Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing
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Low-dose ketamine is a lucrative therapeutic approach in cancer pain, perioperative treatment of pain, and management of treatment-resistant depression. The analgesic potency of its main metabolite norketamine is thought to be one third that of ketamine. However, few studies exist on the pharmacokinetics of orally administered S-ketamine.
In our study, 11 healthy volunteers received S-ketamine 0.25 mg/kg orally and 0.125 mg/kg intravenously. S-ketamine and norketamine concentrations were measured up to 23.5 h post-dose. A population pharmacokinetic model was built to describe S-ketamine and norketamine pharmacokinetics.
A three-compartment model for both S-ketamine and norketamine best described the data. To accommodate for the extensive formation of norketamine after oral S-ketamine, a separate presystemic absorption-phase component was included in addition to its systemic formation. The oral bioavailability of S-ketamine was low, 8 % (11 % interindividual variability), and its clearance was high, 95 L/h/70 kg (13 % interindividual variability). Simulations suggested that after oral dosing, norketamine AUC at steady state is 16.5 times higher than that of S-ketamine.
Given that the analgesic effect of S-ketamine is due to both S-ketamine and norketamine, relatively small oral doses of S-ketamine can be assumed to be a feasible alternative to repeated intravenous dosing, for example in the setting of chronic pain.
KeywordsKetamine S-ketamine Norketamine Population pharmacokinetics CYP2B6 CYP3A4 First-pass effect Well-stirred model
We would like to thank Jouko Laitila and Mikko Neuvonen for conducting the S-ketamine and norketamine concentration measurements. Mrs Eija Mäkinen-Pulli and Mrs Lisbet Partanen are thanked for skillful technical assistance. This study was supported by grants from the Helsinki University Central Hospital Research Fund and the Sigrid Jusélius Foundation, Finland. None of the authors have any financial or personal relationships that could be perceived as influencing the research described. The experiments comply with the current laws of Finland, and the study protocol was approved by the Coordinating Ethics Committee of the Helsinki and Uusimaa Hospital District and by the Finnish Medicines Agency.
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