Gastrointestinal Motility: The Multiple Moving Plug Model
Watch a video comparing the multiple moving plug model to the ACAT model.
The Multiple Moving Plug Model
The multiple moving plug model tracks drug dissolution and absorption from independent plugs moving through the gastrointestinal tract (see Chapter 5).
Videos of GI Motility
Hans Jörg Ehrlein and Michael Schemann have compiled videos of gastrointestinal motility along with insightful commentary. See how the Multiple Moving Plug Model compares to real motility.
Intellipharm was founded on a passion for modeling processes like drug dissolution based on the best mechanistic understanding of the science available. Any model can characterize data, but only mechanistically-based models can predict outcomes.
The most popular model for gastrointestinal transit is the Advanced Compartmental Absorption and Transit (ACAT) model. This model treats the gastrointestinal tract as a series of compartments with first order transit of dissolved and undissolved drug between compartments. The number of compartments was originally determined by adjusting the number of compartments to get the best fit to a cumulative percent of dose in the colon as a function of time (Yu, Crison, and Amidon, Int J Pharm (1996) 140:111-118). Dissolution was not addressed.
Referring to the ACAT model, there is no mechanistic justification for modeling gastrointestinal transit as the flow of discrete drug particles and dissolved drug between compartments independent of the flow of gastrointestinal fluid, nor is it possible to construct a physical model to mimic such a process. Magnetic resonance imaging (MRI) shows that fluid in the gastrointestinal tract exists in discrete plugs or pockets of fluid. As such, there is no mechanism for transit of mass from one plug to the next. It is therefore more realistic to model gastrointestinal transit as discrete moving plugs of fluid in which drug dissolves and from which drug is absorbed.
Intellipharm has an alternative solution that provides a mechanistically-based model to simulate drug dissolution and gastrointestinal motility and their effects on drug absorption. This model is called the Multiple Moving Plug (MMP) model.
The MMP model is a natural extension of the Johnson dissolution model. The Johnson dissolution model uses array variables to track drug originating from different particle size groups. The MMP extends the array variables to include another dimension, which tracks drug emptying from the stomach in a particular plug. You decide how many plugs will empty from the stomach, their volume, the amount of drug in each plug, and when the plug empties from the stomach. Drug mass is now indexed based on its particle size group and the discrete plug in which it travels through the gastrointestinal tract. The plugs are completely independent from each other.
Data on the number and volume of plugs emptying from the stomach is already taking shape (see Mudie et al., Mol Pharm (2014) 11:3039-4047). The MMP model is perfectly suited to take advantage of this data because the mathematical framework of the MMP is mechanistically consistent with the experimental observations.
The compartmental transit model has the advantage of relative simplicity, intuition, and easy correlation with pharmacokinetic models. However, it has not many physical bases that one physiological segment of the gastrointestinal tract can be considered as one or more serial comparments although such an assumption has been commonly and successfully utilized in biology and medicine (Jacquez, 1984).
Fasted-state gastrointestinal (GI) fluid transit is typically represented as a first-order, deterministic process (averaged and viewed as a continuous approximation). The variability in gastric emptying times has been addressed for example by assigning randomly sampled gastric emptying rate constants. Based on observations in several studies and ongoing magnetic resonance imaging (MRI) of GI fluid volumes, we assume that discretized fluid packets are likely to transit in pulses which are variable in both volume and time. It is therefore imperative that a model capture the kinetics of discrete fluid packets, something that is not possible with continuous approximations.
On of the hallmarks of the Johnson dissolution model is the dynamic nature of particle size, diffusion layer thickness, and concentration gradient, all updated continuously during simulation. The MMP continues this practice. Every parameter associated with a plug can be changed continuously to reflect the state of the plug as it moves through the gastrointestinal tract. Solubility, volume, permeability, and intestinal wall metabolism can all be changed continuously to reflect the time-dependent position of the plug in the gastrointestinal tract.