Abstract. Effective integration of in vitro tests and absorption modeling can greatly improve our capability in understanding, comparing, and predicting in vivo performances of clinical drug products. In this case, we used a proprietary drug candidate galunisertib to describe the procedures of designing key in vitro tests, analyzing relevant experimental and trial data, and integrating them into physiologically based absorption models to evaluate the performances of its clinical products. By simulating the preclinical study result, we estimated high in vivo permeability for the drug. Given the high sensitivity of its solubility to pH, supersaturation may play an important role in the absorption of galunisertib. Using the dynamic dissolution test, i.e., artificial stomach-duodenum (ASD) model and simulation, we concluded galunisertib in solution or tablet products could maintain supersaturation during the transit in the gastrointestinal tract (GIT). A physiologically based absorption model was established by incorporating these key inputs in the simulation of Trial 1 results of galunisertib solution. To predict the performance of three tablet products, we developed z-factor dissolution models from the multi-pH USP dissolution results and integrate them into the absorption model. The resultant biopharmaceutical models provided good prediction of the extent of absorption of all three products, but underestimated the rate of absorption of one tablet product. Leveraging the ASD result and optimization with the dissolution model, we identified the limitation of the model due to complexity of estimating the dissolution parameter z and its in vitro-in vivo correlation.
The authors propose the following mechanism mediated by Tween 80. Below CMC, reduced surface tension caused by addition of Tween 80 increases the rate of nucleation of insoluble CS, causing the formation of CS on the surface of the CI-1041 free form. This, in turn, decreases the dissolution rate by decreasing the release of compound into solution. Above CMC, the effect of reduced surface tension on the CS nucleation and therefore its formation may be negated by other factors, such as an increase in viscosity or adsorption of surfactant on the crystal surface.
Micronization is a commonly used enabling technology to improve the bioavailability of compounds where absorption is dissolution rate limited. However, decreasing particle size often results in increased Van der Waals' interactions and electrostatic attraction between particles. This causes agglomeration of particles, thereby compromising the increase in surface area gained by micronization. Comicronization with excipients has been reported to offer significant advantages over neat micronization. The present work describes the comicronization of a model compound CI-1040 at a high drug load that shows an increase in the dissolution rate and bioavailability in male Wistar rats. Physicochemical characterization of the comicronized and neat micronized material is presented to help explain the in-vitro and in-vivo data.
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