Dare to be More Than Average - Biopredictive Dissolution Tests of Oral Dosage Forms in the PhysioCell Apparatus as Reliable Inputs for PK Simulations

Gastric emptying rates, the “housekeeping wave” occurrence, bile salt concentrations, gastrointestinal fluid pH, transit rates, and times - these are just examples of parameters included in semi-mechanistic and physiologically-based pharmacokinetic (PK) models for oral drugs. Every modeler specialized in this field knows how they might influence the predicted PK profile in humans. We also know their average, “typical” values and how to implement them in the model. Also, for our PK models, we need experimental data from well-planned dissolution studies; preferably, the closer the experiments are to the in vivo stage, the better. The question is - are we missing something in these studies?
Among the factors observed in vivo but often neglected in experiments are intermittent gastric contractions of various timings and magnitudes. These might appear to be of little relevance to quickly disintegrating immediate-release oral dosage forms, especially those administered under fasted conditions. In my presentation, I will show two contrasting case studies, each involving the biopredictive dissolution tests in the PhysioCell apparatus as their foundation. In the first one, intermittent gastric stresses had little relevance for the predicted PK profile. In the second one, the timing and magnitude of intermittent stress were the key factors in unraveling the PK variability observed in the clinical trial.
The lecture will conclude with some recommendations and perspectives on designing the in vitro experiments to cover the physiological range of fasted gastric motility and how a modeler can use them to add another layer of variability to the model.