Objectives:The rate of emptying of gastric contents into duodenum defines the availability of orally administered drugs for their absorption and, therefore, has a major impact on the pharmacokinetics (PK) of highly soluble and permeable substances (1). Physiologically-based (PB) PK models rely on correct description of gastric emptying (GE) to predict the bioavailability of drugs, as do models of glucose homeostasis, such as the PB Quantitative Systems Pharmacology (QSP) Diabetes Platform (2,3), when predicting appearance of glucose from ingested meals. The GE is controlled by various processes, whereby the caloric density of the contents seems to be the driving factor (1). Available GET models usually do not distinguish between the energy sources (carbohydrates (CHO), lipids, or proteins) and describe GE by non-mechanistic functions (Open Systems Pharmacology Suite (OSPS)) (4) or do not consider emptying of solids (5).
Our objective is to develop a mechanistic model of GE for solids and liquids that is able to describe the effects of different meal compositions and integrate it into the PB QSP Diabetes Platform.
Methods: The model of GE is based on the PBPK model of PK-Sim® as part of the OSPS, version 7.2 (4). Data on either gastric emptying or gastric retention of unabsorbable marker administered together with water (6–11), glucose (6,8,12–15), lipid (6), or protein (6,7) solutions, or liquid mixed meal (6,7,12,16,17) were used to define model structure and identify parameter values for GE of liquids. Transfer of solids was parametrized by fitting the model to GET data from (18,19). Only data gathered by the scintigraphy or magnetic resonance imaging methods were used.
Results: In the final model, the standard stomach representation as modeled in PK-Sim® was divided into proximal and distal parts. Approximately 1/3 of ingested liquid volume is applied directly to the distal part, whereas 2/3 are applied to the proximal part and transit to the distal part in exponential manner. From the distal part of the stomach, the liquid phase is released into the duodenum, where CHOs are absorbed (saturable transporter mediated uptake). Absorption of lipids and proteins is not modeled as it is probably negligible in duodenum. CHOs, lipids, and proteins in liquid phase (i.e., dissolved) have inhibitory effects on proximal-to-distal and distal-to-duodenal transfer rates, modeled using Hill-equations. Solids from the proximal part of the stomach are transferred to the distal part at a different rate than liquids, the same is true for the distal-to-duodenal transfer. Solids are digested and dissolved to liquid form in the duodenum.
GE of non-caloric liquids changes according to the different phases of the interdigestive migrating myoelectric complex (IMMC). To adequately describe GE of low-caloric liquid meals, transition into the quiescence phase of the IMMC from the fed state was implemented.
The model successfully describes patterns of GE of multicomponent liquid and solid mixed meals, with the majority of simulated points deviating less than 10% from the observed values. The GET model was integrated into the previously described PB QSP model of incretins (20) and parametrized with data from intraduodenal glucose infusion experiments. Coupling of the models resulted in good prediction of incretin hormones’ response to oral glucose administration (data from (21)).
Conclusion: We present a refined mechanistic model of GE that incorporates the distinct effects of CHO, lipids, and proteins and explicitly considers liquid and solid phases of the administered meals. Such a model can significantly improve accuracy of generic drug bioavailability predictions when the influence of meal composition and different phases of the IMMC are investigated with PBPK modeling. As part of the PB QSP Diabetes Platform, the new GE model allows simulation of complex (sub sequential) meal patterns including a detailed characterization of glucose absorption and the dependent dynamics of incretin hormone secretion and subsequent insulin secretion.
References:  Singh BN. Effects of food on clinical pharmacokinetics. Clin Pharmacokinet. 1999 Sep;37(3):213–55.  Open-Systems-Pharmacology - Glucose-Insulin-Model [Internet]. Available from: https://github.com/Open-Systems-Pharmacology/Glucose-Insulin-Model  Schaller S, Willmann S, Lippert J, Schaupp L, Pieber TR, Schuppert A, et al. A Generic Integrated Physiologically based Whole-body Model of the Glucose-Insulin-Glucagon Regulatory System. CPT Pharmacomet Syst Pharmacol. 2013 Aug;2(8):e65.  Open Systems Pharmacology Suite [Internet]. Available from: www.open-systems-pharmacology.org  Guiastrennec B, Sonne D, Hansen M, Bagger J, Lund A, Rehfeld J, et al. Mechanism-Based Modeling of Gastric Emptying Rate and Gallbladder Emptying in Response to Caloric Intake: Models of Gastric and Gallbladder Emptying. CPT Pharmacomet Syst Pharmacol. 2016 Dec;5(12):692–700.  Fisher RS, Rock E, Malmud LS. Effects of meal composition on gallbladder and gastric emptying in man. Dig Dis Sci. 1987 Dec;32(12):1337–44.  Giezenaar C, Lange K, Hausken T, Jones K, Horowitz M, Chapman I, et al. Acute Effects of Substitution, and Addition, of Carbohydrates and Fat to Protein on Gastric Emptying, Blood Glucose, Gut Hormones, Appetite, and Energy Intake. Nutrients. 2018 Oct 7;10(10):1451.  Grimm M, Koziolek M, Saleh M, Schneider F, Garbacz G, Kühn J-P, et al. Gastric Emptying and Small Bowel Water Content after Administration of Grapefruit Juice Compared to Water and Isocaloric Solutions of Glucose and Fructose: A Four-Way Crossover MRI Pilot Study in Healthy Subjects. Mol Pharm. 2018 Feb 5;15(2):548–59.  Mudie DM, Murray K, Hoad CL, Pritchard SE, Garnett MC, Amidon GL, et al. Quantification of Gastrointestinal Liquid Volumes and Distribution Following a 240 mL Dose of Water in the Fasted State. Mol Pharm. 2014 Sep 2;11(9):3039–47.  Sanaka M. Right recumbent position on gastric emptying of water evidenced by 13 C breath testing. World J Gastroenterol. 2013;19(3):362.  Steingoetter A, Fox M, Treier R, Weishaupt D, Marincek B, Boesiger P, et al. Effects of posture on the physiology of gastric emptying: A magnetic resonance imaging study. Scand J Gastroenterol. 2006 Jan;41(10):1155–64.  Gentilcore D, Hausken T, Meyer JH, Chapman IM, Horowitz M, Jones KL. Effects of intraduodenal glucose, fat, and protein on blood pressure, heart rate, and splanchnic blood flow in healthy older subjects. Am J Clin Nutr. 2008 Jan 1;87(1):156–61.  Horowitz M, Edelbroek MA, Wishart JM, Straathof JW. Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects. Diabetologia. 1993 Sep;36(9):857–62.  Jones KL, Horowitz M, Carney BI, Wishart JM, Guha S, Green L. Gastric emptying in early noninsulin-dependent diabetes mellitus. J Nucl Med Off Publ Soc Nucl Med. 1996 Oct;37(10):1643–8.  Jones KL, O’Donovan D, Russo A, Meyer JH, Stevens JE, Lei Y, et al. Effects of drink volume and glucose load on gastric emptying and postprandial blood pressure in healthy older subjects. Am J Physiol-Gastrointest Liver Physiol. 2005 Aug;289(2):G240–8.  Feinle C, Kunz P, Boesiger P, Fried M, Schwizer W. Scintigraphic validation of a magnetic resonance imaging method to study gastric emptying of a solid meal in humans. Gut. 1999 Jan;44(1):106–11.  Umapathysivam MM, Lee MY, Jones KL, Annink CE, Cousins CE, Trahair LG, et al. Comparative Effects of Prolonged and Intermittent Stimulation of the Glucagon-Like Peptide 1 Receptor on Gastric Emptying and Glycemia. Diabetes. 2014 Feb 1;63(2):785–90.  Bennink R, Peeters M, Van den Maegdenbergh V, Geypens B, Rutgeerts P, De Roo M, et al. Comparison of total and compartmental gastric emptying and antral motility between healthy men and women. Eur J Nucl Med Mol Imaging. 1998 Sep 1;25(9):1293–9.  Little TJ, Pilichiewicz AN, Russo A, Phillips L, Jones KL, Nauck MA, et al. Effects of Intravenous Glucagon-Like Peptide-1 on Gastric Emptying and Intragastric Distribution in Healthy Subjects: Relationships with Postprandial Glycemic and Insulinemic Responses. J Clin Endocrinol Metab. 2006 May;91(5):1916–23.  Balazki P, Schaller S, Eissing T, Lehr T. A Physiologically-based Quantitative Systems Pharmacology model of the incretin hormones GLP-1 and GIP. In: PAGE Abstracts of the Annual Meeting of the Population Approach Group in Europe [Internet]. 2018. Available from: www.page-meeting.org/?abstract=8546  Schirra J, Katschinski M, Weidmann C, Schäfer T, Wank U, Arnold R, et al. Gastric emptying and release of incretin hormones after glucose ingestion in humans. J Clin Invest. 1996 Jan 1;97(1):92–103.