2014 - Alicante - Spain

PAGE 2014: Mechanistic Absorption Modelling
Benjamin Guiastrennec

Mechanism-based modelling of gastric emptying and bile release in response to caloric intake

Benjamin Guiastrennec (1), David P. Sonne (2,3), Oskar Alskär (1), Morten Hansen (2,3), Jonatan I. Bagger (2,3), Asger Lund (2,3), Jens F. Rehfeld (4), Mats O. Karlsson (1), Tina Vilsbøll (2), Filip K. Knop (2,3), Martin Bergstrand (1)

(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, (2) Diabetes Research Division, Department of Medicine, Gentofte Hospital, Hellerup, Denmark, (3) Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, (4) Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

Objectives: We aimed to establish a mechanism-based model for gastric emptying (GE), cholecystokinin (CCK) plasma concentrations and gallbladder (GB) emptying in response to caloric intake.

Methods: Data were gathered from 3 clinical studies with paracetamol absorption as a marker for GE, measurements of CCK plasma concentrations and ultrasound monitoring of the GB volume [1,2,3]. The studies included in total 33 healthy subjects and 33 type 2 diabetes patients. The studies featured paracetamol (1.5g) dissolved in: water (100mL), 25, 75 and 125g glucose solution (300mL), or isocaloric low, medium and high fat content liquid meal (350mL).

Previously published paracetamol population pharmacokinetic models [4,5] were modified to incorporate a feedback mechanism from the nutritional content in duodenum regulating the rate of GE. Prior information on glucose turnover in duodenum was taken from a model by Alskär et al [5]. GE was further described in terms of emptying of stomach volume (meal volume).

CCK turnover was modelled with two precursor indirect response models [6]. Release of CCK from the precursor pools was investigated as a function of nutritional content in duodenum and jejunum respectively. GB emptying was modelled with recirculation of bile from the small intestine to the GB via a chain of transit compartments. The effect of CCK or nutritional content on emptying of the GB compartment was investigated.

Results: Glucose in duodenum was found to have an inhibiting effect on GE following a sigmoidal Imax (IC50=2.2g, Hill=3.1) relationship. Given the complex composition of the meals, the effect of low, medium and high fat meals on GE was estimated in glucose equivalent units. All meals were found to similarly inhibit GE, analogous to approximately 125g of glucose.

The typical dual peak profiles seen for the CCK plasma concentrations were successfully described by a model including release of a rapid half-life CCK (6.2min) and a slower half-life CCK (51min) stimulated by nutritional content in duodenum and jejunum respectively. Stimulation of GB emptying was best described by an Emax relationship driven by relative elevation of CCK levels.

Conclusions: An integrated model for GE, CCK plasma concentrations and GB emptying was developed and demonstrated to be predictive across a wide range of nutritional content of liquid meals. This could serve as a basis for improvements in both bottom-up and top-down approaches to describe oral absorption.

[1] Sonne DP, Vilsbøll T, Knop FK. Postprandial Gallbladder Emptying in Patients with Type 2 Diabetes: Potential Implications for Thyroid Function and Glucose Homeostasis. ADA 73 (2013) Abstr 2894-PO.
[2] Hansen M et al. Effect of Bile Acids on GLP-1 Secretion. ClinicalTrials.gov identifier NCT01666223.
[3] Bagger JI et al. Impaired Regulation of the Incretin Effect in Patients with Type 2 Diabetes. J Clin Endocrinol Metab (2011) 96(3): 737–745.
[4] Ogungbenro K et al. A Semi-mechanistic Gastric Emptying Model for the Population Pharmacokinetic Analysis of Orally Administered Acetaminophen in Critically Ill Patients. Pharm Res (2011) 28: 394–404.
[5] Alskär O et al. Modelling of glucose absorption. PAGE 22 (2013) Abstr 2897 [www.page-meeting.org/?abstract=2897].
[6] Sharma A, Ebling WF, Jusko WJ. Precursor-Dependent Indirect Pharmacodynamic Response Model for Tolerance and Rebound Phenomena. J. Pharm. Sci. (1998) 87(12): 1577-1584. 

Reference: PAGE 23 (2014) Abstr 3178 [www.page-meeting.org/?abstract=3178]
Oral: Mechanistic Absorption Modelling
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