Pharmacogenetics of Treatment Responses to Nicotine Replacement Therapy and Bupropion

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Pharmacogenetics of Treatment Responses to
Nicotine Replacement Therapy and Bupropion
Robert A. Schnoll, Ph.D. Department of
Psychiatry Transdisciplinary Tobacco Use Research
Center University of Pennsylvania
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ASAM Disclosure of Relevant Financial
Relationships Content of Activity ASAM State of
the Art Course 2007
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Overview of Presentation

• Pharmacotherapies for nicotine dependence
• Is nicotine dependence and smoking cessation
  heritable?
• Which smokers are at increased risk for relapse
  and how can genetics research be applied to
  improve the outcomes of existing treatments?

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NRTs

• 5 types patch, gum, nasal spray, inhaler,
  lozenge
• Provides direct nicotine replacement (but not as
  effectively as smoking)
• Little variability in effectiveness among NRTs
  (but possibly across sub-types of smokers
  gender, level of nicotine dependence,
  3HC/cotinine ratio)
• Extended use?

Treatment Estimated Quit Rate (95 CI) Patch
17.7 (16.0, 19.5) Gum 17.1
(20.6, 26.7) Lozenge 17.0 (15.0,
20.0) Inhaler 22.8 (16.4,
29.2) Nasal Spray 30.5 (21.8, 39.2)
Note. Indicates 6-month point prevalence data
Fiore et al., 2000 Silagy et al., 2004
Henningfield, 1995.
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Bupropion (Zyban)

• Anti-depressant wellbutrin FDA approved for
  smoking cessation treatment
• Increases dopamine concentrations (among other
  biological effects)
• Prevents negative mood and weight gain during
  withdrawal
• Extended use? Matched?

Quit
Bupropion and Bupropion Patch Placebo or Patch
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Varenicline (Chantix)

• a4b2 nicotinic receptor partial agonist
• Agonist function, stimulates DA, reducing craving
  and withdrawal
• Antagonist function, blocks receptors,
  eliminating reward from slip

Quit
Weeks 9-12 Weeks 9-24 Weeks 9-52
Gonzales et al. (2006) varenicline bupropion
placebo at Weeks 9-12 Weeks 9-24 varenicline
placebo at Weeks 9-52.
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Smoking Initiation and Nicotine Dependence are
Heritable
Medical College of Virginia Study of Female Twins
Kendler et al., Psychol Med., 1999
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Smoking Persistence and Cessation are Heritable
Li et al (2003) Meta-analysis of Persistence
Xian et al (2003) Failed Smoking Cessation
Attempts
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Which Smokers are at Increased Risk for Relapse
and Pharmacogenetic Studies
Nicotine Metabolizing Enzymes (CYP2A6) Dopamine
Receptors (DRD2) Opioid Pathway (OPRM1)
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What is Pharmacogenetics?
Medication Responders
Medication Non-responders
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Nicotine Metabolism

• The CYP2A6 enzyme is responsible for 90 of
  nicotine metabolism
• 80 of nicotine becomes cotinine, which becomes 3
  hydroxy-cotinine
• Several genetic variants for the CYP2A6 enzyme
  have been identified

Hukkanen et al., 2005
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CYP2A6 Variants and Smoking

• CYP2A6 genetic variants predict level of smoking
  and nicotine dependence, and severity of
  withdrawal

Smoking Rate
Nicotine Dependence
Withdrawal Symptoms
Malaiyandi et al., 2006 Kubota et al., 2006
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CYP2A6 Genetic Alleles and Nicotine Metabolism
Phenotype

• 3HC/cotinine ratio represents rate of metabolism
  (smaller value slower metabolism)
• Those with genetic variants thought to slow
  metabolism have a lower 3/HC/cotinine ratio
• Proof of principle and verification of
  3HC/cotinine as a phenotypic marker of CYP2A6
  genetic variants

Malaiyandi et al., 2006 Lerman et al., 2006
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Open Label Pharmacogenetic Trial of NRT (TTURC 1,
n600)
Pre-treatment Assessment Genotyping
Transdermal nicotine x 8 wks
Nicotine nasal spray x 8 wks
95 retention rate
Follow-Up EOT, 6-months, and 12-months
European ancestry only (n420)
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Nicotine Metabolism and NRT
Transdermal Patch, N 240
Nasal Spray, N 240

• Genetically fast metabolizers (4th quartile) did
  poorly on patch vs. slow metabolizers (1st
  quartile)
• No effect in spray because of dose titration
• Fast metabolizers need alternative treatment

Quit
3-HC Cotinine Ratio in Quartiles
Slow
Fast
Lerman et al., 2006
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Nicotine Metabolism and NRT

• Replication from second NRT patch trial
• Fast metabolizers show poor response to standard
  21mg transdermal nicotine patch at 8 weeks (OR
  .60 95 CI .40-.89 p .56 95 CI .37-.85 p

Quit
3-HC Cotinine Ratio in Quartiles
Slow
Fast
Schnoll et al., in preparation
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Bupropion Placebo-Controlled Trial (n600)
Eligibility Screening
Pre-treatment Assessment Genotyping
Bupropion x 10 weeks
Placebo x 10 weeks
Follow-Up EOT, 6-months, and 12-months
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Smoking Cessation, Metabolite Ratio and Bupropion
Treatment
End of Treatment
6-Month Follow-up
Quit
OR (ratio x Trt)2.35 (1.03-5.37) p.04
Nicotine Metabolite Quartile
Patterson et al., in preparation
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Opioid Mechanisms in Nicotine Reward
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The Human OPRM1 Gene
PROMOTOR EXON 1 EXON 2 EXON 3
EXON 4 3UTR

A118G

• The human OPRM1 gene includes a common Exon 1
  Asn40Asp (A118G) mis-sense single nucleotide
  polymorphism (SNP)
• G allele associated with reduced mRNA expression
  and protein levels and is present in 25-30 of
  persons of European ancestry
• Hypothesis Smokers with G allele will have a
  lower liability to relapse in smoking cessation
  treatment

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OPRM1 Asn40Asp Variant is Associated with
Response to NRT
Treatment Phase
Follow-up Phase
quit
Normal Reduced activity
OR 1.9, p.01
Lerman et al., Pharmacogenomics J, 2004
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Summary

• 2 of 3 individuals treated with FDA-approved
  medications for nicotine dependence do not
  respond
• Smokers with increased nicotine metabolism
• Respond poorly to standard 21mg transdermal
  nicotine
• Nicotine Spray and bupropion reverses relapse
  risk among fast metabolizers
• Smokers with decreased nicotine metabolism
• Respond well to standard 21mg transdermal
  nicotine and counseling and do not require more
  intensive treatments such as bupropion
• Smokers with reduced activity OPRM1 variant
• Smokers with reduced activity, G allele, show
  better response to NRT, most notably to
  transdermal nicotine, vs. nicotine spray
• Possible mechanism is reduced nicotine reward
  among carriers of G allele (who report
  significantly less difference in satisfaction
  between regular cigarette and de-nicotinized
  cigarette Ray et al., 2006)

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Caveats

• Smoking cessation and medication response are
  complex polygenic traits
• These initial trials were underpowered to detect
  complex gene x gene and gene x environment
  interactions
• Findings should be considered hypotheses
  generating not confirmatory
• Many findings are not replicated
• Most research conducted in smokers of European
  ancestry
• Literature has limited external validity
• Additional research is needed to assess
  functional variation in genes coding for neuronal
  nicotinic receptor subunits and other
  neurobiological pathways (Glutamate, GABA, etc.)
• Additional pharmacogenetic studies with
  varenicline are needed

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Acknowledgements
University of Pennsylvania TTURC (PI Caryn
Lerman, Ph.D.) Riju Ray, Jake Dahl, Wade
Berrettini, (Molecular genetics) Julie Blendy
Carrie Walters (Preclinical), Janet Audrain
Margaret Rukstalis (Treatment), Christopher
Jepson E. Paul Wileyto (Biostatistics),
Angela Pinto, Freda Patterson Sue Kucharski
(Project and Data Management) University of
Buffalo, Brown University, University of
Pittsburgh, University of Toronto, University of
California San Francisco Leonard Epstein, Ph.D.,
Larry Hawk, Ph.D., Ray Niaura, Ph.D., Ken
Perkins, Ph.D., Rachel Tyndale, Ph.D., Neal
Benowitz, M.D.