title: Population pharmacokinetic-pharmacodynamic model of craving in an enforced smoking cessation population: indirect response and probabilistic modeling.
abstract: OBJECTIVE
  A population pharmacokinetic-pharmacodynamic model accounting for placebo effect was used to relate nicotine concentration and enforced smoking cessation craving score measured by the Tiffany rating scale short form.
  
  
  METHODS
  Twenty-four smokers were enrolled in a placebo-controlled, randomized, double-blind, three periods, crossover trial. The study objective was to describe the nicotine-induced changes on craving scores. Two modeling strategies based on a mechanistic (indirect response models with drug-related inhibition on the k(in) synthesis rate and with a drug-related stimulation of the k(out) removal rate were evaluated) and a probabilistic (logistic regression) approach were used.
  
  
  RESULTS
  Placebo response model properly fitted the circadian changes on craving scores. The analysis revealed that the indirect response model with inhibition on k(in) was the preferred model for the smoking data whereas the preferred model for the Nicotine Replacement Therapy data was the one with stimulation on k(out). The logistic analysis showed that the nicotine concentration was a significant predictor of reduction in craving during the free-smoking period.
  
  
  CONCLUSIONS
  Nicotine dosage regimen can influence the nicotine mechanism of action: an instantaneous delivery at an individually selected time seems to inhibit the onset of craving while constant delivery at a pre-defined time seems to attenuate the craving.
authors.affiliation: GlaxoSmithKline Group, Glaxo Wellcome SpA, Verona, Italy. rog31390@glaxowellcome.co.uk
authors.forename: R
authors.initials: R
authors.lastname: Gomeni
authors.forename: V
authors.initials: V
authors.lastname: Teneggi
authors.forename: L
authors.initials: L
authors.lastname: Iavarone
authors.forename: L
authors.initials: L
authors.lastname: Squassante
authors.forename: A
authors.initials: A
authors.lastname: Bye
mesh_terms: D000328:Adult; D016739:Behavior, Addictive / Q000188:drug therapy / Q000523:psychology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008960:Models, Psychological; D015233:Models, Statistical; D009538:Nicotine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018722:Nicotinic Agonists / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012463:Saliva / Q000378:metabolism; D016540:Smoking Cessation / Q000379:methods / Q000523:psychology / Q000706:statistics & numerical data*
chemical_list: D018722:Nicotinic Agonists; D009538:Nicotine