• Samuel Fanta, Mari Kinnunen, Janne T Backman, and Eija Kalso.
• Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, PO Box 705, FI-00029 HUS, Helsinki, Finland, samuel.fanta@helsinki.fi.
• Eur. J. Clin. Pharmacol. 2015 Apr 1;71(4):441-7.

PurposeLow-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.MethodsIn 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.ResultsA 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.ConclusionsGiven 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.

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