Dose-Dependent Pharmacokinetics and Metabolisms of Prolonged-Release Ketamine Tablets in Healthy Subjects

Abstract

The anaesthetic effects of ketamine and its major metabolite norketamine (NK) are explained by NMDA receptor antagonism. There is ample new evidence, firstly, that metabolites of NK, as the 2R,6R/2S,6S-enantiomers of hydroxynorketamin (HNK), exert neuro-modulating effects by AMPA-receptor activation and, secondly, that the plasma levels of NK after oral dosing are higher than after intravenous administration. Therefore, we evaluated pharmacokinetics and metabolism of a newly developed prolonged-release ketamine dosage form to confirm its suitability for chromic treatment of CNS-diseases (e.g. depression) according to the new “Ketamine Metabolite Paradigm”. The dose-escalation study was performed in five consecutive periods (7 days wash-out) in 15 healthy subjects (5 females. 20-35 years, BMI 19.4-27.6 kg/m2). The racemic analytes were measured using validated LC-MS/MS methods. PR-K was safe and well tolerated.Tabled 15 mg i.v.10 mg p.o.20 mg p.o.40 mg p.o.80 mg p.o.AUC (ng×h/ml)52.3 ± 12.213.4 ± 13.333.5 ± 35.863.5 ± 42.6124 ± 72.9Cmax (ng/ml)29.9 ± 8.481.63 ± 1.333.70 ± 3.936.66 ± 4.2511.8 ± 6.56Tmax (h)-5.34 ± 1.185.70 ± 0.6495.87 ± 0.9156.27 ± 0.594*†F (%)-12.3 ± 10.715.3 ± 14.4*14.9 ± 8.94*14.6 ± 7.56*T½ (h)5.89 ± 2.614.96 ± 1.256.74 ± 2.02*7.21 ± 1.56#*7.68 ± 1.43#*†AUCNK/K1.79 ± 0.55721.6 ± 14.2#16.9 ± 8.58#*14.9 ± 8.50#*14.0 ± 6.50#*†AUCHNK/K0.334 ± 0.1287.33 ± 7.05#19.8 ± 16.4#*14.4 ± 8.99#*16.2 ± 7.93#*‡p<0.05 #vs. 5 mg i.v., *vs. 10 mg, †vs 20 mg, ‡vs. 40 mg p.o. (Wilcoxon) Open table in a new tab p<0.05 #vs. 5 mg i.v., *vs. 10 mg, †vs 20 mg, ‡vs. 40 mg p.o. (Wilcoxon) Prolonged-release ketamine undergoes dose-dependent “fist-pass” metabolism which generates substantially increased plasma exposure of downstream metabolites with potential neuro-modulating effects compared to ketamine after intravenous administration.