title: Biochemical estimation of noncompliance with smoking of very low nicotine content cigarettes.
abstract: BACKGROUND
  The reduction of the nicotine content of cigarettes to nonaddicting levels is a potential federal regulatory intervention to reduce the prevalence of cigarette smoking and related disease. Many clinical trials on the effects and safety of nicotine reduction are ongoing. An important methodologic concern is noncompliance with reduced nicotine content cigarettes in the context of freely available conventional cigarettes. We propose two approaches using biomarkers to estimate noncompliance in smokers of very low nicotine content (VLNC) cigarettes in a clinical trial.
  
  
  METHODS
  Data from 50 subjects in a study of gradual nicotine reduction were analyzed. Using plasma cotinine concentrations measured at baseline and while smoking VLNC cigarettes, we compared within-subject ratios of plasma cotinine comparing usual brand to VLNC in relation to nicotine content of these cigarettes. In another approach, we used nicotine pharmacokinetic data to estimate absolute plasma cotinine/cigarettes per day (CPD) threshold values for compliance based on the nicotine content of VLNC.
  
  
  RESULTS
  The two approaches showed concordance, indicating at least 60% noncompliance with smoking VLNC. In a sensitivity analysis assuming extreme compensation and extreme values for nicotine metabolic parameters, noncompliance was still at least 40%, much higher than self-reported noncompliance.
  
  
  CONCLUSIONS
  Biomarker analysis demonstrates a high degree of noncompliance with smoking VLNC cigarettes, indicating that smokers are supplementing these with conventional cigarettes.
  
  
  CONCLUSIONS
  We propose a practical approach to assessing compliance with smoking VLNC in clinical trials of nicotine reduction.
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology and Experimental Therapeutics, University of California San Francisco, San Francisco, California. Department of Bioengineering & Therapeutic Sciences, Division of Clinical Pharmacology and Experimental Therapeutics, University of California San Francisco, San Francisco, California. neal.benowitz@ucsf.edu.
authors.forename: Neal L
authors.initials: NL
authors.lastname: Benowitz
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California.
authors.forename: Natalie
authors.initials: N
authors.lastname: Nardone
authors.affiliation: Tobacco Research Program and Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Hatsukami
authors.affiliation: Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Donny
mesh_terms: D015415:Biomarkers / Q000097:blood*; D003367:Cotinine / Q000097:blood*; D006801:Humans; D009538:Nicotine / Q000493:pharmacokinetics*; D010349:Patient Compliance; D016540:Smoking Cessation / Q000379:methods*; D000074606:Smoking Prevention; D061485:Tobacco Use Cessation Devices
chemical_list: D015415:Biomarkers; D009538:Nicotine; D003367:Cotinine