Population pharmacokinetic model for D-β-Hydroxybutyrate following ketone monoester ingestion

Background: Ketone bodies, the evolutionary response to starvation in humans, are produced in the liver from fatty acids in response to low blood glucose and insulin, and used by the body as fuels. Ketogenic diets have long been used to treat intractable paediatric epilepsy, with therapeutic evidence for ketosis in other neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease.1 A novel means of achieving ketosis by nutritional consumption of a ketone monoester has recently been established.2 However, detailed understanding of pharmacokinetics (PK) has not been undertaken.
Aim: To understand the PK of D-β-Hydroxybutyrate (BHB), and to determine sources of variability following nutritional ketone monoester ingestion.

Methods: Serial blood BHB concentration data (n=37) were obtained in healthy volunteers following administration of a single oral dose of ketone monoester ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate). Two different formulations were administered at five dose levels. A nonlinear mixed effect modelling approach was used to develop a population PK model using NONMEM (v7.2).

Results: A one compartment disposition model with negative feedback effect on endogenous production of BHB provided the best description of the data. Absorption was best described by two consecutive first-order inputs and elimination by dual processes involving first-order and capacity limited elimination. Covariates describing variability in absorption parameters were formulation (on relative oral bioavailable fraction and first-order absorption rate constant) and dose (on relative oral bioavailable fraction). Lean body weight (on first-order clearance) and sex (on apparent volume of distribution) were also significant covariates.

Discussion: The PK of BHB is complicated by complex absorption process, endogenous production and nonlinear elimination. Formulation and dose appear to strongly influence the kinetic profile following ketone monoester ingestion. Multiple peak concentrations were predominant at higher doses suggesting exploration of dose dependent multiple absorption sites and/or metabolic interconversion will be critical in future studies.

1. Veech R.L. (2004). Prostaglandins Leukotrienes and Essential Fatty Acids. 70(3):309-319.
2. Clarke K. et al. (2012). Regul Toxicol Pharmacol. 63(3):401-408