Biorelevant Two-Stage In Vitro Testing for rDCS Classification and in PBPK Modeling-Case Example Ritonavir

Abstract

Biorelevant two-stage in vitro testing is increasingly used as a tool for various applications in drug development. Three important applications of two-stage in vitro testing are the classification of weakly basic drug compounds as part of the refined Developability Classification System, the prediction of intraluminal drug concentrations in the gastrointestinal tract and the prediction of plasma concentration profiles using physiologically based pharmacokinetic modeling. For the weakly basic, antiretroviral drug ritonavir, two-stage testing is triggered as a customized investigation in the refined Developability Classification System classification process to assess whether the drug could supersaturate and precipitate when exposed to the steep change in pH that occurs during drug transfer from the stomach into the small intestine. It was shown that for 2 Norvir® formulations, a tablet and an oral powder formulation, the two-stage test yielded similar results to the more complex "transfer" model with regard to the supersaturation and precipitation behavior of these amorphous solid dispersion formulations. Furthermore, solubility and two-stage data were mechanistically modeled in the in vitro data Analysis Toolkit and the results used as input parameters for a physiologically based pharmacokinetic model built in the Simcyp Simulator.

Keywords: Amorphous solid dispersions (ASD); Biopharmaceutical Classification System (BCS); Developability; Dissolution; In silico modeling; In vitro models; Physiologically based pharmacokinetic (PBPK) modeling; Precipitation; SimCyp PBPK modeling; Supersaturation.