Statelova, Marina, Vertzoni, Maria and Kourentas, Alexandros (2022) Simulation of intraluminal performance of lipophilic weak bases in fasted healthy adults using the DDDPlusTM Artificial Stomach Duodenum model. The AAPS journal, 24 (5).

Abstract

The majority of newly developed drug molecules exhibit weakly basic characteristics with high lipophilicity. The risk of intraluminal compound precipitation has been studied in vivo and extensively in vitro using advanced dissolution transfer setups mimicking drug transfer from the stomach to the less favorable small-intestinal environment. The present investigation aims to evaluate the usefulness of the recently introduced Artificial Stomach-Duodenum in silico tool in the DDDPlusTM platform (ASD-D+) to simulate intraluminal drug behavior.

The weakly basic drugs ketoconazole and dipyridamole were used as model drugs within the ASD-D+ model at two dose levels. The simulated amounts per volume were compared to intraluminal data collected fasted healthy adults. Four different in silico transfer models running on a continuous or a stepwise mode were utilized for the simulations.

Each transfer model exhibited different capabilities to simulate observed intraluminal drug presence. Three in silico models overestimated the total drug amount measured in vivo (dissolved and solid), while two models matched the intraluminal drug concentrations. The stepwise model enabled adequate simulations of both drug concentration and total drug. The present investigation highlighted the importance of simulating drug transfer (total drug amount) appropriately within the applied methodology prior to estimating precipitation kinetics. As a future step, optimization of ASD-D+ model would be required to enable continuous simulations of solid/semi-solid dosage forms and enable further evaluation. Lastly, prediction of drug precipitation kinetics following simulation of gastrointestinal transfer may provide mechanistic understanding of drug absorption and appropriate justification of drug formulated parameters within physiologically-based pharmacokinetic models.

Item Type:	Article
Keywords:	DDDPlusTM, intraluminal drug behavior, gastrointestinal transfer model, precipitation, ketoconazole, dipyridamole
Date Deposited:	20 Sep 2022 00:45
Last Modified:	20 Sep 2022 00:45
URI:	https://oak.novartis.com/id/eprint/47314