Unit:
Department of PharmacyLibrary of the School of Science
Author:
Pentafragka Christina
Dissertation committee:
Christos Reppas, Professor, Department of Pharmacy, National and Kapodistrian University of Athens, Greece
Mira Symillides, Associate Professor, Department of Pharmacy, National and Kapodistrian University of Athens, Greece
Maria Vertzoni, Assistant Professor, Department of Pharmacy, National and Kapodistrian University of Athens, Greece
Jennifer Dressman, Professor, Institute of Pharmaceutical Technology, Johann Wolfgang Goethe University, Germany
Catriona O’ Driscoll, Professor, School of Pharmacy, University College Cork, Ireland
George Imanidis, Professor, Institute of Pharma Technology, University of Applied Sciences Northwestern Switzerland, Switzerland; Department of Pharmaceutical Sciences, University of Basel, Switzerland
Dimitrios Fatouros, Professor, Department of Pharmacy, Aristotle University of Thessaloniki, Greece
Original Title:
Drug disposition and characteristics of contents in the upper gastrointestinal lumen of healthy adults after a standard high-calorie high fat meal – Implications for the in vitro drug testing conditions
Translated title:
Drug disposition and characteristics of contents in the upper gastrointestinal lumen of healthy adults after a standard high-calorie high fat meal – Implications for the in vitro drug testing conditions
Summary:
Objectives
To quantify the presence in the upper gastrointestinal lumen and understand the gastrointestinal transfer process of highly permeable drugs under conditions simulating the situation after disintegration of immediate release dosage forms administered in bioavailability/bioequivalence studies in the fed state.
To measure the physicochemical characteristics of gastric contents and contents of the upper small intestine and their respective aqueous and micellar phases, after administration of the meal used to induce fed state conditions in bioequivalence/bioavailability studies (standard meal).
To evaluate the need for adjustments in in vitro methodologies used to date to assess intraluminal behavior of per os administered drug products in the fed state and specifically: (a) to evaluate the sufficiency of simulation of intraluminal characteristics with liquid media used to date in in vitro testing of intraluminal behavior of per os administered drugs, and (b) to evaluate the competency of the in vitro simulation of the intraluminal environment using the TIM-1 model.
Methods
Eight healthy male adult volunteers participated in a randomized, single dose, two-phase, crossover study. The standard meal, containing the non-absorbable marker phenol red, was administered to the antrum via a naso-gastro-intestinal tube. The drugs, paracetamol and danazol, were administered in solution form (Phase I) and in suspension form (Phase II) with a glass of tap water, 30 min after initiation of the meal. Samples were aspirated from the antrum and the upper small intestine over the next four hours. Samples were analyzed for drug content, phenol red content, pH, buffer capacity, viscosity, osmolality, and presence of solubilizing agents.
The clinical study protocol was mimicked in TIM-1 experiments.
Results
Apparent concentrations in the aqueous phase of antral contents were higher than apparent concentrations in the micellar phase of upper small intestinal contents for paracetamol. The opposite was observed for danazol. The gastrointestinal transfer of paracetamol (aqueous solution or suspension) and danazol (aqueous suspension) could be described as an apparent first-order process. The transfer of the long-chain triglyceride solution of danazol presented high intersubject variability.
The viscosity of contents from the upper gastrointestinal lumen in the fed state was much higher than values reported in the fasted state.
New biorelevant media for the simulation of intragastric contents and the aqueous phase of intragastric contents were suggested. The TIM-1 model simulated adequately the presence of paracetamol (solution or suspension) and danazol (suspension) in the upper gastrointestinal lumen, but not the gastric secretions, the digestion of lipids, and the bile acid levels.
Conclusions
Concentrations in the aqueous/micellar phase of luminal contents and values of parameters controlling drug transfer after the standard meal were reported for the first time.
Representative viscosity values in the stomach and the upper small intestine and Level II composition of the aqueous phase of gastric contents, after the standard meal, were proposed for the first time.
Biorelevant media simulating the intragastric conditions after ingestion of a standard meal could be simplified whereas FeSSIF-V2 composition was confirmed to be representative of the micellar phase of contents of the upper small intestine. The TIM-1 model could be a useful tool in drug development in the future after optimization of conditions in the gastric and jejunal compartments.
Main subject category:
Health Sciences
Keywords:
gastrointestinal drug transfer, fed state, upper gastrointestinal lumen, physicochemical characteristics, micellar phase, TIM-1 model
