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

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.