3 S-ketamine oral thin film pharmacodynamics Methods This report is accompanied by a report on the population pharmacokinetics of the S-ketamine OTF, in chapter 2.8 Here we describe the pharmacodynamic endpoints that were collected simultaneously with the pharmacokinetic data. Ethics and Subjects The protocol was approved by the Central Committee on Research Involving Human Subjects (Competent authority: Centrale Commissie Mensgebonden Onderzoek (CCMO), The Hague, the Netherlands; registration number NL75727.058.20) and the Medical Research Ethics Committee of Leiden University Medical Center (Medisch Ethische Toetsingscommissie Leiden-Den Haag-Delft, The Netherlands; identifier P20.111) and was registered at the trial register of the Dutch Cochrane Center (www.onderzoekmetmensen.nl) under identifier NL9267. Healthy male and female volunteers (aged 18-45 years, body mass index 19 and 30 kg.m-2) were recruited. All recruited subjects gave written and oral informed consent, after which they were screened. Inclusion and exclusion criteria are given in chapter 2. Eating, drinking, brushing teeth or gum chewing was not allowed in the morning of the OTF application to avoid changes/variabilities in saliva pH, which could potentially affect the mucosal permeability and S-ketamine plasma concentration variability. Study Design This phase 1 study had an open-label randomized crossover design. The subjects were randomized to receive one OTF on one occasion (50 mg S-ketamine) and two on another (100 mg S-ketamine) with at least 7 days between visits. The thin film is a rectangular 4.5 cm2 orodispersible film containing 57.7 mg Sketamine hydrochloride (S-ketamine HCL). The S-ketamine HCL is dispersed within a matrix to produce a film corresponding to 50 mg S-ketamine free base. The film(s) was/were placed either under the tongue or buccally on the mucosa. After placement of the films, the subject was not allowed to swallow for 10 min. The randomization sequence was determined by the randomization option in the Electronic Data Capture system CASTOR (www.castoredc.com). The OTFs were obtained from LTS Lohmann Therapie-Systeme AG (Andernach, Germany) and were dispensed by the pharmacy on the morning of dosing. Measurement of pharmacodynamic endpoints lasted for 6 h. For blood sampling and measurement of S-ketamine, S-norketamine and S-hydroxynorketamine, see the accompanying report.2 In all subjects, on both occasions, an intravenous S-ketamine infusion followed the 6 h OTF test phase and was included in the pharmacokinetic 43
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