Mechanistic modeling of gastrointestinal motility with integrated dissolution for simulating drug absorption.

Kevin Charles Johnson

doi:10.5599/admet.829

Abstract

A new computational method – the multiple moving plug (MMP) model – is described to simulate the effect of gastrointestinal motility and dissolution on the pharmacokinetic profile of any given drug. The method is physiologically more consistent with the experimental evidence that fluid exists in discrete plugs in the gastrointestinal tract, and therefore is more realistic than modeling the gastrointestinal tract as a series of compartments with first-order transfer. The number of plugs used in simulations, their gastric emptying times and volumes, and their residence times in the small intestine can be matched with experimental data on motility. In sample simulations, drug absorption from a series of fluid plugs emptied from the stomach at evenly spaced time intervals showed lower Cmax and higher Tmax than an equivalent dose emptied immediately as a single plug. To the extent that new techniques can establish typical ranges for the volumes of fluid emptied from the stomach and their respective timing, the MMP model may be able to predict the effect of gastric emptying on the variability seen in pharmacokinetic profiles. This could lead to an expanded safe space for the regulatory acceptance of formulations based on dissolution data.

Highlights

Several reports have expressed the view that gastrointestinal (GI) transit is more realistically modeled as discrete plugs of fluid emptying from the stomach and moving through the small intestine rather than as a first-order process between static compartments [1,2,3]
The multiple moving plug (MMP) model [3] is a natural extension of a well-established dissolution model [7,8,9], the default model in GastroPlus [10], and can simulate the effects of both the gastric emptying of plugs and the dissolution within the plugs on plasma drug concentrations
The theoretical advantage of the MMP model lies in its mechanistically-based mathematical integration of dissolution, gastric emptying, and intestinal motility in a way that is closer to how these processes occur in the GI tract

Summary

Introduction

Several reports have expressed the view that gastrointestinal (GI) transit is more realistically modeled as discrete plugs of fluid emptying from the stomach and moving through the small intestine rather than as a first-order process between static compartments [1,2,3]. The MMP model is capable of utilizing either experimental data or stochastic simulations of the volumes and timing of plugs emptying from the stomach. Because the number of parameter changes that could be simulated is unlimited, only kaj was altered to explore the potential effect of gastric emptying on the drug plasma concentration profile.

Results

Conclusion