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- Title
Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing.
- Authors
Fanta, Samuel; Kinnunen, Mari; Backman, Janne; Kalso, Eija
- Abstract
Purpose: 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.
- Subjects
BIOAVAILABILITY; CHRONIC pain; CROSSOVER trials; DOSE-effect relationship in pharmacology; INTRAVENOUS therapy; KETAMINE; ORAL drug administration; RESEARCH funding; STATISTICAL sampling
- Publication
European Journal of Clinical Pharmacology, 2015, Vol 71, Issue 4, p441
- ISSN
0031-6970
- Publication type
Article
- DOI
10.1007/s00228-015-1826-y