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.
['Emami Riedmaier|Arian|A|', 'Lindley|David J|DJ|', 'Hall|Jeffrey A|JA|', 'Castleberry|Steven|S|', 'Slade|Russell T|RT|', 'Stuart|Patricia|P|', 'Carr|Robert A|RA|', 'Borchardt|Thomas B|TB|', 'Bow|Daniel A J|DAJ|', 'Nijsen|Marjoleen|M|']
D000818:Animals D001702:Biopharmaceutics D019086:Bridged Bicyclo Compounds, Heterocyclic D003198:Computer Simulation D065692:Cytochrome P-450 CYP3A Inhibitors D004347:Drug Interactions D005502:Food D018565:Food-Drug Interactions D006801:Humans D007408:Intestinal Absorption D008954:Models, Biological D010539:Permeability D051381:Rats D017207:Rats, Sprague-Dawley D012995:Solubility D013449:Sulfonamides
physiologically based pharmacokinetic modeling food effect amorphous drug interaction absorption, distribution, metabolism, and excretion (ADME) bioavailability clinical pharmacokinetics intestinal absorption passive diffusion/transport