Mechanism-based modeling of biological processes involved in oral absorption

Abstract: For orally administered drugs, the rate and extent of absorption are governed by the physiology of the gastrointestinal tract, the characteristics of the dosage form and the physico-chemical properties of the drug. This thesis primarily aimed to improve the mechanistic understanding and the predictability of processes involved in the absorption of orally administered drugs using a population modeling approach. A secondary aim was to propose an optimized dosing regimen for first line anti-tuberculosis drugs in underweight Indian children.A model characterized the effect of pH, mechanical stress and formulation on in vitro extended release (ER) tablet erosion. The model was further used in combination with anatomical tablet location data to predict the in vivo erosion dynamics. The proposed approach could help address challenges related to the development of future ER formulations.Gastric emptying regulates the rate of entry of nutrients into the small intestine. Bile acids are essential for the intestinal absorption of lipophilic drugs, but the determination of their local intestinal concentrations is difficult. A modeling framework was developed to characterize the relationships between nutritional intake, rate of gastric emptying, gallbladder emptying–refilling patterns and plasma concentrations of bile acids. This modeling framework could be used in combination with systems pharmacology models to predict the drug-drug interactions and food effects associated with gastric emptying, as well as to link the postprandial changes in plasma bile acid concentrations to the variability in drugs’ absorption.Optimal doses of first-line antituberculosis drugs have not been firmly established. In an underweight Indian children population, the pharmacokinetic-pharmacodynamic model identified rifampin as single predictor of unfavorable treatment outcome. Children with low body weight and/or HIV coinfection had a higher probability of unfavorable treatment outcome. Doses increase were proposed and could provide crucial information for future guidelines.In summary, the developed models enabled the prediction of the in vivo erosion profile of ER formulations based on in vitro dissolution data. A modeling framework predicted the postprandial gastric emptying rate and enterohepatic circulation of bile acids. Finally, a model-based approach was used to identify risk factors and propose optimized dose recommendations in tuberculosis-infected Indian children.