title: The Population Pharmacokinetics of D-β-hydroxybutyrate Following Administration of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate.
abstract: The administration of ketones to induce a mild ketosis is of interest for the alleviation of symptoms associated with various neurological disorders. This study aimed to understand the pharmacokinetics (PK) of D-β-hydroxybutyrate (BHB) and quantify the sources of variability following a dose of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (ketone monoester). Healthy volunteers (n = 37) were given a single drink of the ketone monoester, following which, 833 blood BHB concentrations were measured. Two formulations and five dose levels of ketone monoester were used. A nonlinear mixed effect modelling approach was used to develop a population PK model. A one compartment disposition model with negative feedback effect on endogenous BHB production 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 (CL = 10.9 L/h) and capacity limited elimination (V max = 4520 mg/h). Covariates identified were formulation (on relative oral bioavailable fraction and 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. 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 administration. Further work is needed to quantify mechanisms of absorption and elimination of ketones for therapeutic use in the form of ketone monoester.
authors.affiliation: School of Pharmacy, University of Otago, P.O. Box 56, Dunedin, 9054, New Zealand. vittal.shivva@otago.ac.nz.
authors.forename: Vittal
authors.initials: V
authors.lastname: Shivva
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Pete J
authors.initials: PJ
authors.lastname: Cox
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Kieran
authors.initials: K
authors.lastname: Clarke
authors.affiliation: Laboratory of Metabolic Control, NIAAA/NIH, Rockville, Maryland, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Veech
authors.affiliation: School of Pharmacy, University of Otago, P.O. Box 56, Dunedin, 9054, New Zealand.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Tucker
authors.affiliation: School of Pharmacy, University of Otago, P.O. Box 56, Dunedin, 9054, New Zealand.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Duffull
mesh_terms: D005260:Female; D006801:Humans; D006885:Hydroxybutyrates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008962:Models, Theoretical
chemical_list: D006885:Hydroxybutyrates
keywords: D-β-hydroxybutyrate; exogenous ketosis; ketone monoester; pharmacokinetics; population models