Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia, accounting for approximately 60 – 80% of all cases [1]. In the United States of America alone, an estimated 6.2 million patients aged 65 and older are affected [1]. Currently, there are several theories regarding the cause and underlying mechanisms of AD. They include the formation of amyloid β plaques [2], neurofibrillary tangles in the neurons [3] as well as chronic inflammation of brain tissues [4]. Many pathophysiological pathways contributing to the disease are yet to be explored.

Previous investigations confirmed a reduced expression of glucose transporters in the central nervous system (CNS) of Alzheimer's patients [5], [6]. Also, enhancing their glucose metabolism contributed to a prolonged lifespan [7]. In this context, the ketones acetoacetate and β-hydroxybutyrate serve as the primary energy source and provide up to 80% of the brain’s energy when glucose is not available [8], [9], [10]. This led to the development of ketogenic diets including the use of medium-chain fatty acids to improve the energy supply and achieve functional improvements in patients with AD [11], [12].

Tricaprilin is a semi-synthetic medium-chain triglyceride (MCT) composed of 8-carbon fatty acids with an aqueous solubility of 0.4 mg/L. Other MCTs are being used for the dietary management of AD [13], [14]. After peroral administration, tricaprilin is digested into octanoic acid by lipases in the gastrointestinal (GI) tract, followed by the absorption of the fatty acid from the duodenum [15], [16]. Octanoate is then converted to ketone bodies by oxidation in the liver [15]. Medium-chain fatty acids such as octanoic acid display preferential absorption and oxidation over long-chain fatty acids [17]. These ketones serve the CNS as an important energy source [9], [10], [12]. Therefore, due to the considerable ketogenic potential of octanoic acid [14], tricaprilin holds great promise in the treatment of AD. Glucose enters the brain through an active transport mechanism that can be saturated [18]. A non-linear relationship between brain and plasma glucose levels has been revealed [19], [20]. As compared to the transporter-mediated uptake of glucose into the CNS, there is a linear relationship between the blood and brain concentrations of octanoate [21]. Therefore, increased plasma ketone levels following the administration of tricaprilin contribute to a corresponding increase in the brain ketone concentration.

So far, pharmacokinetic studies primarily involved direct quantification of the plasma ketone levels after tricaprilin administration [14], [22]. However, the contribution of the sequential individual processes related to the suggested mode of action such as digestion of tricaprilin and release of the fatty acid, absorption, and conversion of octanoic acid into ketone bodies have not been further elucidated. Physiologically based biopharmaceutics (PBB) modeling leverages the knowledge of the physiological processes involved and, together with selected in vitro and in vivo data sets, enables the prediction of the biopharmaceutical behavior of drugs. To cover the complexity underlying the pharmacokinetics of tricaprilin, we designed a PBB model based on in vitro digestion studies and human clinical data reported in the literature [23], [24], [25]. The model was validated using the outcome of a phase I clinical trial evaluating single-dose administration of the tricaprilin formulation AC-SD-03 to healthy volunteers. The spray-dried powder improves the dispersibility and surface area as compared to pure triglyceride. Additionally, it allows efficient taste masking and prolongs the shelf-life as compared to emulsion systems. The plasma levels of octanoic acid and ketone bodies were quantified for each individual.