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Evaluating the Real-World Effectiveness of Bupropion Versus Varenicline for Smoking Cessation: Exploring the Role of Nicotine Metabolism and Medication Adherence

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Evaluating the Real-World Effectiveness of Bupropion Versus Varenicline for Smoking Cessation: Exploring the Role of Nicotine Metabolism and Medication Adherence Evaluating the Real-World Effectiveness of Bupropion Versus Varenicline for Smoking Cessation: Exploring the Role of Nicotine Metabolism and Medication Adherence By Jiahui Zhang A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Pharmacology and Toxicology University of Toronto © Copyright by Jiahui Zhang (2017) Evaluating the Real-World Effectiveness of Bupropion Versus Varenicline for Smoking Cessation: Exploring the Role of Nicotine Metabolism and Medication Adherence Jiahui Zhang Degree of Master of Science Graduate Department of Pharmacology and Toxicology University of Toronto ABSTRACT Bupropion and varenicline are effective, first-line prescription-only pharmacotherapies for smoking cessation; however, their real-world use is limited by affordability and accessibility. Using a novel internet-based randomized design, we evaluated the real-world effectiveness of mailed bupropion and varenicline, as well as the roles of nicotine metabolism (NMR) and medication adherence, in a sample of interested smokers using web-based recruitment and follow up. Quit rates at end of treatment (EOT) were significantly higher for varenicline (30.2%) compared to bupropion (19.6%). Quit rates at 6 months (14.0%) and 12 months (12.1%) were not significantly different between bupropion and varenicline. Increased medication compliance significantly improved cessation outcomes at EOT. NMR was associated with nicotine dependence. Varenicline benefited Slow Metabolizers of nicotine whilst bupropion benefited Normal Metabolizers. Even though real-world quit rates were comparable to clinical trials, improving medication compliance and implementing personalized pharmacological and behavioral interventions are promising approaches to increase efficacy of smoking cessation pharmacotherapies. ii ACKNOWLEDGEMENTS First and foremost, I would like to express my sincerest appreciation to my supervisor, Dr. Laurie Zawertailo for her professional guidance and endless patience, which made this thesis come into fruition and my masters’ experience invaluable. This thesis would also not be possible without the support of my advisor, Dr. Tyndale, the study manager, Sarwar Hussain, the study co-investigators, Dr. Bernard LeFoll and Dr. Peter Selby, and the study collaborators at Tyndale and Kennedy Labs. I would also like to thank Inovex Inc and MediTrust Pharmacy for their service through the past 3 years. This thesis would also not be possible without the hard work of Tara Mansoursadeghi-Gilan and her numerous contributions to the MATCH project. I would like to acknowledge the wonderful staff of the Nicotine Dependence Service at the Centre for Addiction and Mental Health (CAMH) and the Pharmacology and Toxicology Department at the University of Toronto for their support. I would like to recognize the funding source for the project, which was a grant awarded to Dr. Laurie Zawertailo from Global Research Awards for Nicotine Dependence, a peer-reviewed research grant competition funded by Pfizer Pharmaceuticals. Lastly, I am grateful for the ongoing support of my wonderful family and friends for always encouraging me. iii TABLE OF CONTENTS ACKNOWLEDGMENT ......................................................................................................................... iii LIST OF TABLES .................................................................................................................................. x LIST OF FIGURES ............................................................................................................................... xi LIST OF APPENDICES ...................................................................................................................... xiii 1. INTRODUCTION ............................................................................................................................... 1 1.1.1 Smoking and Its Impact.................................................................................................... 1 1.1.2. Health Risks of Smoking ................................................................................................. 1 1.1.3. Economic Impact of Smoking ......................................................................................... 2 1.1.4. Smoking Prevalence in Canada ...................................................................................... 2 1.1.5. Importance of Reducing Smoking Rates ........................................................................ 2 1.2 Statement of Problem and Study Rationale .................................................................................... 4 1.2.1. Challenges of Smoking Cessation .................................................................................. 4 1.2.2. Challenges in Intervention’s Efficacy .............................................................................. 4 1.2.3. Challenges in Preventing Relapse .................................................................................. 6 1.3 Statement of Purpose and Objectives of Study .............................................................................. 7 1.4 Statement of Hypotheses and Rationale for Hypotheses ............................................................... 8 1.5 Review of the Literature ................................................................................................................. 12 1.5.1. Neuropharmacology of Nicotine Addiction .................................................................... 12 1.5.1.1 Nicotine Content in Cigarettes ........................................................................ 12 1.5.1.2. Nicotine Acetylcholine Receptors and Neurotransmitter Release ................ 13 1.5.1.3. The Role of Dopamine on Nicotine Addiction ............................................... 14 1.5.1.4. Desensitization and Up-Regulation of the nAChRs ...................................... 14 1.5.1.5. Other Modulators Affected by Smoking ........................................................ 16 1.5.2. Behavioral Pharmacology of Nicotine Addiction ........................................................... 17 1.5.2.1. Smoking as a Learned and Reinforced Behavior ......................................... 17 1.5.2.2. Personality Traits and Smoking ..................................................................... 18 1.5.3. Clinical Components of Nicotine Addiction ................................................................... 18 1.5.3.1. Clinical Diagnosis of Nicotine Addiction ........................................................ 18 1.5.3.2. Smoking Cessation Biomarkers .................................................................... 19 iv 1.5.3.3. Nicotine Addiction Susceptibility .................................................................... 20 1.5.4. Smoking Cessation Interventions ................................................................................. 22 1.5.4.1. Smoking Cessation with No Interventions ..................................................... 22 1.5.4.2. Behavioural Interventions ............................................................................. 23 1.5.4.3. Nicotine Replacement Therapy ..................................................................... 23 1.5.4.4. Bupropion ...................................................................................................... 24 1.5.4.4.1. Mechanism of Action of Bupropion ................................................ 25 1.5.4.4.2. Pharmacokinetics of Bupropion ..................................................... 25 1.5.4.4.3. Clinical Efficacy Studies involving Bupropion ................................ 26 1.5.4.4.4. Safety of Bupropion ........................................................................ 27 1.5.4.4.5. Compliance with Bupropion Treatment.......................................... 27 1.5.4.5. Varenicline ..................................................................................................... 28 1.5.4.5.1. Mechanism of Action of Varenicline ............................................... 28 1.5.4.5.2. Pharmacokinetics of Varenicline .................................................... 29 1.5.4.5.3. Clinical Efficacy Studies of Varenicline .......................................... 29 1.5.4.5.4. Safety of Varenicline ...................................................................... 30 1.5.4.5.5. Compliance with Varenicline Treatment ........................................ 31 1.5.4.5.6. Clinical Trials Comparing Efficacies of Bupropion vs Varenicline . 31 1.5.4.6. Technology-Based Interventions ................................................................... 32 1.5.5. Nicotine Metabolism and Tobacco Dependence .......................................................... 33 1.5.5.1. Nicotine Metabolism and Its Metabolites ....................................................... 33 1.5.5.2. Nicotine Metabolite Ratio (NMR) .................................................................. 33 1.5.5.3. NMR and Smoking Behaviors ....................................................................... 34 1.5.5.4. NMR and Smoking Cessation Treatment Outcomes .................................... 35 1.5.6. Summary of Objectives and Hypotheses ...................................................................... 36 2. METHODS ....................................................................................................................................... 37 2.1 General Study
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