical” opioid adverse events
• US Phase I study completed
– No treatment-related AEs; no seroconversion
• US Phase II study ongoing (N=32)
– Randomized, double-blind, placebo controlled
Available at www.clinicaltrials.gov. Accessed on 12.29.13.
NP2 Mechanism of Action
Available at www.paineurope.com. Accessed on 12.29.13.
Investigational Analgesic Products
Compound
Molecular Target
Comments
Iosmapimod
p38 kinase
---
Tanezumab
NGF
Completed (osteoarthritis)
Ralfinamide
Nav1.7
Missed primary endpoint
Lacosamide
Nav1.7
---
TTX-CINP-201
Nav1.3?
Phase II recruiting
SSR 240612
Bradykinin-B1 receptor
---
ADL5859/-747
δ-opioid receptor
Failed in phase II trials
KRN-5500
Acetylcholinesterase; fatty
acid amide hydrolase
CIPN phase II completed;
FDA fast track designation
NP2-Enkephalin Sensory nerves
Phase II active; not recruiting
Lotsch J and Geisslinger G. British Journal of Pharmacology. 2011: 163: 447-60.
Available at www.clinicltrials.gov. Accessed on 12.29.13.
Objectives
• Describe the principles and therapeutic
implications of pharmacogenomics related
to pain management
• Review several novel analgesic drug
targets identified from pharmacogenomic
studies
• Evaluate limitations and practical
challenges of pharmacogenomic testing
and adoption of results
Objectives
• Describe the principles and therapeutic
implications of pharmacogenomics related
to pain management
• Review several novel analgesic drug
targets identified from pharmacogenomic
studies
• Evaluate limitations and practical
challenges of pharmacogenomic testing
and adoption of results
PGx – Healthcare Implications
•
•
•
•
•
•
•
Pain management treatment strategies
Payer cost management strategies
Medical informatics
Patient prognostic expectations
Drug research and development
Accelerated drug approval
Public health policy
Benson A. Personalized Medicine in Oncology. 2012; 1(4): 1-5.
Sadhasivam S and Chidambaran V. Pharmacogenomcis. 2012; 13(15): 1719-40.
PGx Study Limitations
•
•
•
•
•
•
Small sample sizes due to low prevalence
Variability in polymorphisms assessed
Multigenic factors altering drug responses
Limited documentation of concurrent meds
Different end points evaluated
Population characteristics may affect study
outcomes
Walko C, et al. Journal of Pharmacy Practice. 2012; 25(4): 439-46.
Practice-Based Evidence (PBE)
• Prospective, observational cohort study
• Data captured as part of routine clinical pain
management
• Complement randomized controlled trials
• Help identify phenotypic and genotypic
variables associated with favorable outcomes
• Limited ability to infer causality
• Hypothesis generation for subsequent
validation via “traditional” methodology
Bruehl S, et al. The Journal of Pain. 2013; 14(2): 103-13.
PGx – Limitations to Implementation
•
•
•
•
•
•
•
Variable treatment response
Effects of pain heterogeneity
Limited ability to interpret test results
↑ costs/time associated with testing
Healthcare providers’ knowledge limited
Unknown drug resistance mechanisms
New alleles of interest discovered daily
Ma J, et al. Journal of Pharmacy Practice. 2012. 25(4):417-27.
Personalized Analgesia Algorithm Considerations
• Mandatory brain imaging
– Dopaminergic modulation of opioid response
• Endogenous opioid quantification
– Reduced responsiveness to opioid analgesics
• Effects of concurrent non-drug treatments
– Acupuncture, relaxation training, exercise
• Outcomes measurement
– Functional magnetic resonance imaging (fMRI)
Bruehl S, et al. The Journal of Pain. 2013; 14(2): 103-13.
PGx Testing – Ethical Considerations
Haga S and Burke W. Genet Med. 2008. 10(6): 391-5.
Genomics Online Resources
• www.cdc.gov/genomics/
• www.fda.gov/drugs/scienceresearch/resear
chareas/pharmacogenetics/default.htm
• ghr.nlm.nih.gov/glossary
• www.genome.gov
“If it were not for the
great variability among
individuals, medicine
might as well be a
science and not an art.”
(Sir William Osler)
1892
Opioid Pharmacogenomics:
The Path to Personalized Medicine
Leigh M. Boehmer, Pharm.D., BCOP
Clinical Pharmacist, Medical Oncology
Barnes Jewish Hospital
March 8, 2014