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=3

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=<p>Ketamine is a versatile drug used for many indications and is administered <italic>via</italic> various routes. Here, we report on the pharmacodynamics of sublingual and buccal fast-dissolving oral-thin-films that contain 50 mg of <italic>S-</italic>ketamine in a population of healthy male and female volunteers. Twenty volunteers received one or two 50 mg <italic>S-</italic>ketamine oral thin films in a crossover design, placed for 10 min sublingually (<italic>n</italic> = 15) or buccally (<italic>n</italic> = 5). The following measurements were made for 6 h following the film placement: antinociception using three distinct pain assay; electrical, pressure, and heat pain, and drug high on an 11-point visual analog scale. Blood samples were obtained for the measurement of plasma <italic>S-</italic>ketamine, <italic>S</italic>-norketamine, and <italic>S</italic>-hydroxynorketamine concentrations. A population pharmacodynamic analysis was performed in NONMEM to construct a pharmacodynamic model of <italic>S</italic>-ketamine and its metabolites. <italic>P</italic>-values &lt; 0.01 were considered significant. The sublingual and buccal 50 and 100 mg <italic>S-</italic>ketamine oral thin films were antinociceptive and produced drug high with effects lasting 2–6 h, 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 <italic>S</italic>-norketamine or <italic>S</italic>-hydroxynorketamine. <italic>S</italic>-ketamine potency was lower for antinociception (C<sub>50</sub> ranging from 1.2 to 1.7 nmol/mL) than for drug high (C<sub>50</sub> 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 to 5 min. In conclusion, the 50-mg <italic>S-</italic>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. The study was registered at the trial register of the Dutch Cochrane Center (<ext-link ext-link-type="uri" xlink:href="http://www.trialregister.nl" xmlns:xlink="http://www.w3.org/1999/xlink">www.trialregister.nl</ext-link>) under identifier NL9267 and the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database under number 2020-005185-33.</p>