Bridging the Gap between Food Effects under Clinical Trial Conditions and Real Life: Modeling Delayed Gastric Emptying of Drug Substances and Gastric Content Volume Based on Meal Characteristics

Abstract

Delayed gastric emptying is known to have a major impact on drug absorption. While the test meal recommended by the FDA and EMA to study food effects represents a worst-case scenario, it does not reflect the reality of the patients. Physiologically based pharmacokinetic (PBPK) models could bridge the gap between clinical settings of food effect studies and the diverse nonclinical situations by simulating the effect of meals with different compositions and volumes. A mathematical equation based on a stretched exponential function was reparameterized to describe the gastric emptying process of mixed solid meals. The model was fitted to literature data including the gastric emptying data of 23 meals from 15 studies. Using a multiple linear regression model, we were able to predict the two function parameters from the meal characteristics caloric content and the percentage of calories derived from fat. After implementation into the PBPK software PK-Sim, the model, together with a separate compartment for liquid gastric contents, was compared to commercially available software. The model is able to simulate the gastric emptying of mixed solid meals containing drugs based on specific meal characteristics. A second compartment allows for distribution between liquid and solid components and rapid gastric emptying along the Magenstrasse.