Pharmacokinetic Modeling of Ketamine Enantiomers and Their Metabolites After Administration of Prolonged‐Release Ketamine With Emphasis on 2,6‐Hydroxynorketamines

Abstract

Modeling of metabolite kinetics after oral administration of ketamine is of special interest because of the higher concentrations of active metabolites because of the hepatic first-pass effect. This holds especially in view of the potential analgesic and antidepressant effects of 2R,6R-and 2S,6S-hydroxynorketamine at low doses of ketamine. Therefore, a 9compartment model was developed to analyze the pharmacokinetics of ketamine enantiomers and their metabolites after racemic ketamine administered intravenously (5 mg) and as 4 doses (10, 20, 40, and 80 mg) of a prolonged-release formulation (PR-ketamine). Using a population approach, the serum concentration-time data of the enantiomers of ketamine, norketamine, dehydronorketamine, and 2,6-hydroxynorketamine obtained in 15 healthy volunteers could be adequately fitted. The estimated model parameters were used to simulate serum concentration-time profiles; after multiple dosing of PR-ketamine (2 daily doses of 20 mg), the steady-state concentrations of R-and S-ketamine were 1.4 and 1.3 ng/mL, respectively. The steady-state concentration of 2R,6R-hydroxynorketamine exceeded those of R-norketamine (4-fold), R-dehydonorketamine (8-fold), and R-ketamine (46-fold), whereas that of 2S,6S-hydroxynorketamine exceeded that of S-ketamine by 14-fold. The model may be useful for identifying dosing regimens aiming at optimal plasma concentrations of 2,6-hydroxynorketamines.

S-Ketamine Oral Thin Film—Part 1: Population Pharmacokinetics of S-Ketamine, S-Norketamine and S-Hydroxynorketamine

“…A minor metabolic pathway is the hydroxylation of S -ketamine into 4-hydroxyketamine and some other metabolites (e.g., hydroxyhpenylketamine) ( 12 ) The majority of S -ketamine (80%) undergoes hepatic N -demethylation into S -norketamine by cytochrome P450 (CYP) enzymes 2B6 and 3A4 ( 12 , 13 ). We cannot exclude that some part of the S -ketamine is metabolized in extrahepatic tissues, such as oral or gut mucosal cells ( 14 – 16 ). This possibility is represented in the pharmacokinetic model ( Figure 2 ) by the dotted red lines, which symbolize metabolic pathways of the oral and gut mucosa.…”

Relationship Between Dissolution Rate in Vitro and Absorption Rate in Vivo of Ketamine Prolonged-Release Tablets

“…The same kind of function (Eqs. 4 and 5) was used previously to describe the absorption (or input) rate of drugs into the systemic circulation (central compartment) after administration of extended release formulations [5,6] (Eq. 7):…”

“…The in vivo input parameters have been previously estimated in 15 healthy volunteers after intravenous and oral dosing of 20 mg PR-ketamine tablets using a population approach [5]. The linear range for serum measurements was 0.5-200 ng/ml.…”

“…6), i.e., F, MT 1a , RD 2 1a , MT 2a , RD 2 2a and p, were estimated for the R-enantiomer after oral administration of PR-ketamine tablets. Note that there was no significant difference in the bioavailability between the R-and S-enantiomer [1,5]. These parameters were used to calculate the normalized input rate in vivo, f a (t) (Eq.…”

Analysis of Complex Absorption After Multiple Dosing: Application to the Interaction Between the P-glycoprotein Substrate Talinolol and Rifampicin

“…Although the oral route is the most convenient and most used method of drug delivery, pharmacokinetic modeling is often based on noncompartmental methods (numerical integration) or oversimplified models like the first order absorption model. For the more complex absorption behaviors of extended release formulations or to study food effects, flexible empirical input rate models, such as the inverse Gaussian density function [1][2][3][4][5], or a sum of inverse Gaussian functions [6][7][8][9][10], have been successfully applied. The latter was capable of fitting double-peak data [11] and has some advantages over models based on transit compartments (gamma density) or a Weibull function [8].…”