The Population Pharmacokinetics of d-β-hydroxybutyrate Following Administration of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate

Abstract

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.

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

“…The applications of ketogenic diets and ketone bodies as therapeutic tools have also arisen in non-cancerous contexts including obesity and NAFLD/NASH (Browning et al, 2011; Foster et al, 2010; Schugar and Crawford, 2012); heart failure (Huynh, 2016; Kolwicz et al, 2016; Taegtmeyer, 2016); neurological and neurodegenerative disease (Martin et al, 2016; McNally and Hartman, 2012; Rho, 2015; Rogawski et al, 2016; Yang and Cheng, 2010; Yao et al, 2011); inborn errors of metabolism (Scholl-Bürgi et al, 2015); and exercise performance (Cox et al, 2016). The efficacy of ketogenic diets has been especially appreciated in therapy of epileptic seizure, particularly in drug-resistant patients.…”

“…An inherent advantage of the former is that 2 moles of physiological d -βOHB are produced per mole of KE, following esterase hydrolysis in the intestine or liver. Safety, pharmacokinetics, and tolerance have been most extensively studied in humans ingesting R-3-hydroxybutyl R-βOHB, at doses up to 714 mg/kg, yielding circulating d -βOHB concentrations up to 6 mM (Clarke et al, 2012a; Cox et al, 2016; Kemper et al, 2015; Shivva et al, 2016). In rodents, this KE decreases caloric intake and plasma total cholesterol, stimulates brown adipose tissue, and improves insulin resistance (Kashiwaya et al, 2010; Kemper et al, 2015; Veech, 2013).…”

“…In rodents, this KE decreases caloric intake and plasma total cholesterol, stimulates brown adipose tissue, and improves insulin resistance (Kashiwaya et al, 2010; Kemper et al, 2015; Veech, 2013). Recent findings indicate that during exercise in trained athletes, R-3-hydroxybutyl R-βOHB ingestion decreased skeletal muscle glycolysis and plasma lactate concentrations, increased intramuscular triacylglycerol oxidation, and preserved muscle glycogen content, even when co-ingested carbohydrate stimulated insulin secretion (Cox et al, 2016). Further development of these intriguing results is required, because the improvement in endurance exercise performance was predominantly driven by a robust response to the KE in 2/8 subjects.…”

Utilization of Data Below the Analytical Limit of Quantitation in Pharmacokinetic Analysis and Modeling: Promoting Interdisciplinary Debate

“…Method numbering system according to Beal, 2001 [12] where appropriate. Keep BLQ observations in the model and estimate the likelihood of those values being between 0 and LLOQ M4 [12,35,116,180,186,187] All BLQ data are substituted with LLOQ/2 M5 [12,24,[30][31][32][33]35,55,62,133,153, BLQ data are substituted with LLOQ/2, however subsequent, consecutive BLQ observations from the same subject are discarded M6 [1,12,34,35,59,63,117,[225][226][227][228][229][230][231][232][233][234][235][236][237][238][239][240][241][242][243] All BLQ data are substituted with 0 M7 [12,31,33,207,244] All BLQ data are substituted with LLOQ …”

Evaluation of a ketogenic formulation for treating patients with acute brain injury

“…These diets are generally poorly tolerated, associated with atherogenic lipids and relatively ineffective at raising the BHB concentrations in adults much higher than 0.5 mmol/l 241,242 .…”