Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, PO Box 705, FI-00029 HUS, Helsinki, Finland, samuel.fanta@helsinki.fi.
Samuel
S
Fanta
Mari
M
Kinnunen
Janne T
JT
Backman
Eija
E
Kalso
D000284:Administration, Oral; D000328:Adult; D000700:Analgesics / Q000008:administration & dosage / Q000493:pharmacokinetics; D059350:Chronic Pain / Q000188:drug therapy; D064368:Healthy Volunteers; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D007649:Ketamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D055815:Young Adult
D000700:Analgesics; D007649:Ketamine; C033419:norketamine