生物制药
溶解
药品
广告
生物制药
溶解度
药物开发
IVIVC公司
活性成分
生物等效性
剂型
药物输送
药物发现
医学
溶解试验
作者
Arian Emami Riedmaier,David Lindley,Jeffrey A. Hall,Steven Castleberry,Russell T. Slade,Patricia Stuart,Robert A. Carr,Thomas B. Borchardt,Daniel A.J. Bow,Marjoleen Nijsen
标识
DOI:10.1016/j.xphs.2017.09.027
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI