title: Population pharmacokinetics of modafinil and its acid and sulfone metabolites in Chinese males.
abstract: BACKGROUND
  Modafinil is a psychostimulant used to treat excessive sleepiness. The aim of this study was to develop a population pharmacokinetic model of modafinil and its major metabolites in Chinese male adults and to identify covariates that predict variability in disposition.
  
  
  METHODS
  Eighty healthy volunteer subjects were randomized to 4 oral dose groups: 3 doses of 50 mg of modafinil, 3 doses of 100 mg of modafinil, 2 doses of 200 mg of modafinil plus 1 dose of placebo, or 3 doses of placebo (each dose given 8 hourly). Blood samples were collected up to 58 hours post-first dose for plasma concentrations of modafinil and its metabolites. Pharmacokinetic data analyses were performed using noncompartmental and compartmental approaches. The population pharmacokinetic study was conducted using the nonlinear mixed-effects model software, NONMEM, and validated using the bootstrap, crossvalidation and visual predictive check approaches.
  
  
  RESULTS
  Data were best described by a 5-compartment model: 2 compartments for modafinil (first-order absorption from gut compartment) and 1 each for modafinil acid and modafinil sulfone. A covariate analysis identified body weight as influencing volumes of the central and peripheral compartments for modafinil. All the parameters were estimated with good precision (relative standard error < 39%). The visual predictive check found that the final pharmacokinetic model adequately predicted observed concentrations of all 3 molecular species. The authors developed dosing schedules to achieve minimum trough plasma modafinil concentrations of 3 mcg/mL.
  
  
  CONCLUSIONS
  A robust population pharmacokinetic model for modafinil and its metabolites was developed for the first time. Based on this model, individualized dosing based on weight is now possible.
authors: Bioengineering Laboratory, Defence Medical and Environmental Research Institute, DSO National Laboratories, Singapore.
authors: Kok-Yong
authors: KY
authors: Seng
authors: Lu
authors: L
authors: Fan
authors: How Sung
authors: HS
authors: Lee
authors: Wei Peng
authors: WP
authors: Yong
authors: Boon Cher
authors: BC
authors: Goh
authors: Lawrence Soon-U
authors: LS
authors: Lee
mesh_terms: D000081:Acetamides / Q000097:blood; D000328:Adult; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D000077408:Modafinil; D008954:Models, Biological; D012846:Singapore; D013450:Sulfones / Q000097:blood; D055815:Young Adult
chemical_list: D000081:Acetamides; D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D013450:Sulfones; D000077408:Modafinil