Biopharmaceutic IVIVE—Mechanistic Modeling of Single- and Two-Phase In Vitro Experiments to Obtain Drug-Specific Parameters for Incorporation Into PBPK Models

• Published in: Journal of pharmaceutical sciences Vol. 108; no. 4; pp. 1604 - 1618
• Main Authors: Pathak, Shriram M., Schaefer, Kerstin Julia, Jamei, Masoud, Turner, David B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2019
• Subjects: Administration, Oral; biopharmaceutical IVIV_E; Biopharmaceutics - methods; Computer Simulation; dipyridamole; Dipyridamole - administration & dosage; Dipyridamole - pharmacokinetics; dissolution; Drug Development - methods; Drug Liberation; Duodenum - metabolism; Humans; Intestinal Absorption; Intestinal Mucosa - metabolism; mechanistic modeling; Models, Biological; PBPK; precipitation; Solubility; Workflow; PBPK; precipitation; dipyridamole; biopharmaceutical IVIV_E; mechanistic modeling; dissolution
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1016/j.xphs.2018.11.034

The physiological relevance of single-phase (aqueous only) and 2-phase (aqueous and organic phase) in vitro dissolution experiments was compared by mechanistic modeling. For orally dosed dipyridamole, stepwise, sequential estimation/confirmation of biopharmaceutical parameters from in vitro solubility-dissolution data was followed, before applying them within a physiologically based pharmacokinetic (PBPK) model. The PBPK model predicted clinical dipyridamole luminal and plasma concentration profiles reasonably well for a range of doses only where the precipitation rate constant was derived from the 2-phase experiment. The population model predicted a distribution of maximal precipitated fractions from 0% to 45% of the 90 mg dose (mean 7.6%). Such population information cannot be obtained directly from a few in vitro experiments; however well they may represent an “average” and several extreme subjects (those with low-high luminal fluid volumes, pH, etc.) because there is no indication of outcome likelihood. For this purpose, direct input of in vitro dissolution/precipitation profiles to a PBPK model is insufficient—mechanistic modeling is required. Biopharmaceutical in vitro-in vivo extrapolation tools can also simulate the effect of key experimental parameters (dissolution volumes, pH, paddle speed, etc.) on dissolution/precipitation behavior, thereby helping to identify critical variables, which may impact the number or design of in vitro experiments.