Characterization of the Hydrodynamics in the USP Basket Apparatus Using Computational Fluid Dynamics.

Computational fluid dynamics (CFD) has been extensively used for the USP paddle apparatus II, but limited CFD studies have been conducted on the USP basket apparatus I. We expanded on past CFD basket studies to consider the presence of a tablet inside the basket, compared predictions to in vivo conditions, and confirmed observations around the complexity of nonuniform hydrodynamics. Tablets near the basket perimeter experienced near 5-fold increase in maximum velocity and surface shear stress compared to tablets placed at the center of the basket. At higher basket speeds, the predicted velocities at the center of the basket were closer to in vivo predictions but the surface shear stress was about 2 orders of magnitude lesser. Simulations with a high viscosity fluid (1 Pa-s) showed a 10-fold increase in shear stress on a tablet but a decrease in strain rate compared to low-viscosity medium (0.001 Pa-s) which could impact dissolution rates. Also presented are the insights into turbulent energy dissipation rates that could help in a priori prediction of dissolution rates. Overall, the CFD analysis presented in this work reveals significant differences between the basket and in vivo conditions and will help inform relevant in vitro testing.

Mechanistic Physiologically Based Pharmacokinetic Modeling of the Dissolution and Food Effect of a Biopharmaceutics Classification System IV Compound-The Venetoclax Story.

Venetoclax, a selective B-cell lymphoma-2 inhibitor, is a biopharmaceutics classification system class IV compound. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to mechanistically describe absorption and disposition of an amorphous solid dispersion formulation of venetoclax in humans. A mechanistic PBPK model was developed incorporating measured amorphous solubility, dissolution, metabolism, and plasma protein binding. A middle-out approach was used to define permeability. Model predictions of oral venetoclax pharmacokinetics were verified against clinical studies of fed and fasted healthy volunteers, and clinical drug interaction studies with strong CYP3A inhibitor (ketoconazole) and inducer (rifampicin). Model verification demonstrated accurate prediction of the observed food effect following a low-fat diet. Ratios of predicted versus observed Cmax and area under the curve of venetoclax were within 0.8- to 1.25-fold of observed ratios for strong CYP3A inhibitor and inducer interactions, indicating that the venetoclax elimination pathway was correctly specified. The verified venetoclax PBPK model is one of the first examples mechanistically capturing absorption, food effect, and exposure of an amorphous solid dispersion formulated compound. This model allows evaluation of untested drug-drug interactions, especially those primarily occurring in the intestine, and paves the way for future modeling of biopharmaceutics classification system IV compounds.