Predicting Intestinal Precipitation—A Case Example for a Basic BCS Class II Drug

Abstract

This study indicated that simple in vitro methods of in vivo precipitation of orally administered bases overpredict the intestinal crystalline precipitation in vivo in humans. Hydrodynamic conditions were identified as one important factor that needs to be better addressed in future in vivo predictive methods.

Precipitation in and Supersaturation of Contents of the Upper Small Intestine After Administration of Two Weak Bases to Fasted Adults

“…Nevertheless, in vivo data relevant to precipitation are almost non-existent. It has recently been shown that intestinal precipitation of a weak base that is under development by AstraZeneca is less of a limitation for in vivo drug absorption than implied from equilibrium solubility and in vitro test assessments (5). Although that was probably the first study dealing with in vivo precipitation/supersaturation of bases, observations were made indirectly (using plasma data), and, therefore, quantitative assessment of the degree of precipitation/supersaturation in vivo was not possible.…”

An In Vitro Methodology for Forecasting Luminal Concentrations and Precipitation of Highly Permeable Lipophilic Weak Bases in the Fasted Upper Small Intestine

“…To date, two approaches have been used for predicting lumenal concentrations of weak bases, In the first, concentrations of lipophilic weak bases in the upper small intestine after oral administration in the fasted state have been modelled by combining theoretical particle dissolution and particle growth kinetic models (6,7) or, in the case of administration of liquid dosage forms, by combining nucleation and particle growth models (8), according to the classical theory of crystallization. These approaches have been shown to be useful in forecasting the average plasma profile (7), the cumulative % dose absorbed vs. time plots (6) and the linearity of C max vs.…”

“…Dose data (8) in humans. In the second approach, concentrations of lipophilic weak bases in the upper small intestine after oral administration in the fasted state have been modelled using in vitro setups either in the form of single compartment systems (8) or, more frequently, in the form of multiple compartment systems (9)(10)(11)(12). One of these systems has been shown to be useful in forecasting the total % dose absorbed in humans (9).…”

“…by using plasma data or pharmacokinetic parameters in animals or in humans rather than by using luminal data in humans. In addition, with the exception of a few theoretical models (7,8), such evaluations are based on predictability of AUC t or of % dose absorbed. Luminal concentrations and the extent of precipitation of lipophilic (highly permeable) weak bases in the upper small intestine are likely to affect early exposure and C max to a greater extent than total exposure, as total exposure is more dependent upon efficient dissolution of the dose throughout the GI tract.…”

“…The first was to develop an in vitro methodology for prediction of concentrations and potential precipitation of highly permeable, lipophilic weak bases in fasted upper small intestine based on luminal data of ketoconazole and dipyridamole (5). The second objective was to evaluate the usefulness of the methodology in predicting luminal precipitation of AZD0865 and SB705498 based on plasma data (8,13, GSK data on file). AZD0865 (MW 366.46 g/mol) has an alkaline pKa of 6.1 and logP of 4.2 (8).…”