title: Population pharmacokinetics of caffeine in healthy male adults using mixed-effects models.
abstract: OBJECTIVE
  Caffeine has been shown to maintain or improve the performance of individuals, but its pharmacokinetic profile for Asians has not been well characterized. In this study, a population pharmacokinetic model for describing the pharmacokinetics of caffeine in Singapore males was developed. The data were also analysed using non-compartmental models.
  
  
  METHODS
  Data gathered from 59 male volunteers, who each ingested a single caffeine capsule in two clinical trials (3 or 5 mg/kg), were analysed via non-linear mixed-effects modelling. The participants' covariates, including age, body weight, and regularity of caffeinated-beverage consumption or smoking, were analysed in a stepwise fashion to identify their potential influence on caffeine pharmacokinetics. The final pharmacostatistical model was then subjected to stochastic simulation to predict the plasma concentrations of caffeine after oral (204, 340 and 476 mg) dosing regimens (repeated dosing every 6, 8 or 12 h) over a hypothetical 3-day period.
  
  
  RESULTS
  The data were best described by a one-compartmental model with first-order absorption and first-order elimination. Smoking status was an influential covariate for clearance: clearance (mL/min) = 110*SMOKE + 114, where SMOKE was 0 and 1 for the non-smoker and the smoker respectively. Interoccasion variability was smaller compared to interindividual variability in clearance, volume and absorption rate (27% vs. 33%, 10% vs. 15% and 23% vs. 51% respectively). The extrapolated elimination half-lives of caffeine in the non-smokers and the smokers were 4.3 +/- 1.5 and 3.0 +/- 0.7 h respectively. Dosing simulations indicated that dosing regimens of 340 mg (repeated every 8 h) and 476 mg (repeated every 6 h) should achieve population-averaged caffeine concentrations within the reported beneficial range (4.5-9 microg/mL) in the non-smokers and the smokers respectively over 72 h.
  
  
  CONCLUSIONS
  The population pharmacokinetic model satisfactorily described the disposition and variability of caffeine in the data. Mixed-effects modelling showed that the dose of caffeine depended on cigarette smoking status.
authors.affiliation: Bioengineering Laboratory, Defence Medical and Environmental Research Institute, DSO National Laboratories, Singapore, Singapore. skokyong@dso.org.sg
authors.forename: K-Y
authors.initials: KY
authors.lastname: Seng
authors.forename: C-Y
authors.initials: CY
authors.lastname: Fun
authors.forename: Y-L
authors.initials: YL
authors.lastname: Law
authors.forename: W-M
authors.initials: WM
authors.lastname: Lim
authors.forename: W
authors.initials: W
authors.lastname: Fan
authors.forename: C-L
authors.initials: CL
authors.lastname: Lim
mesh_terms: D044466:Asian People; D002110:Caffeine / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011446:Prospective Studies; D012846:Singapore; D012907:Smoking / Q000378:metabolism*; D013269:Stochastic Processes; D055815:Young Adult
chemical_list: D000697:Central Nervous System Stimulants; D002110:Caffeine