title: Decoupling the role of image size and calorie intake on gastric retention of swelling-based gastric retentive formulations: pre-screening in the dog model.
abstract: Gastric retention is postulated as an approach to improve bioavailability of compounds with narrow absorption windows. To elucidate the role of image size on gastric retention and pharmacokinetics, formulations with different image sizes and swelling kinetics but similar dissolution rates were designed and imaged in dogs. Diet had a clear effect, with increasing calorific intake prolonging retention in the dog model. In contrast to clinical observations, no obvious effect of image size on gastric retention was observed in the dog, with the larger gastric retentive (GR) and smaller controlled release (CR) formulations both demonstrating similar gastric emptying. Comparable pharmacokinetic profiles were observed for the two formulations, corroborating the imaging data and providing evidence of similar in vivo dissolution rates and dosage form integrity in the dog. Food, specifically meal composition, resulted in comparable enhancements in exposure in the dog and clinic due to prolonged gastric retention. However, differentiating retention based on image size in the dog was not feasible due to the smaller pyloric aperture compared to humans. This work illustrates that the dog is capable of determining the pharmacokinetic advantage of gastric retention relative to immediate release (IR) or CR formulations, however, has limited value in differentiating between CR and GR formulations.
authors.affiliation: Biopharmaceutics, Product Value Enhancement, Pharmaceutical Sciences & Clinical Supplies, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA, USA. anita lalloo@merck.com
authors.forename: Anita K
authors.initials: AK
authors.lastname: Lalloo
authors.forename: Emma L
authors.initials: EL
authors.lastname: McConnell
authors.forename: Lan
authors.initials: L
authors.lastname: Jin
authors.forename: Richard
authors.initials: R
authors.lastname: Elkes
authors.forename: Christian
authors.initials: C
authors.lastname: Seiler
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000818:Animals; D001464:Barium / Q000493:pharmacokinetics; D001682:Biological Availability; D002482:Cellulose / Q000737:chemistry / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics; D003952:Diagnostic Imaging; D004285:Dogs; D004339:Drug Compounding; D002149:Energy Intake; D005215:Fasting; D018565:Food-Drug Interactions; D005746:Gastric Emptying; D065347:Hypromellose Derivatives; D007785:Lactose / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D008687:Metformin / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D012995:Solubility; D013229:Stearic Acids / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D003692:Delayed-Action Preparations; D013229:Stearic Acids; D001464:Barium; D065347:Hypromellose Derivatives; C031183:stearic acid; D002482:Cellulose; D008747:Methylcellulose; D008687:Metformin; D007785:Lactose; C109691:microcrystalline cellulose