title: Development of a Unified Dissolution and Precipitation Model and Its Use for the Prediction of Oral Drug Absorption.
abstract: Drug absorption is a complex process involving dissolution and precipitation, along with other kinetic processes. The purpose of this work was to (1) establish an in vitro methodology to study dissolution and precipitation in early stages of drug development where low compound consumption and high throughput are necessary, (2) develop a mathematical model for a mechanistic explanation of generated in vitro dissolution and precipitation data, and (3) extrapolate in vitro data to in vivo situations using physiologically based models to predict oral drug absorption. Small-scale pH-shift studies were performed in biorelevant media to monitor the precipitation of a set of poorly soluble weak bases. After developing a dissolution-precipitation model from this data, it was integrated into a simplified, physiologically based absorption model to predict clinical pharmacokinetic profiles. The model helped explain the consequences of supersaturation behavior of compounds. The predicted human pharmacokinetic profiles closely aligned with the observed clinical data. In summary, we describe a novel approach combining experimental dissolution/precipitation methodology with a mechanistic model for the prediction of human drug absorption kinetics. The approach unifies the dissolution and precipitation theories and enables accurate predictions of in vivo oral absorption by means of physiologically based modeling.
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel , Basel, Switzerland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Jakubiak
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel , Basel, Switzerland.
authors.forename: Björn
authors.initials: B
authors.lastname: Wagner
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel , Basel, Switzerland.
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Grimm
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel , Basel, Switzerland.
authors.forename: Jeannine
authors.initials: J
authors.lastname: Petrig-Schaffland
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel , Basel, Switzerland.
authors.forename: Franz
authors.initials: F
authors.lastname: Schuler
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel , Basel, Switzerland.
authors.forename: Rubén
authors.initials: R
authors.lastname: Alvarez-Sánchez
mesh_terms: D000284:Administration, Oral; D003198:Computer Simulation; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000493:pharmacokinetics*; D065569:Gastrointestinal Absorption / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D010539:Permeability / Q000187:drug effects*; D014018:Tissue Distribution
chemical_list: D000069347:Erlotinib Hydrochloride
keywords: BCS; FaSSIF; FeSSIF; biorelevant media; dissolution; formulation testing; in vitro−in vivo correlation; oral absorption; physiologically based pharmacokinetic modeling; precipitation; simulated intestinal fluids; solubility; supersaturation; weak bases