AUTHOR=Simons Pieter , Olofsen Erik , van Velzen Monique , van Lemmen Maarten , van Dasselaar Tom , Mohr Patrick , Hammes Florian , van der Schrier Rutger , Niesters Marieke , Dahan Albert 

TITLE=S-Ketamine oral thin film—Part 2: Population pharmacodynamics of S-ketamine, S-norketamine and S-hydroxynorketamine

JOURNAL=Frontiers in Pain Research

VOLUME=Volume 3 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pain-research/articles/10.3389/fpain.2022.946487

DOI=10.3389/fpain.2022.946487

ISSN=2673-561X

ABSTRACT=Ketamine is a versatile drug used for many indications and is administered via various routes. Here we report on the pharmacodynamics of sublingual and buccal fast-dissolving oral-thin-films that contain 50 mg of S-ketamine in a population of healthy male and female volunteers.
Twenty volunteers received one or two 50 mg S-ketamine oral thin films in a crossover design, placed for 10 min sublingually (n = 15) or buccally (n = 5). The following measurements were made for 6 hour following film placement: antinociception using three distinct pain assay, electrical pain, pressure pain and heat pain, and drug high on a 11-point visual analogue scale. Blood samples were obtained for measurement of plasma S-ketamine, S-norketamine and S-hydroxynorketamine concentration. A population pharmacodynamic analysis was performed in NONMEM to construct a pharmacodynamic model of S-ketamine and its metabolites. P-values < 0.01 were considered significant. The sublingual and buccal 50 and 100 mg S-ketamine oral thin films were antinociceptive and produced drug high with effects lasting 2-6 hours, although a clear dose-response relationship for antinociception could not be established. The effects were solely related to the parent compound with no contribution from S-norketamine or S-hydroxynorketamine. S-ketamine potency was lower for antinociception (C50 ranging from 1.2 to 1.7 nmol/mL) than for drug high (C50 0.3 nmol/ml). The onset/offset of effect as defined by the blood-effect-site equilibration half-life did not differ among endpoints and ranged from 0-5 min. In conclusion, the 50 mg S-ketamine oral thin film was safe and produced long-term antinociception in all three nociceptive assays with side effects inherent to the use of ketamine.