Pharmacokinetics and pharmacodynamics of orally administered S-ketamine in healthy participants
Joost. C. van Mechelen, Tobias A. Wieles, Laura G. J. M. Borghans, Marije E. Otto, Maria J. Juachon, Amy L. Gillespie, Martijn S. van Noorden, Catherine J. Harmer, Albert M. van Hemert, Joop M. A. van Gerven, Gabriël E. JacobsBackground:
Oral S-ketamine (S-KETPO) is being explored as an alternative to intravenous maintenance treatment (S-KETIV) in treatment-resistant depression (TRD). However, the first-pass effect with S-KETPO significantly alters S-ketamine’s bioavailability and the systemic exposure of its active metabolites, raising potential safety and efficacy concerns.
Aims:
This study characterized the pharmacodynamic and safety profiles of S-KETPO related to its pharmacokinetics in healthy participants, compared head-to-head with an S-KETIV dose that had previously demonstrated antidepressant effects in TRD .
Methods:
In a randomized, double-blind, placebo-controlled, double-dummy, four-way cross-over study, 16 healthy participants received a single dose of S-KETPO 0.20 and 0.45 mg/kg, S-KETIV 0.40 mg/kg and placebo. Plasma concentrations of S-KET and its active metabolites norketamine (S-NOR) and S-hydroxynorketamine (S-HNK) were measured, safety assessments were conducted up to 24 hours post-dose, and central nervous system (CNS) effects were evaluated up to 6 hours post-dose.
Results:
Absolute bioavailability of S-KETPO was poor (9–12%). Peak plasma concentrations for S-KETPO 0.20 mg/kg, 0.45 mg/kg and S-KETIV were 9.81, 22.7 and 146 ng/mL (S-KET); 62.0, 127 and 55.2 ng/mL (S-NOR); and 29.5, 62.1 and 32.2 ng/mL (S-HNK), respectively. S-KETPO S-NOR:S-KET and S-HNK:S-KET metabolite-to-parent compound ratios were 7.52, 6.98 and 0.42, and 3.78, 3.71 and 0.23, for KETPO 0.20 mg/kg, S-KETPO 0.45 mg/kg, and S-KETIV, respectively. S-KETIV produced sedative, psychomotor and psychotomimetic effects coinciding with reductions in quantitative electroencephalography (qEEG) alpha, beta and delta power, whereas S-KETPO 0.45 mg/kg demonstrated inconsistent effects on vigilance and arousal but clear albeit relatively smaller reductions in qEEG alpha, beta and delta power coinciding with limited psychotomimetic effects, and finally, KETPO 0.20 mg/kg lacked effects altogether. Safety was comparable across treatments.
Discussion and Conclusion:
Oral administration of S-ketamine alters pharmacokinetic and pharmacodynamic profiles, resulting in poor bioavailability, increased pharmacologically active metabolite exposures, and limited CNS effects relative to intravenous administration. The current findings have implications for S-KETPO dose selection, which may impact safety and/or therapeutic outcomes in future TRD studies.
Trial Registration:
The study was registered in the ‘Overview of Medical Research in the Netherlands’ (OMON) under NL-OMON55261.