title: An investigation into the utility of a multi-compartmental, dynamic, system of the upper gastrointestinal tract to support formulation development and establish bioequivalence of poorly soluble drugs.
abstract: In recent years mechanical systems have been developed that more closely mimic the full dynamic, physical and biochemical complexity of the GI Tract. The development of these complex systems raises the possibility that they could be used to support formulation development of poorly soluble compounds and importantly may be able to replace clinical BE studies in certain circumstances. The ability of the TNO Simulated Gastro-Intestinal Tract Model 1 (TIM-1) Dynamic Artificial Gastrointestinal System in the 'lipid membrane' configuration to support the development of Biopharmaceutics Classification System Class 2 compounds was investigated by assessing the performance of various AZD8055 drug forms and formulations in the TIM-1 system under standard fasting and achlorhydric physiological conditions. The performance data were compared with exposure data from the phase 1 clinical study. Analysis of the AZD8055 plasma concentrations after tablet administration supported the conclusions drawn from the TIM-1 experiments and confirmed that these complex systems can effectively support the product development of poorly soluble drugs. Particularly, the TIM-1 system was able to show that AZD8055 exposure would increase in an approximately dose proportional manner and not be limited by the solubility or dissolution. Additionally, the investigations also showed that the exposure produced by a solution and a tablet would be the same. Specific instances when the TIM-1 system may not be predictive of clinical product performance have also been identified.
authors.affiliation: Clinical Science, AstraZeneca R&D, Alderley Park, Macclesfield, UK. paul.dickinson@astrazeneca.com
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dickinson
authors.forename: Ragheb
authors.initials: R
authors.lastname: Abu Rmaileh
authors.forename: Lee
authors.initials: L
authors.lastname: Ashworth
authors.forename: Richard A
authors.initials: RA
authors.lastname: Barker
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Burke
authors.forename: Claire M
authors.initials: CM
authors.lastname: Patterson
authors.forename: Nick
authors.initials: N
authors.lastname: Stainforth
authors.forename: Mohammed
authors.initials: M
authors.lastname: Yasin
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002415:Cats; D002626:Chemistry, Pharmaceutical / Q000639:trends; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008954:Models, Biological; D009025:Morpholines / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D012995:Solubility; D013552:Swine; D013810:Therapeutic Equivalency; D041742:Upper Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism*
chemical_list: D009025:Morpholines; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol