title: Validated in vitro/in vivo correlation of prolonged-release oxycodone/naloxone with differing dissolution rates in relation to gastrointestinal transit times.
abstract: OBJECTIVE
  To formally establish the relationship between oxycodone dissolution, in vitro, from a prolonged-release, oral, combination of oxycodone and naloxone (OXN PR) tablets with in vivo absorption, by developing a validated Level A in vitro/in vivo correlation (IVIVC) and subsequently ascertaining the temporal absorption of oxycodone during gastrointestinal transit.
  
  
  METHODS
  In vitro dissolution data from formulations of OXN PR (20/10 mg) tablets with slow, medium and fast dissolution rates were generated using United States Pharmacopeia I apparatus 2 (paddle at 50 rpm) in simulated gastric fluid, pH 1.2. These batches were administered to healthy volunteers and plasma concentration data were collected during a randomised, open-label, cross-over study. A Level A correlation was established for oxycodone through the determination of in vivo absorption profiles obtained by deconvolution of plasma concentrations with in vitro dissolution data. The IVIVC model was validated using the internal predictability assessment.
  
  
  RESULTS
  A Level A correlation between the in vitro and in vivo release data was established. The polynomial function describing the IVIVC produced a goodness of fit (R(2)) of 0.99.
  
  
  CONCLUSIONS
  The rate of absorption of oxycodone from OXN PR tablets correlated well with the in vitro release rates, demonstrating that a Level A IVIVC with internal predictability has been successfully developed for OXN PR tablets. In conjunction with a previous gastrointestinal transit study, this report demonstrates that the majority of oxycodone enters the circulation before reaching the colon, thus it is important that naloxone counteracts opioid-induced bowel dysfunction throughout the entire gut.
authors.affiliation: Mundipharma Research Ltd, Cambridge Science Park, Milton Road, Cambridge, CB4 0GW, UK.
authors.forename: Gill E
authors.initials: GE
authors.lastname: Mundin
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Smith
authors.forename: Jana
authors.initials: J
authors.lastname: Mysicka
authors.forename: Gerhard
authors.initials: G
authors.lastname: Heun
authors.forename: Mathias
authors.initials: M
authors.lastname: Krämer
authors.forename: Udo
authors.initials: U
authors.lastname: Hahn
authors.forename: Christian
authors.initials: C
authors.lastname: Leuner
mesh_terms: D000042:Absorption; D019540:Area Under Curve; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D005772:Gastrointestinal Transit / Q000187:drug effects*; D006801:Humans; D008297:Male; D009270:Naloxone / Q000097:blood / Q000493:pharmacokinetics*; D010098:Oxycodone / Q000097:blood / Q000493:pharmacokinetics*; D013607:Tablets; D053719:Tandem Mass Spectrometry
chemical_list: D013607:Tablets; D009270:Naloxone; D010098:Oxycodone