Please use this identifier to cite or link to this item: http://dx.doi.org/10.25673/74700
Title: Pharmacokinetic modeling of ketamine enantiomers and their metabolites after administration of prolonged-release ketamine with emphasis on 2,6-Hydroxynorketamines
Author(s): Weiss, Michael
Siegmund, Werner
Issue Date: 2022
Type: Article
Language: English
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 9-compartment 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.
URI: https://opendata.uni-halle.de//handle/1981185920/76652
http://dx.doi.org/10.25673/74700
Open Access: Open access publication
License: (CC BY-NC-ND 4.0) Creative Commons Attribution NonCommercial NoDerivatives 4.0(CC BY-NC-ND 4.0) Creative Commons Attribution NonCommercial NoDerivatives 4.0
Sponsor/Funder: Publikationsfonds MLU
Journal Title: Clinical pharmacology in drug development
Publisher: Wiley-Blackwell
Publisher Place: Oxford [u.a.]
Volume: 11
Issue: 2
Original Publication: 10.1002/cpdd.993
Page Start: 194
Page End: 206
Appears in Collections:Open Access Publikationen der MLU