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Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2015 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, no 4, p. 441-447Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 71, no 4, p. 441-447
Keywords [en]
Ketamine, S-ketamine, Norketamine, Population pharmacokinetics, CYP2B6, CYP3A4, First-pass effect, Well-stirred model
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-258826DOI: 10.1007/s00228-015-1826-yISI: 000351224600006PubMedID: 25724645OAI: oai:DiVA.org:uu-258826DiVA, id: diva2:842926
Available from: 2015-07-23 Created: 2015-07-20 Last updated: 2018-01-11Bibliographically approved

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