Physiological Dynamics in the Upper Gastrointestinal Tract and the Development of Gastrointestinal Absorption Models for the Immediate-Release Oral Dosage Forms in Healthy Adult Human

In Vitro Simulation of the Fasted Gastric Conditions and Their Variability to Elucidate Contrasting Properties of the Marketed Dabigatran Etexilate Pellet-Filled Capsules and Loose Pellets

“…Furthermore, the predictive power of the models was assessed by analyzing whether predicted points of dissolution profiles were within the uncertainty range that described the variability of experiments, including properties of dosage forms as well as peristaltic pumps of the PhysioCell apparatus. Such variability intervals were calculated, based on the maximal standard deviation (SD) of the six experiments in the center point of the experimental matrix that were performed under identical conditions (tests 1,4,8,12,16,20) for capsules and pellets separately. To account for the possible flow rate variability, the variability intervals were shifted in time.…”

“…16,17 Furthermore, MMC cycles determine transit times of the dissolved drug, 18,19 volume of the gastric fluid, 20−23 and secretion. 1,12 Since the MMC cycles are characterized by substantial variability, their effect on an in vivo performance of oral drug products can be significant. A recent study conducted by Braeckmans et al showed a variable behavior of an IR tablet with fosamprenavir (BCS class II) according to the phase of the MMC cycle during the intake, which was determined with high-resolution manometry.…”

“…Considering the characteristics of immediate-release (IR) orally taken drugs, it is clear that their interaction with gastric conditions can be crucial for the drug release and absorption . An advanced understanding of the gastrointestinal tract (GIT) physiology is essential for the prediction of the fate of a drug in vivo . , Fasted conditions are constituted by a variety of physicochemical and biological parameters of the gastric fluid: pH, , buffering capacity, overall composition, − temperature gradients, rheological properties, and enzymatic activity .…”

“…Researchers distinguished cyclically repeating phases in the fasted stomach, called the migrating motor complex (MMC): phase I of minimal contractile activity, phase II characterized by irregular contractions of intermittent magnitude, and phase III of the most frequent pressure events of maximal strength, including the “housekeeper wave” . Various lengths of the MMC cycle were determined: from 100 min and up to 230 min, but also, the duration of each of the phases is not constant. − The pressure events are variable in terms of timing and magnitude, starting from below 10 mbar and reaching up to 460 mbar in phase III. , Furthermore, MMC cycles determine transit times of the dissolved drug, , volume of the gastric fluid, − and secretion. , …”

Model-Informed Drug Development: In Silico Assessment of Drug Bioperformance following Oral and Percutaneous Administration

“…The estimated drug permeability data, together with the drug dissolution rate, are eventually used to assess the rate and extent of drug absorption. Absorption has been described by a variety of theories and equations over the years, as outlined in a number of reviews [ 16 , 153 , 154 , 155 , 156 ]. Most PBB models use compartmental absorption and transit (CAT) models, such as the advanced compartmental absorption and transit (ACAT) model within GastroPlus TM software [ 151 ] or the advanced dissolution, absorption, and metabolism (ADAM) model within Simcyp™ PBPK Simulator [ 157 ].…”