Mélanie Wilbaux (1), Bettina Woelnerhanssen (2), Christoph Beglinger (2), Anne Christin Meyer-Gerspach (2), Johannes N. Van Den Anker (1, 3), Marc Pfister (1, 4)
(1) Department of Paediatric Clinical Pharmacology, Paediatric Pharmacology and Pharmacometrics Research Center, University Children’s Hospital Basel (UKBB), Basel, Switzerland, (2) Division of Gastroenterology and Hepatology, University Hospital of Basel, Basel, Switzerland, (3) Division of Pediatric Clinical Pharmacology, Children’s National Health System, Washington, DC, USA, (4) Quantitative Solutions LP, Menlo Park, CA, USA.
Objectives: Recent research indicates that dynamics of gastric emptying may be different in obese and non-obese adults and can affect both glucose absorption and glycemic control. Goal of this work was to develop a semi-mechanistic model that can be used to characterize effects of gastric emptying on glucose absorption and glycemic control in obese and non-obese healthy adults.
Methods: Data: Glucose, insulin, incretin (gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)) and gastric emptying data from 36 obese and 24 non-obese healthy adults were available. Oral glucose tolerance tests (OGTTs) were performed in each study subject with a solution containing 10g, 25g or 75g of glucose. Blood samples and gastric emptying rates were collected at 0, 15, 30, 45, 60, 90, 120 and 180 min.
Model: A semi-mechanistic model was developed to characterize gastric emptying effects on glucose absorption and glycemic control. A population analysis was performed with non-linear mixed effects models using NONMEM 7.3.
Results: Glucose kinetics after administration of 10g, 25g or 75g glucose (OGTT) was characterized by a one-compartment model. The complex absorption profile of glucose was adequately described using individual gastric emptying profiles as time-varying covariate on glucose absorption rate. Observed insulin profiles affected both glucose production and clearance. Multiple differences between obese and non-obese subjects were identified, including: (1) a faster glucose absorption rate in obese subjects (KaObese= 10 * KaNon-obese) and (2) a different insulin effect on clearance: linear insulin effect for non-obese and saturable (Emax) insulin effect for obese. There were no clear incretin effects on model parameters at the investigated dose levels. According to goodness-of-fit plots, glucose kinetics were properly fitted in obese and non-obese healthy adults, and visual predictive check demonstrated the good predictive performance of the model.
Conclusions: A semi-mechanistic model is useful to better understand interactions between gastric emptying, glucose absorption and glycemic control in obese and non-obese adults. Such model can be applied to investigate effects of bariatric surgery on glucose kinetics and characterize differences in glucose absorption between adults, children, infants and neonates.
Reference: PAGE 24 (2015) Abstr 3616 [www.page-meeting.org/?abstract=3616]
Poster: Drug/Disease modeling - Endocrine