(T0930-05-32) A Mechanistic Framework for PBPK Modelling of the Impact of Osmotically Active Species, including Excipients, on Oral Drug Absorption: The Underlying Mechanistic Model

Purpose: Physiologically-based pharmacokinetic (PBPK) models are increasingly used for biopharmaceutics applications to aid drug product development. For modelling the solubility (concentration), dissolution and absorption rate of poorly soluble drugs accurate simulation of gut luminal fluid volumes and their dynamic changes after intake of fluid with drug can be critical. A number of excipients, particularly, but not only, sugar alcohols, are osmotically active and if present in sufficient amounts stimulate fluid secretion into the lumen significantly impacting both luminal fluid volumes and reducing residence time (Matsui et al., 2025 and references therein). Osmotically active laxatives act in the same way but often contain multiple osmotically active species. The aim is to build and evaluate a mechanistic framework within which to simulate these effects. In particular such a model has applications to paediatric subjects where sugar alcohols are widely used in drug products. For soluble BCS 3 drugs the residence time effect maybe dominant with significant reductions in AUC and Cmax (See Symposium Tuesday November 11^th 10:30 am by Kazuki Matsui).

Methods: A mechanistic model coded in LUA is incorporated into the ADAM model of the Simcyp Simulator (Pathak et al 2017). The model assumes that the body dynamically maintains both the volume and the osmolality of luminal fluids within defined (baseline) ranges and that to do this fluid and ions are secreted or absorbed dynamically until both baselines are restored. Tap water is hypotonic compared to baseline luminal fluids and stimulates net fluid absorption while sufficient amounts of osmotically active excipients (laxatives) generate solutions hypertonic compared to baseline osmolalities stimulating net fluid secretion. Fluid absorption and secretion rates are linked to the osmotic gradient (difference between current and baseline osmolality) as quantified in humans by Lambert et al. (2008). We describe a model based upon these concepts validated against published studies where dynamic luminal fluid volumes have been characterized using MRI techniques - the model includes simulations of the between (or within) subject variability of fluid volumes and osmolality. Baseline gut lumen fluid volumes and osmolality values for the different gut regions were collected from the literature. Osmotically active excipients can be either non-absorbable or absorbable within the model. For the latter gut wall permeability values are required. For the sugar alcohol mannitol (see below) its proximal jejunum permeability (paracellular) is 0.24 x 10-4 cm/s giving fa of ~0.25 which matches clinical studies. For residence time reduction associated with increased luminal fluid volumes data from the literature were collated quantifying the link between the amount of osmotically active excipient and fold reduction in residence times.

Results: The model was validated/evaluated in a multistep process. 1. Simulation of baseline values for both fluid volume and osmolality for the small intestine (Figure 1); 2. Simulation of dynamic changes in luminal fluid volumes and osmolality after a standard tap water drink of 240 mL (Figure 1); 3. Simulation of the impact of relatively small amounts of absorbable (e.g., chloride ion) and non-absorbable ions (e.g., sulphate ions) on luminal fluid kinetics (Figure 2); 4. Simulation of the impact of 17.5g of the osmotically active excipient mannitol taken with a 350 mL drink of water on luminal fluid volumes verified against reported luminal fluid volumes based on MRI (Marciani et al., 2010) (Figure 3). For cases 1, 2 and 4 the model is able to reproduce the observed data very well albeit there is some underprediction of the population variability. For case 3 there are no data available to validate the results. However, the simulations well illustrate the expected behaviour of the model for absorbable vs non-absorbable osmotically active ions.

Conclusion: A mechanistic model coupled to a PBPK framework for the simulation of time variant luminal fluid volume and osmolality has been described and validated against available data from MRI. The model enables the impact of osmotically active excipients such as sugar alcohols to be modelled including their impact in reducing residence times in the small intestine. The model is able to simulate both baseline and dynamic time variant gut lumen fluid volumes both for a representative subject and for a population of subjects (Mudie et al., 2014) albeit with some underprediction of the population variability. The model is also able to simulate the significant temporal impact of 17.5 g of mannitol on luminal fluid volumes and residence times. More data are required to further validate the model. For highly soluble, poorly permeable BCS 3 drugs it is likely that the reduction in residence time is the dominant effect although the concentration gradient driving absorption into the enterocytes may also be significantly reduced. For relevant excipients no- or minimal-effect thresholds can be estimated.

References: Lambert et al. (2008) Combined Effects of Glucose and Fructose on Fluid Absorption from Hypertonic Carbohydrate Electrolyte Beverages. JEP 11:46.
Marciani et al. (2010) Postprandial Changes in Small Bowel Water Content in Healthy Subjects and Patients With Irritable Bowel Syndrome. Gastroenterol 138:469
Matsui (2025) Biopharmaceutics Aspects of Sugar Alcohols: Implementation of Patient-Centricity in Pharmaceutical Development and Clinical Use. Mol Pharm 22:1775
Pathak et al. (2017) Model-based Analysis of Biopharmaceutical Experiments to Improve Mechanistic Oral Absorption Modelling - An Integrated in Vitro in Vivo Extrapolation (IVIV_E) Perspective using Ketoconazole as a Model Drug. Mol Pharm 14:4305.

Acknowledgements: The author would like to acknowledge useful discussions on this topic with Dr Kazuki Matsui of ONO Pharmaceutical Co, Japan.

Figure 1: Simulated (left) and observed (right) whole small intestine luminal fluid volumes vs time after a 240 mL drink (0 mOsm)

Figure 2: Simulated whole small intestine luminal fluid volumes vs time after a 240 mL drink for deionised water (green line), 30 mM chloride (black line) (absorbable ion), and 30 mM sulphate ion (red line) (non-absorbable ion).

Figure 3: Simulated and observed whole small intestine luminal fluid volumes vs time after a 350 mL drink containing 17.5 g of pre-dissolved mannitol. The clinical study considered 11 subjects. The simulations were done for 10 repeat virtual trials of 11 subjects with the mean and percentiles for all 110 subjects on the left side and selected trials each with 11 subjects shown on the right side.