The rat as a model for ketogenic drug formulation development

Abstract

AbstractBackgroundKetogenic compounds such as ketone esters and medium chain triglycerides have been tested as treatments for mild‐to‐moderate Alzheimer’s disease (AD) in several studies. Ketogenic compounds are given at high doses in an attempt to compensate for regional cerebral glucose hypometabolism characteristic of AD. Upon ingestion, ketogenic compounds lead to the induction of ketosis. Previous studies have shown the formulation of the ketogenic compounds can influence kinetics of digestion of the drug and transformation into active moieties which induces ketosis, hence any changes in formulation may influence clinical outcomes. In order to rapidly screen new formulations, we have investigated the rat as pharmacokinetic (PK) model of ketogenic potential of formulations in human. PK studies are performed using different formulations to define dose, dosing frequency, route of dosing and onset of action.MethodWe have previously tested several formulations in human PK studies and found several differences in Cmax, Tmax and AUC related to the release from the excipients. In the present study we evaluated the PK profiles of these same formulations in rat to determine if rats qualitatively replicated the human results. Healthy young adult male Sprague Dawley (SD) rats were used as a test system for this PK study. Five animals per group were used, animals were between 9 to 12 weeks old and the weight variation of animals did not exceed ± 20% of the mean weight. Animals were dosed by oral gavage and concentrations of acetoacetate and β‐hydroxybutyrate in rat serum were determined by LC/MS. Ketone body concentrations (µM) were calculated as a sum of acetoacetate (µM) and β‐hydroxybutyrate (µM) concentrations. Ketone body data was analyzed using WinNonlin.ResultRats qualitatively mirrored results from human studies. Formulations that exhibited slow release and thereby lower ketogenic in humans similarly were found to be slow releasing and less ketogenic in SD rats. Formulations that exhibited fast release and more ketogenic in humans were found to be fast releasing and more ketogenic in SD rats.ConclusionFrom these preliminary studies rat represents a model to evaluate future ketogenic drug formulations for ketogenic potential in human.