title: Mechanistic investigation of the negative food effect of modified release zolpidem.
abstract: OBJECTIVE
  When administered orally as either an immediate or modified release dosage form, zolpidem demonstrates a negative food effect, i.e. decrease in Cmaxand AUC. The aim of the study was to arrive at a better understanding of the absorption of this BCS class I compound in vivo and to simulate the observed plasma profiles using in vitro and in silico methods.
  
  
  METHODS
  Pharmacokinetic profiles of zolpidem are presented from a bioavailability (8mg intravenous; 10mg immediate release Stilnox®; 10mg and 12.5mg modified release Ambien® CR) and from a food effect study (12.5mg modified release Ambien® CR). The dissolution behavior of the 12.5mg strength was investigated using compendial methods in the USP apparatus II and using biorelevant methods in the USP apparatus III and IV. The mean plasma profiles as well as selected individual plasma profiles were simulated with Simcyp® and GastroPlus™. The absorption behavior was additionally investigated using the Qgutmodel, which entails algebraic deconvolution of all individual profiles, incorporating both first pass gut and liver extraction.
  
  
  RESULTS
  It was possible to simulate the mean plasma profiles using a "middle-out" approach, based on in vitro data combined with pharmacokinetic parameters obtained after intravenous administration, using PBPK software (Simcyp® and GastroPlus™), resulting in average fold error (AFE) values <1.5. Deconvolution verified that the in vivo absorption rate from the modified release formulation is controlled by the formulation in the fasted state, whereas in the fed state, the absorption rate is mainly controlled by gastric emptying. One-stage in vitro tests suggested that interactions with meal components, resulting in incomplete release, may be the source of the negative food effect for both the immediate and modified release formulations.
  
  
  CONCLUSIONS
  The present study demonstrated that a combination of biorelevant dissolution testing with modeling approaches enables a mechanistic understanding of the absorption of zolpidem from various formulations and can serve as a useful biopharmaceutical approach for the development of modified release solid oral dosage forms.
authors.affiliation: Institute of Pharmaceutical Technology, Goethe University Frankfurt am Main, Max von Laue St. 9, 60438 Frankfurt am Main, Germany.
authors.forename: Cord J
authors.initials: CJ
authors.lastname: Andreas
authors.affiliation: AstraZeneca, Pharmaceutical Technology & Development, Silk Road Business Park, Charter Way, Macclesfield SK10 2NA, United Kingdom.
authors.forename: Xavier
authors.initials: X
authors.lastname: Pepin
authors.affiliation: Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens Panepistimiopolis, 15784 Zografou, Athens, Greece.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Markopoulos
authors.affiliation: Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens Panepistimiopolis, 15784 Zografou, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Vertzoni
authors.affiliation: Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens Panepistimiopolis, 15784 Zografou, Athens, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Reppas
authors.affiliation: Institute of Pharmaceutical Technology, Goethe University Frankfurt am Main, Max von Laue St. 9, 60438 Frankfurt am Main, Germany. Electronic address: Dressman@em.uni-frankfurt.de.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Dressman
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D018592:Cross-Over Studies; D065546:Drug Liberation; D005215:Fasting / Q000097:blood / Q000378:metabolism*; D005260:Female; D018565:Food-Drug Interactions; D041981:Gastrointestinal Tract / Q000378:metabolism; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D008297:Male; D008892:Milk; D008954:Models, Biological; D011725:Pyridines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D012710:Serum Albumin, Bovine; D012984:Software; D055815:Young Adult; D000077334:Zolpidem
chemical_list: D006993:Hypnotics and Sedatives; D011725:Pyridines; D012710:Serum Albumin, Bovine; D000077334:Zolpidem
keywords: Biorelevant dissolution testing; Deconvolution; Food effects; PBPK modeling; Qgut; USP apparatus III (BioDis); USP apparatus IV (flow-through cell); Zolpidem