Purpose

Regulatory agencies have encouraged the use of mechanistic absorption (MAM) and physiologically-based pharmacokinetic (PBPK) modeling to reduce cost and time to market for new and generic drug products. Models require parameterization, and many physicochemical parameters must be determined as a part of the development process. For low solubility weak bases with high solubility in gastric and low solubility in intestinal fluids, precipitation requires evaluation. Simple in vitro transfer experiments have been shown to overestimate precipitation in vivo. The biphasic test incorporates an absorptive phase to lower supersaturation similar to in vivo and to provide more accurate precipitation estimates. In this work, we present an in silico model to extract precipitation parameters from a biphasic in vitro dissolution test coupled with a MAM/PBPK model to predict precipitation in vivo. The goal was to test whether the biphasic in vitro assay provides more relevant parameters for in vivo extrapolation.

2018 AAPS Annual Meeting PharmSci 360, November 4-7, 2018, Washington, DC

By James Mullin, Ke X. Szeto, Viera Lukacova, Michael B. Bolger