title: Evaluation of two dynamic in vitro models simulating fasted and fed state conditions in the upper gastrointestinal tract (TIM-1 and tiny-TIM) for investigating the bioaccessibility of pharmaceutical compounds from oral dosage forms.
abstract: Pharmaceutical research needs predictive in vitro tools for API bioavailability in humans. We evaluated two dynamic in vitro gastrointestinal models: TIM-1 and tiny-TIM. Four low-soluble APIs in various formulations were investigated in the TIM systems under fasted and fed conditions. API small-intestinal bioaccessibility profiles were evaluated between the two systems and in comparison with human data. Both TIM systems showed a higher bioaccessibility of ciprofloxacin and nifedipine during 3-4h after dosing immediate release (IR) compared to modified release (MR) formulations. Higher bioaccessibility levels from IR formulations were observed under fasted state in the first 30-90 min in tiny-TIM as compared to TIM-1, resulting in a tmax similar to clinical data. Absence (ciprofloxacin) or presence (posaconazole) of a food effect on bioaccessibility was observed in both TIM systems in line with human data. A higher bioaccessibility of fenofibrate from nano- vs micro-particle formulation was found in both TIM systems. This dataset shows the predictive quality of the TIM systems for clinical data on API small-intestinal bioaccessibility from IR and MR formulations and food effects. Tiny-TIM provides higher throughput and better prediction for IR formulations. TIM-1 provides detailed information on site-specific release of APIs, relevant for MR formulations and food effects.
authors.affiliation: TNO, P.O. 360, 3700 AJ Zeist, The Netherlands; TNO Triskelion, P.O. Box 844, 3700 AV Zeist, The Netherlands. Electronic address: miriam.verwei@tno.triskelion.nl.
authors.forename: Miriam
authors.initials: M
authors.lastname: Verwei
authors.affiliation: TNO, P.O. 360, 3700 AJ Zeist, The Netherlands; TNO Triskelion, P.O. Box 844, 3700 AV Zeist, The Netherlands.
authors.forename: Mans
authors.initials: M
authors.lastname: Minekus
authors.affiliation: TNO, P.O. 360, 3700 AJ Zeist, The Netherlands.
authors.forename: Evelijn
authors.initials: E
authors.lastname: Zeijdner
authors.affiliation: TNO, P.O. 360, 3700 AJ Zeist, The Netherlands; TNO Triskelion, P.O. Box 844, 3700 AV Zeist, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Schilderink
authors.affiliation: TNO Triskelion, P.O. Box 844, 3700 AV Zeist, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Havenaar
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D059305:Diet, High-Fat / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004435:Eating / Q000187:drug effects / Q000502:physiology; D005215:Fasting / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D019518:Postprandial Period / Q000187:drug effects / Q000502:physiology*; D041742:Upper Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism*
chemical_list: D004364:Pharmaceutical Preparations
keywords: Food effect; In vitro gastrointestinal model; Oral dosage form; Pharmaceutical bioaccessibility; TIM system