title: Nicotine Population Pharmacokinetics in Healthy Adult Smokers: A Retrospective Analysis.
abstract: OBJECTIVE
  Characterizing nicotine pharmacokinetics is challenging in the presence of background exposure. We performed a combined retrospective population pharmacokinetic analysis of 8 trials, including exposure to Tobacco Heating System and cigarettes (both inhaled), nicotine nasal spray and oral nicotine gum.
  
  
  METHODS
  Data from 4 single product use trials were used to develop a population pharmacokinetic model with Phoenix®NLME™ and to derive exposure parameters. Data from 4 separate ad libitum use studies were used for external validation. A total of 702 healthy adult smokers (54% males; 21-66 years of age; smoking ≥10 cigarettes/day; from US, Europe and Japan) were eligible for participation.
  
  
  RESULTS
  Two-compartment linear disposition combined with zero-order absorption model was adequate to describe nicotine pharmacokinetics, and a mono-exponentially decreasing background component was utilized to account for nicotine carry-over effects. Apparent nicotine clearance was typically 0.407 L/min in males and 26% higher in females (68% inter-individual variability). Bioavailability was product-specific, decreased with increasing nicotine ISO yield, and increased with increasing body weight. Absorption duration was apparently prolonged with nicotine gum. The typical initial and terminal half-lives were 1.35 and 17 h, respectively. The presence of menthol did not impact the determinants of the area under the curve. The model adequately described the external validation data.
  
  
  CONCLUSIONS
  The population model was able to describe in different populations the nicotine pharmacokinetics after single product use and after 4 days of ad libitum use of Tobacco Heating System, cigarettes, and of different nicotine replacement therapies with various routes of administration.
authors.affiliation: Certara Strategic Consulting, Paris, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Marchand
authors.affiliation: PMI R&D (Part of Philip Morris International Group of Companies), Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Brossard
authors.affiliation: Certara Strategic Consulting, Paris, France.
authors.forename: Henri
authors.initials: H
authors.lastname: Merdjan
authors.affiliation: PMI R&D (Part of Philip Morris International Group of Companies), Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Lama
authors.affiliation: PMI R&D (Part of Philip Morris International Group of Companies), Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. rolf.weitkunat@pmi.com.
authors.forename: Rolf
authors.initials: R
authors.lastname: Weitkunat
authors.affiliation: PMI R&D (Part of Philip Morris International Group of Companies), Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Lüdicke
mesh_terms: D000280:Administration, Inhalation; D000281:Administration, Intranasal; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001682:Biological Availability; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009538:Nicotine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000074164:Nicotine Chewing Gum; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D012189:Retrospective Studies; D012737:Sex Factors; D000074285:Smokers; D055815:Young Adult
chemical_list: D000074164:Nicotine Chewing Gum; D009538:Nicotine