Modeling digestion, absorption, and ketogenesis after administration of tricaprilin formulations to humans

At present, tricaprilin is used as a ketogenic source for the management of mild to moderate Alzheimer's disease. After administration of the medium-chain triglyceride, tricaprilin is hydrolyzed to octanoic acid and further metabolized to ketones, acting as an alternative energy substrate for the brain. In this investigation, we developed a physiologically-based biopharmaceutics model simulating in vivo processes following the peroral administration of tricaprilin. The model includes multiple data sources to establish a partially verified framework for the simulation of plasma profiles. The input parameters were identified based on existing literature data and in vitro digestion studies. Model validation was conducted using the data from a phase I clinical trial. A partial parameter sensitivity analysis elucidated various influences on the plasma ketone levels that are mainly responsible for the therapeutic effects of tricaprilin. Based on our findings, we concluded that dispersibility and lipolysis of tricaprilin together with the gastric emptying patterns are limiting ketogenesis, while other steps such as the conversion of octanoic acid to ketone bodies play a minor role only.